Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section B – Genesis of Cancer

Chapter 12 – Genetic Factors: Hereditary Cancer Predisposition Syndromes

Kenneth Offit,Peter Thom,
Donna Bernstein

SUMMARY OF KEY POINTS

• The discovery of inherited mutations of oncogenes and tumor suppressor genes associated with increased risk for cancer provides important clinical opportunities for early detection and prevention of common and rare forms of human malignancies. • Syndromes of cancer predisposition often involve multiple organ systems, affect paired organs with bilateral or multifocal tumors, and have onset at an earlier age compared to nonfamilial tumors. The diagnosis of particular cancer predisposition syndromes can usually be confirmed with molecular genetic testing of patients who have hereditary malignancies. Genetic testing can then be extended to relatives as a predictive test to guide their preventive management. • Medical, surgical, and radiation oncologists, genetic counselors, and allied professionals are playing a leading role in the integration of genetic testing into the practice of preventive oncology. This chapter reviews both common and more recently described familial cancer syndromes, with an emphasis on the clinical application of cancer genetic testing in the management of patients who have or are at risk for cancer.

Over the past decade, the availability of clinical testing for inherited mutations of cancer predisposition genes has had a major impact on the practice of clinical oncology.^[1] As these genes were identified and characterized, guidelines for the responsible clinical translation of this information were developed by medical and surgical subspecialty societies (e.g., the statements of the American Society of Clinical Oncology in 1996^[2] and 2003^[3] and related educational materials ^{[4] [5] [6]}). These guidelines emphasized that in the process of offering a predictive genetic test to a patient or family that is affected by cancer, the provider and the individual who is being tested must be prepared to deal with all the medical, psychological, and social consequences of a positive, negative, or ambiguous result. These guidelines define the form and content of genetic counseling as a component of cancer risk assessment and management.

A selected set of syndromes of cancer predisposition, listed in Table 12-1 , is reviewed in this chapter. More detailed discussions of breast and colon cancer susceptibility are found in the chapters that discuss these tumors. A more comprehensive list of syndromes is provided in Table 12-2 . Whether offered by a physician, genetic counselor, or other health care professional, genetic testing for inherited cancer risk requires careful informed consent. The elements of informed consent for genetic testing are summarized in Box 12-1 .

Genes whose alterations result in hereditary predisposition to cancers have been classified as oncogenes or tumor suppressor genes. The molecular mechanisms of these two classes of genes are presented in previous chapters. A minority of human cancer predisposition syndromes result from inherited mutations of oncogenes (e.g., RET, MET, KIT). The majority of cancer predisposition syndromes are due to inherited defects in tumor suppressor genes. The tumor suppressor genes have been subdivided into “gatekeepers” such as APC, p53, Rb, and VHL, which directly prevent runaway cell growth, and “caretakers” such as ATM, MSH2, and MLH1, defects which indirectly cause neoplasia by leading to increased mutations of other critical genes.^[7] Yet a third class of genes, including PTEN and SMAD4,act as “landscapers,” since defects in these genes cause alterations in the “terrain” for epithelial cell growth, leading to eventual neoplastic changes. Complicating this descriptive approach is the observation that the same gene may act as a “landscaper” for one tumor system and a “gatekeeper” for another, violating the principle of Occam's razor; furthermore, some recently characterized pathways do not fit any of these models. In practice, this etiologic nosology of genetic mechanisms is of less clinical relevance than are the phenotypes of these cancer susceptibility syndromes (see Table 12-2 ). For this reason, the discussion that follows is grouped by the major component tumors of the organ system that is primarily affected. The syndromes that are included in this chapter are the ones that are most commonly encountered in oncologic practice, as well as several recently defined entities associated with mutations of novel cancer susceptibility genes. The most common of these syndromes, predisposing to cancers of the breast, ovary, colon, and prostate, affect tens of thousands of Americans who are diagnosed with these cancers each year in the United States and result in increased risk for a second neoplasm for the millions of cancer survivors.

Table 12-1 -- Selected Cancer Predisposition Syndromes

Syndrome	Gene
Major cancer predisposition syndromes
Hereditary breast and ovarian cancer syndromes	BRCA1, BRCA2
Familial adenomatous polyposis	APC, MYH
Hereditary nonpolyposis colon cancer syndrome	hMSH2, hMLH1, hMSH6
Hereditary prostate cancer	Multiple loci
Multiple endocrine neoplasias (I, II)	MEN1, RET
Hereditary melanoma syndromes	CDKN2Ap16, CDK4
Familial retinoblastoma	RB1
Neurofibromatosis I, II	NF1, NF2
von Hippel Lindau syndrome	VHL
Recently described cancer predisposition syndromes
Gorlin syndrome	PTCH
Carney complex	PRKAR1A
Cowden syndrome	PTEN
Birt-Hogg-Dubé syndrome	BHD
Rhabdoid predisposition syndrome	hSNF5/INI1
Hereditary gastric cancer	CDH1
Hereditary leiomyomatosis and renal cell cancer syndrome	FH
Paraganglioma/chemodectoma syndromes	SDH-A, -B, -C, -D

Table 12-2 -- Syndromes of Inherited Cancer Predisposition in Clinical Oncology

Syndrome (OMIM[*] Entry)	Component Malignancies	Mode of Inheritance	Genes
HEREDITARY BREAST CANCER SYNDROMES
Hereditary breast and ovarian cancer syndrome 113705 600185	Breast cancer Ovarian cancer Colon cancer Prostate cancer	Dominant	BRCA1 BRCA2
	Pancreatic cancer (medulloblastoma/Fanconi anemia)	Recessive	BRCA2
Li-Fraumeni syndrome 151623	Soft-tissue sarcoma Breast cancer Osteosarcoma Leukemia Brain tumors Adrenocortical carcinoma	Dominant	p53 CHK2
Cowden syndrome 158350	Breast cancer Thyroid cancer Lhermitte-Duclos disease Other cancers	Dominant	PTEN
Bannayan-Riley-Ruvalcaba syndrome 153480	Breast cancer Meningioma Thyroid follicular cell tumors	Dominant	PTEN
Ataxia telangiectasia 208900	Leukemia Lymphoma Ovarian cancer Gastric cancer Brain tumors Thyroid, parotid cancer Colon cancer Other cancers	Recessive	ATM
HEREDITARY GASTROINTESTINAL MALIGNANCIES
Hereditary nonpolyposis colon cancer (HNPCC), including “Lynch II” syndrome 120435 120436 114500 114400	Colon cancer Endometrial cancer Ovarian cancer Pancreatic cancer Stomach and small bowel cancers	Dominant	MSH2 MLH1 MSH6
Familial adenomatous polyposis (including attenuated phenotype and Ashkenazi low-penetrance phenotype) 175100	Colon cancer Gastric cancer Thyroid cancer Hepatoblastoma Medulloblastoma Astrocytoma	Dominant, recessive	APC, MYH
Hereditary gastric cancer 137215	Stomach cancers Lobular breast carcinomas Colon cancer	Dominant	CDH1
Juvenile polyposis 174900	Gastrointestinal cancers	Dominant	SMAD4/DPC4 BMPR1A PTEN
Hereditary pancreatic cancer susceptibility 606856	Pancreatic cancer	Dominant	Palladin
Peutz-Jeghers syndrome 175200	Colon cancer Small bowel cancer Breast cancer Ovarian cancer Pancreatic cancer	Dominant	STK11
Hereditary melanoma pancreatic cancer syndrome 606719	Pancreatic cancer Melanoma	Dominant	CDKN2A/p16
Hereditary pancreatitis 167800	Pancreatic cancer	Dominant	PRSS, SPINK1, CFTR
Turcot syndrome 276300	Colon cancer Basal cell carcinoma Ependymoma Medulloblastoma Glioblastoma Papillary thyroid carcinoma Leukemia	Dominant	MLH1 APC PMS2
Familial gastrointestinal stromal tumor 606764	Gastrointestinal stromal tumors	Dominant	c-KIT
GENODERMATOSES WITH CANCER PREDISPOSITION
Melanoma syndromes 155600 155601	Malignant melanoma	Dominant	CDKN2 (p16) CDK4 CMM
Basal cell cancers (Gorlin syndrome) 109400	Basal cell cancers Brain tumors	Dominant	PTCH
Cowden syndrome	See above	Dominant	PTEN
Neurofibromatosis 1 162200	Neurofibrosarcomas Pheochromocytomas Optic gliomas	Dominant	NF1
Neurofibromatosis 2 101000	Vestibular schwannomas	Dominant	NF2
Tuberous sclerosis 191100	Myocardial rhabdomyoma Multiple bilateral renal angiomyolipoma Ependymoma Renal cancer Giant cell astrocytoma	Dominant	TSC1 TSC2
Carney complex 160980	Myxoid subcutaneous tumors Primary adrenocortical nodular hyperplasia Testicular Sertoli cell tumor Pituitary adenoma Mammary ductal fibroadenoma Schwannoma Pheochromocytoma	Dominant	PRKAR1A
Muir Torre syndrome 158320	Sebaceous carcinoma Sebaceous epitheliomas Sebaceous adenomas Basal cell carcinoma Colon cancer Duodenal carcinoma Laryngeal carcinoma Malignant gastrointestinal tract tumors Malignant genitourinary tract tumors Breast cancer	Dominant	MLH1 MSH2
Xeroderma pigmentosum 278730 278700 278720 278760	Skin cancer Melanoma Leukemia	Recessive	XPA XPC XPD (ERCC2) XPF
Rothmund-Thomson syndrome 268400	Basal cell carcinoma Squamous cell carcinoma Osteogenic sarcoma	Recessive	RECQL4 RECQL5
LEUKEMIA/LYMPHOMA PREDISPOSITION SYNDROMES
Bloom syndrome 210900	Leukemia Carcinoma of the tongue Esophageal carcinoma Wilms' tumor Colon cancer	Recessive	BLM
Fanconi anemia 607139, 300515, 227645, 605724, 227646, 600901, 602956, 605882, 608111, 603467, 609644, 610832	Leukemia Esophogus cancer Skin carcinoma	Recessive	FANCA, FANCB, FANCD1, FANCC, FANCE, FANCD2, FANCF, FANCG, FANCL, FANCJ, FANCM, FANCN
Shwachman-Diamond syndrome 260400	Hepatoma Myelodysplasia Acute myelogenous leukemia	Recessive	SBDS
Nijmegen breakage syndrome 251260	Lymphoma Glioma Medulloblastoma Rhabdomyosarcoma	Recessive	NBS1
Cannale Smith syndrome 601859	Lymphoma	Dominant	FAS FASL
Immunodeficiency syndromes
Wiskott Aldrich	Hematopoietic malignancies	X-linked recessive	WASP
301000	Lymphomas
Common variable immune deficiency		Recessive	TNFRSF13B
240500		Dominant	Unknown
Severe combined immune deficiency	B-cell lymphoma	X-linked recessive	IL2RG
102700 300400 202500		Recessive	ADA JAK3 RAG1 RAG2 IL7R CD45 Unknown
X-linked Lymphoproliferative syndrome 308240	Lymphoma	X-linked recessive	SH2D1A
GENITOURINARY CANCER PREDISPOSITION SYNDROMES
Hereditary prostate cancer 176807 601518	Prostate cancer	Dominant	HPC1 HPCX PCAP PCBC PRCA
Simpson-Golabi-Behmel syndrome 312870	Embryonal tumors Wilms' tumor	X-linked recessive	GPC3
Von Hippel Lindau syndrome 193300	Hemangioblastomas of retina and central nervous system Renal cell cancer Pheochromocytomas	Dominant	VHL
Beckwith-Wiedemann syndrome 130650	Wilms' tumor Hepatoblastoma Adrenal carcinoma Gonadoblastoma	Dominant	CDKN1C
Wilms' tumor syndrome 194070	Nephroblastoma	Dominant	WT1
WAGR (Wilms tumor, aniridia, growth retardation) 194072	Wilms' tumor	Dominant	WT1
Birt-Hogg-Dubé syndrome 135150	Renal tumors	Dominant	FLCL
Papillary renal cancer syndrome 605074 164860	Renal cancer	Dominant	MET
Constitutional t(3;8) translocation 603046	Renal cell cancer	Dominant	TRC8
Hereditary bladder cancer	Bladder cancer	Sporadic Unknown	Unknown
109800
Hereditary testicular cancer 273300	Testicular cancer	Possibly X-linked Possibly recessive	Unknown Unknown
Rhabdoid predisposition syndrome 601607	Rhabdoid tumors	Dominant	HSNF5/INI1
CENTRAL NERVOUS SYSTEM/VASCULAR CANCER PREDISPOSITION SYNDROMES
Hereditary paraganglioma 185470 115310	Paraganglioma Pheochromocytoma	Dominant	SDHD SDHC SDHB
Retinoblastoma 180200	Retinoblastoma Osteosarcoma	Dominant	RB1
Rhabdoid predisposition syndrome 601607	Rhabdoid tumors Medulloblastoma Choroid plexus tumors Primitive neuroectodermal tumors	Dominant	HSNF5/INI1
SARCOMA/BONE CANCER PREDISPOSITION SYNDROMES
Multiple exostoses 133700 133701	Chondrosarcoma	Dominant	EXT1 EXT2
Leiomyoma/renal cancer syndrome 605839	Papillary renal cell carcinoma Uterine leiomyosarcomas	Dominant	FH
Carney complex	See above	Dominant	PRKAR1A
Werner syndrome 277700	Sarcoma/osteosarcoma Meningioma	Recessive	WRN RECQL2 RECQL3
Li-Fraumeni syndrome 151623 609266	Soft tissue sarcoma Osteosarcoma Breast cancer Brain tumors Pancreatic cancer Lung cancer Leukemia Adrenocortical cancer Prostate cancer Colon cancer Wilms' tumor	Dominant	TP53, CHEK2 LFS3
ENDOCRINE CANCER PREDISPOSITION SYNDROMES
MEN1 131100	Pancreatic islet cell tumors Pituitary adenomas Parathyroid adenomas	Dominant	MEN1
MEN2 171400	Medullary thyroid cancers Pheochromocytoma Parathyroid hyperplasia	Dominant	RET
Hereditary papillary thyroid cancer 188500	Papillary thyroid cancer	Dominant	RET

*	OMIM, On-Line Mendelian Inheritance in Man: http://www3.ncbi.nlm.nih.gov/Omim/.

Box 12-1

ELEMENTS OF INFORMED CONSENT FOR GENETIC CANCER TESTING

1. What the test is intended to do, that is, determine whether a mutation can be detected in a specific cancer susceptibility gene. 2. What can be learned from both a positive and negative test, including information on the magnitude of health risks associated with a positive test as well as the risks that may remain even after a negative test. 3. The possibility that no additional risk information will be obtained after testing or that the test will result in a finding of unknown significance (e.g., a polymorphism) that might require further studies. 4. The options for approximation of risk without genetic testing, for example, using empiric risk tables for breast cancer given differing family histories. 5. The risk of passing a mutation on to children, including options for assisted reproduction (e.g., preimplantation genetics, if discussion appropriate). 6. The importance of notification of family members that they might share a hereditary risk for cancer with every effort made to assist in contacting of family members and providing them access to counseling and testing. 7. The medical options and limited proof of efficacy for surveillance and cancer prevention for individuals with a positive test as well as the accepted recommendations for cancer screening even if genetic testing is negative. 8. The technical accuracy of the test, that is, the sensitivity and specificity of the analytic methodology. 9. The risks of psychological distress and family disruption whether a mutation is found or not found. 10. The risk of employment and/or insurance discrimination following disclosure of genetic test results and the level of confidentiality of results compared to other medical tests and procedures. 11. The risks that nonrelatedness of family members will be discovered and how this information will be disclosed (or not disclosed). 12. The fees and costs of testing, including the laboratory test and the associated consultation by the health professional who is providing pretest education, results disclosure, and follow-up, and the costs of preventive procedures, which might not be covered by third-party payers.

Modified from Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, Wiley-Liss, 1998, with permission.

MAJOR SYNDROMES OF CANCER PREDISPOSITION

The major syndromes of cancer predisposition that affect adults include common syndromes associated with breast, ovarian, colon, and prostate cancer as well as a number of other less common but equally important cancer predispositions. Some of these syndromes, including multiple endocrine neoplasia type I, retinoblastoma, melanoma, and von Hippel Lindau syndrome, are described elsewhere in this text. For comprehensive reviews of these cancer predispositions, see the following sources: for multiple endocrine neoplasia type I, Lakhani and colleagues^[8] and Marx^[9]; for retinoblastoma, Balmer and colleagues^[10]; for melanoma, Hayward^[11] and Felsani and colleagues^[12]; and for von Hippel Lindau syndrome, Kaelin^[13], Woodward and Maher,^[14] and Sudarshan and Linehan.^[15] For reviews of neurofibromatosis, which are not covered elsewhere in this text, see Ferner,^[16] Lee and Stephenson,^[17] and Hottinger and Khakoo.^[18]

Breast and Ovarian Cancer Syndromes

Clinical Features

Although only about 18,000 cases of breast cancer each year are associated with an obvious hereditary predisposition, over 200,000 breast cancer survivors in the United States developed primary cancers as a result of a hereditary predisposition and remain at risk for secondary cancers. ^{[19] [20]} Genetic testing has emerged as one of the most important indicators of risk factors pointing to a need for intensified screening for breast cancer.^[21] When detected at an early stage, more than 90% of breast cancers are curable. These statistics underscore the rationale for the use of genetics in clinical oncology. The details of the management of women and men who are at hereditary risk for breast cancer have recently been reviewed in detail^[22] and will be summarized here.

From 1 in 150 to 1 in 800 individuals in the population carry a genetic susceptibility to breast cancer, ^{[23] [24] [25]} and the prevalence is much higher in certain ethnic groups. Syndromes of breast cancer susceptibility are linked to mutations of BRCA1 and BRCA2, as well as a smaller number of cases with germline mutations of p53, PTEN, CHEK2, and rarer syndromes ( Table 12-3 ).

Table 12-3 -- Known Genes Associated with Hereditary Breast Cancer Predisposition

Gene	Syndrome	Relative Risk of BC	BC Risk by Age 70	Associated Cancers
HIGH PENETRANCE
BRCA1 [2] [3] [4] [5] [6] [7]	HBOC	17 (20–29) 32 (40–49) 14 (60–69)	39–87%	Ovarian, other
BRCA2 [2] [4] [5] [6] [7]	HBOC	19 (20–29) 10 (40–49) 11 (60–69)	26–91%	Ovarian, pancreatic, prostate, other
p53 [8] [9] [10]	Li-Fraumeni syndrome	1.46 overall 5.96 (15–29)	56% to 45 years >90% to 70 years	Soft-tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, leukemia, other
PTEN [11] [12] [13]	Cowden disease Bannayan-Riley-Ruvalcaba syndrome Proteus Proteus-like syndrome	∼2–4	25–50%	Thyroid (follicular and rarely papillary) endometrial, genitourinary, other
STK11/LKB1 [14] [15]	Peutz-Jeghers syndrome	∼15	54%	Small intestine, colorectal, uterine, testicular and ovarian sex chord tumors, other
CDH1 [16] [17] [18]	Hereditary diffuse gastric carcinoma	∼3.25	39%	Lobular breast, diffuse gastric, other
LOW PENETRANCE
ATM (heterozygote) [19] [20] [21]	Ataxia-telangiectasia in homozygotes	∼3–4	—	Undefined in heterozygotes
CHK2 (CHEK2) [22] [23] [24] [25]	Li-Fraumeni variant	2 (women) 10 (men)	—	Undefined
BRIP1[y]	Fanconi anemia in heterozygotes/compounds	2	—	Undefined in heterozygotes
PALB2[z]	None known	2.3	—	Undefined in heterozygotes

BC, breast cancer; HBOC, hereditary breast and ovarian cancer syndrome.

a	Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117–1130.
b	Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers: Breast Cancer Linkage Consortium. Lancet 1994;343:692–695.
c	Offit K: BRCA mutation frequency and penetrance: new data, old debate. J Natl Cancer Inst 2006;98:1675–1677.
d	Satagopan JM, Offit K, Foulkes W, et al: The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2001;10:467–473.
e	Lalloo F, Varley J, Ellis D, et al: Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet 2003;361:1101–1102.
f	Chen S, Iversen ES, Friebel T, et al: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 2006;24:863–871.
g	Birch JM, Alston RD, McNally RJ, et al: Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 2001;20:4621–4628.
h	Chompret A, Brugières L, Ronsin M, et al: P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 2000;82:1932–1937.
i	Evans DG, Birch JM, Thorneycroft M, et al: Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome. J Med Genet 2002;39:941–944.
j	Brownstein MH, Wolf M, Bikowski JB: Cowden's disease: a cutaneous marker of breast cancer. Cancer 1978;41:2393–2398.
k	Starink TM, van der Veen JP, Arwert F, et al: The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986;29:222–233.
l	Zbuk KM, Stein JL, Eng C: PTEN hamartoma tumor syndrome (PHTS) [cited 2005 Nov 30]. Gene Rev. Available from: http://www.genetests.org/servlet/access?db=geneclinics&site=gt&id=8888891&key=cVUld9gO6ESTy&gry=&fcn=y&fw=XU2v&filename=/profiles/phts/index.html
m	Giardiello FM, Brensinger JD, Tersmette AC, et al: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:1447–1453.
n	Hearle N, Schumacher V, Menko FH, et al: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 2006;12:3209–3215.
o	°Yoon KA, Ku JL, Yang HK, et al: Germline mutations of E-cadherin gene in Korean familial gastric cancer patients. J Hum Genet 1999;44:177–180.
p	Brooks-Wilson AR, Kaurah P, Suriano G, et al: Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet 2004;41:508–517.
q	Pharoah PD, Guilford P, Caldas C, et al: Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001;121:1348–1353.
r	Athma P, Rappaport R, Swift M: Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996;92:130–134.
s	Berstein JL, Concannon P, Langholz B, et al: Multicenter screening of mutations in the ATM gene among women with breast cancer: the WECARE Study. Radiat Res 2005;163:698–699.
t	Bretsky P, Haiman CA, Gilad S, et al: The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev 2003;12:733–738.
u	CHEK2 Breast Cancer Case-Control Consortium: CHEK2 * 1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 2004;74:1175–1182.
v	Meijers-Heijboer H, van den Ouweland A, Klijn J, et al: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002;31:55–59.
w	Thompson D, Seal S, Schutte M, et al: A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev 2006;15:2542–2545.
x	Shaag A, Walsh T, Renbaum P, et al: Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 2005;14:555–563.
y	Seal S, Thompson D, Renwick A, et al: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 2006;38:1239–1241.
z	Rahman N, Seal S, Thompson D, et al: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 2007;39:165–167.

Cowden syndrome was initially described as a dominant inheritance of multiple hamartomatous lesions, including papillomas of the lips and mucous membranes and acral keratoses of the skin.^[26] As described following, this syndrome was ultimately linked to germline mutations of PTEN. In Li-Fraumeni syndrome, early-onset breast cancer occurs with soft-tissue sarcomas, osteosarcoma, leukemia,brain tumors, adrenal cortical tumors, and other cancers. Rarely, a typical breast-ovarian kindred may be found to have a germline p53 mutation.^[27] In Northern European families, specific mutations of CHEK2 are associated with familial breast cancer.^[28] However, the common European CHEK2 mutation is rare in North America.^[29] Both benign and malignant breast tumors occur in Muir-Torre syndrome, a variant of hereditary nonpolyposis colon cancer that is associated with germline mutations of MSH2 and MLH1. Women with Peutz-Jeghers syndrome carry germline mutations in theSTK11 gene and are at increased risk for breast cancer. Although this situation is still under study, initial studies of selected kindreds demonstrated that carriers of some ATM mutations have an elevated breast cancer risk.^[30]

All told, linkage studies suggest that in about 50% of breast cancer kindreds, the cancer was linked to BRCA1, in 30% to BRCA2, and in the remainder to BRCA3 and other as yet unidentified genes.^[31] In up to two thirds of families with both male and female breast cancer, the cancers were due to BRCA2, while over 80% of families with both breast and ovarian cancer harbored BRCA1 mutations.^[32]Multiple, common, lower-penetrance genes are likely to account for a significant component of currently unexplained familial breast cancer risk.^[33] Two such low-penetrance breast cancer alleles that were revealed in large population studies are BRIP1 and PALB2. ^{[34] [35] [36]} Recently, a host of putative lower-penetrant gene mutations have been identified through whole-genome association studies, ^{[37] [38]}although the clinical relevance of these associations remains unclear.

Compared to the 10% breast cancer risk for women in the general population, estimates of the breast cancer risk that is conferred by a common susceptibility gene ranged from 67% to 69% by age 70 based on epidemiologic analyses. ^{[23] [24]} Genetic linkage studies of families that were selected because of early-onset breast or ovarian cancer gave risk estimates as high as 70% to 90% in families in which mutations of either of these two genes were segregated. ^{[39] [40] [41]} Ovarian cancer risks in these families varied from 10% to 80%, and risk for a second breast cancer was as high as 64% by age 70. More recent estimates based on population studies led to slightly lower risk estimates, with a lifetime breast cancer risk of 56% by age 70 (confidence interval: 40% to 73%), and ovarian cancer risk estimated at 16%.^[42] Penetrance estimates that were determined through clinic-based ascertainment of families revealed a 64% risk for breast or ovarian cancer by age 70.^[43] The role of ascertainment and other possible biases in deriving these estimates as well as risks for cancer of the prostate, colon, pancreas, and other sites in BRCA mutation carriers has been reviewed.^[44] In addition to Fanconi anemia, individuals with compound BRCA2 mutations may develop childhood medulloblastomas.^[45]

Genetics

BRCA1 is a large gene, spanning over 100,000 bases of genomic DNA with 22 coding and 2 noncoding exons. BRCA2 is also large, consisting of 27 exons across 70 kb of genomic DNA. Both genes, by coincidence, have a large exon 11. An update of reported mutations is accessible through the Internet at http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic.

The majority of BRCA1 mutations cause premature truncation of the peptide by frameshift or nonsense sequence changes. However, many of the 5% to 10% of BRCA mutations that are missense are problematic because they are of unknown clinical significance. The proportion of these variants that are of unknown significance was as high as 10% to 23% in some series, posing counseling challenges.^{[46] [47]} The role of BRCA1 and BRCA2 in DNA damage response and homologous recombination is reviewed elsewhere.^[48]

Founder BRCA mutations have been documented in genetically isolated populations. In North American families, the most common founder mutations occur in individuals of Ashkenazi Jewish origin. These include a two-base-pair deletion in codon 23 of BRCA1, termed 185delAG, another BRCA1 mutation, 5382insC, and the 6174delT mutation in BRCA2. ^{[49] [50] [51]} About 1 in 40 Ashkenazi Jews harbor one of the common BRCA1 or BRCA2 mutations, ^{[42] [43] [50]} a relatively high carrier frequency for an inherited cancer predisposition syndrome. Other mutations in BRCA1 and BRCA2 occur in the Ashkenazim; 16 out of 737 Ashkenazi Jews who were tested in a clinic-based ascertainment had a nonfounder mutation (2%).^[52] In another study of Ashkenazi individuals with a personal history of breast or ovarian cancer who had previously been shown not to have a founder mutation, 3 of 70 (4.3%) had a deleterious nonfounder mutation.^[53] Founder mutations in populations other than the Ashkenazim have also been observed. ^{[54] [55] [56]}

BRCA1-linked tumors are associated with a medullary subtype and higher mitotic indices.^[57] They were of higher grade, were more frequently estrogen and progesterone receptor negative, ^{[58] [59]} and demonstrated a basal-like phenotype.^[60] They displayed a more “aggressive” phenotype, including a higher proportion of cells in S phase, and other indices. ^{[57] [59] [61] [62] [63]} The prognostic significance of BRCA mutations is still being defined.

Clinical Management

Three elements of breast surveillance that are recommended to BRCA heterozygotes are self-examination, clinician examination, and mammography. The evidence base underlying these recommendations has been reviewed, ^{[22] [64]} and updated guidelines are available on the Web.^[65]

Increasingly, breast cancer screening including mammography and magnetic resonance imaging (MRI) together have been shown to have greatest sensitivity.^[66] For women who are at the highest hereditary risk for breast cancer, those whose breasts are difficult to examine, or those who have had biopsies showing atypia, it might be appropriate to discuss the option of removing the healthy breasts as a preventive measure (prophylactic mastectomy). Retrospective studies support the risk-reducing role of surgery in high-risk patients ^{[67] [68]} (also reviewed in the work of Kinzler^[7]). Prospective and combined consortium studies have also shown the efficacy of this approach. ^{[69] [70]}

Because of their antiestrogen properties, tamoxifen, raloxifene, and a newer class of synthetic estrogen receptor modulators emerged as hormonal chemopreventive agents that have been shown to decrease breast cancer rates in individuals who are at increased risk.^[71] The safety of these drugs in premenopausal women remains to be established. Two studies on the impact of tamoxifen on subsequent breast cancer risk in BRCA1 and BRCA2 mutation carriers have shown conflicting conclusions, ^{[72] [73]} though only one of these studies was sufficiently powered to reach significant results. Tamoxifen was confirmed to decrease contralateral breast cancer risk in a follow-up of one of these studies of BRCA mutation carriers.^[74]

Small trials have demonstrated the ability of ultrasound with Doppler and CA-125 to find early-stage ovarian cancers in BRCA mutation carriers. ^{[75] [76]} However, the efficacy of this approach has not been proven in large, prospective studies. Therefore, prophylactic removal of the ovaries is presented as an option to women with strong family histories of ovarian cancer, in families linked to BRCA1 or BRCA2,or to women who are considering hysterectomy in the setting of a germline mutation associated with nonpolyposis colon cancer syndrome. Studies have confirmed that such surgeries may not only decrease the incidence of subsequent breast and ovarian cancer, but also find occult early stage ovarian neoplasms, ^{[77] [78]} decreasing mortality.^[79] These studies have also confirmed that serous surface carcinoma, also called papillary serous carcinoma, can still occur following prophylactic oophorectomy, ^{[80] [81]} leading most authors to use the term risk-reducing salpingo-oophorectomy.

Combination oral contraceptives that contain estrogen and high-dose progestin result in a time-dependent, protective effect against ovarian cancer in some but not all studies of BRCA mutation carriers. ^{[82] [83] [84]} There remains the concern of a small increased risk of breast cancer due to oral contraceptives in this group, particularly in those with BRCA1 mutations.^[85]

Common Colon Cancer Predisposition Syndromes

Highly penetrant, dominant, susceptibility syndromes account for about 5% of colon cancer. The most common syndrome is hereditary nonpolyposis colon cancer, with familial adenomatous polyposis constituting a rarer familial syndrome. For adults, genetic epidemiologic analyses suggested a common susceptibility allele for both colon cancer and adenomatous polyps that accounted for at least 15% and possibly half of cases. ^{[86] [87]}

Polyposis Syndromes

FAMILIAL ADENOMATOUS POLYPOSIS

Clinical Features.

Familial adenomatous polyposis (FAP; adenomatous polyposis coli) presents with hundreds to thousands of adenomatous polyps at a young age. Virtually all affected individuals exhibit polyposis by age 35 years, and all will develop colon cancer. Colon cancer is therefore inevitable if the colon is not removed; the cancer occurs at an average age of 39 years. Flexible sigmoidoscopy at an early age establishes the diagnosis, and prophylactic colectomy is performed in the teen years. Patients remain at risk for primary adenomas and carcinomas of the duodenum and rectum as well as desmoid tumors, osteomas, thyroid carcinoma, hepatoblastoma, and other hepatopancreatic tumors.^[88]

Genetics.

FAP arises from germline mutations in the APC gene.^[89] Genotype phenotype correlations have been described, particularly for congenital hypertrophy of the retinal epithelium and the number of polyps observed. An attenuated form of FAP is associated with mutations at the extreme 5′ and 3′ ends of the gene. ^{[90] [91]} Up to 30% of patients with multiple adenomas (15 to 100 adenomas) who test negative for APC mutations carry biallelic mutations in MYH,^[92] discussed in detail later.

Clinical Management.

In classic FAP, APC gene testing should be performed by 10 to 12 years of age, about the time that sigmoidoscopy begins. Unaffected individuals with wild-type APC who have an affected family member with a known mutation are screened in the same way as the general population.^[93] In the case of attenuated FAP, in which adenomas might not occur until the twenties or thirties, the age at which genetic testing and clinical surveillance begin is not clearly defined. Once an APC gene mutation has been identified and when adenomas are found, prophylactic colectomy is performed, usually in the teen years.^[94] Sulindac, a nonsteroidal anti-inflammatory drug, may reduce adenoma development in individuals with FAP, and similar effects were noted with celecoxib, a COX-2 inhibitor. ^{[95] [96]} However, the possibility of delaying colectomy while patients are treated pharmacologically has not yet been established. Patients require lifelong surveillance for extracolonic tumors, including tumors of the upper GI tract as well as the ileal pouch (if proctocolectomy is performed).^[97]

MYH-ASSOCIATED POLYPOSIS.

Some FAP probands carry biallelic mutations in the base excision repair gene, MYH. ^{[92] [98]} MYH-associated polyposis (MAP) is considered a recessive syndrome; parents of affected homozygote or compound heterozygote mutation carriers have been reported to be unaffected.^[99] However, both monoallelic and biallelic germline mutations in MYH have been associated with multiple adenomas. ^{[99] [100]} Biallelic carriers have a higher frequency of CRC than do monoallelic patients.^[101] Patients with multiple adenomas (more than 15) without APC mutations are more likely to have biallelic MYHmutations than are controls ^{[100] [102]} Combining APC and MYH sequencing increases the yield of diagnosis from 34.4% to 41.3%.^[103] The mutations Y165C and G382D are recurring in Caucasian Europeans, making up 86% of biallelic mutations in three series. ^{[99] [100] [101]} In 358 early-onset polyposis cases that were unselected for APC mutation status, two cases carried biallelic MYH mutations, and eight MYH mutation heterozygotes were identified. No MYH mutations were detected in 354 controls, leading the authors to conclude that biallelic MYH mutations might account for up to 3% of early onset colorectal cancer. Patients in this series did not exhibit profuse polyposis, consistent with previous reports, and distally located tumors were prevalent. ^{[104] [105]}

Management.

As with FAP, prophylactic colectomy is generally recommended for MYH-associated polyposis. Because over one third of biallelic MYH mutation carriers might not develop multiple polyps but remain at elevated colorectal cancer risk, colonoscopy with polypectomies is thought to be not sufficiently preventive for this population.^[106] Surgical options for MYH mutation carriers include ileorectal anastomosis for younger patients with few rectal adenomas and a milder family history or with attenuated FAP or total proctocolectomy with the creation of an ileal pouch and anal anastomosis for more diffuse polyposis.

Hereditary Nonpolyposis Colon Cancer

CLINICAL FEATURES.

A constellation of colon and endometrial cancers became known as Lynch syndrome or hereditary nonpolyposis colon cancer (HNPCC).^[107] Five additional tumor sites demonstrated increased observed/expected (O/E) ratios in HNPCC kindreds: cancers of the stomach (O/E = 4.1), ovary (O/E = 3.5), small intestine (O/E = 25), ureter (O/E = 22), and kidney (O/E = 3.2).^[108] There is a 70% to 75% risk of colon cancer by age 65 in HNPCC families. ^{[109] [110]} The penetrance was 92% by age 60 in one series,^[111] with a median age at colon cancer diagnosis of 44 to 46 years. A 40% to 60% endometrial cancer risk by age 70 was reported, ^{[112] [113] [114] [115]} with a median age of onset from the late forties to early fifties.^[116] The risk for endometrial cancer in the general population is 3%.

At a 1991 meeting in Amsterdam, the International Collaborative Group on HNPCC defined the syndrome as (1) histologically verified colorectal cancer in three or more relatives, including a first-degree relative of the other two; (2) colorectal cancer involving at least two generations; and (3) one or more colorectal cancers diagnosed before 50 years of age. The subsequent “Amsterdam II criteria” for HNPCC were redefined to include extracolonic HNPCC-associated cancers.^[117] In 1996, guidelines known as the Bethesda criteria delineated individuals at risk for HNPCC for whom molecular genetic analysis may be considered.^[118] A revised set of Bethesda Guidelines was developed to identify subjects who are at high risk of having a germline mismatch repair gene mutation^[119] Multivariate logistic regression risk models using personal and family medical histories estimate the probability of carrying an HNPCC mutation. ^{[120] [121] [122]}

While there do not appear to be defining histologic features of HNPCC tumors, mucinous types are more common. Adenomas, like the cancers in HNPCC, appear more frequently on the right side. Multiple lesions occur in about 20% of at-risk individuals. Generally, fewer than 100 polyps present in these cases.^[123]

GENETICS.

About 45% to 70% of HNPCC families harbor mutations in one of the three genes: MSH2, MLH1, and MSH6. ^{[124] [125] [126] [127]} Mutations in two other genes, PMS1 and PMS2, have been associated with HNPCC syndrome,^[128] and rare, atypical Lynch syndrome pedigrees with identifiable MLH3 mutations have also been described.^[129] Of these, mutations of MSH2 and MLH1 were far more frequent than the others, accounting for about 30% each of families meeting Amsterdam criteria for HNPCC. Over 75% of mutations in MSH2 and MLH1 were inactivating insertions, deletions, alterations in premessenger RNA splicing signals, and nonsense mutations. However, 23% of 120 mutations surveyed were missense mutations.^[130] Mutations of MSH6 less frequently result in the “replication error repair” phenotype but account for a significant number of familial colon cancer families.^[131] The replication error repair phenotype is commonly detected as microsatellite instability (MSI) utilizing polymerase chain reaction screening of tumors with microsatellite markers. The MSI phenotype is present in about 80% of HNPCC-associated colon cancers^[132] and in about 15% of sporadic colon tumors,^[133] as well as in other tumors associated with HNPCC (e.g., uterine, gastric cancers). MSI results in a genomewide increased mutation rate, causing mutations in oncogenes, tumor suppressors, and in microsatellite regions.^[134]

In young patients (less than 35 years old), the detection of the MSI phenotype is quite common (seen in 58%) and may be associated with detectable HNPCC gene mutations in only half of the cases.^[135]Testing for MIS and/or immunohistochemistry (IHC) for HNPCC-associated protein expression is recommended in all patients with colorectal cancer who are younger than 50 years of age, have a family history of colon or endometrial cancer, or have a personal history of metachronous colon or endometrial cancers.^[136]

Lack of MLH1 or MSH2 protein expression in tumors is correlated with MSI, allowing the use of immunohistochemistry along with MSI analysis.^[137] Lack of expression of the MLH1 protein indicates that germline testing should begin with the MLH1 gene. Similarly, if there is no expression of MSH2, the germline testing should begin with MSH2 gene. Immunohistochemical analysis can also be utilized to evaluate MSH6 and PMS2 protein expression. In older patients with colorectal cancer, hypermethylation of the MLH1 promoter may account for the lack of MLH1 protein expression.^[138] This epigenetic (nonhereditary) mechanism of MLH1 promoter hypermethylation is responsible for the majority of the remaining patients whose tumors are characterized by defective DNA mismatch repair.^[139]

CLINICAL MANAGEMENT.

It has been shown that screening for cancer in HNPCC improves patient survival.^[140] Individuals with HNPCC are advised to undergo colonoscopic surveillance every 1 to 2 years, preferably annually, starting at age 20 to 25 years and perhaps at age 30 for MSH6 mutation carriers. ^{[141] [142]} Endometrial cancer screening generally includes transvaginal ultrasound and endometrial biopsy at age 30 to 35 years. Annual urinalysis with cytology is also recommended, although minimal data support the efficacy in detecting urothelial tumors. A baseline upper endoscopy should be performed, but the optimal subsequent screening interval has yet to be established. Prophylactic subtotal colectomy is generally performed after the first malignancy diagnosis, sparing the rectum.^[143] A retrospective study of prophylactic bilateral oophorectomy and hysterectomy showed protection from uterine and endometrial cancer,^[144] though the estimates were influenced by a retrospective study design.^[145] Nonetheless, a combination of risk-reducing bilateral oophorectomy and hysterectomy is a reasonable option after childbearing or at the time of subtotal colectomy for a colon cancer occurring in women with HNPCC.

Prostate Cancer

Clinical Features

Of the quarter of a million men who will be diagnosed with prostate cancer in 2008, about 5% to 10% will have a strong family history of the disease. The estimated prostate cancer susceptibility allele frequency is 0.003 to 0.006, meaning that about 1 in 170 to 1 in 85 individuals has inherited a genetic mutation, which in males confers susceptibility to prostate cancer. The penetrance for this dominant prostate cancer susceptibility syndrome was estimated to be 88% by age 85. The syndrome may account for 43% of prostate cancers that are diagnosed before age 56 and 9% that are diagnosed by age 85.^{[146] [147]} While only an estimated 2% of prostate cancer in the general population is diagnosed before age 56, this proportion is increasing with the introduction of newer screening modalities. The clinical features, stage, histology, and PSA at diagnosis of hereditary prostate cancer were comparable to those of nonhereditary cases.^[147]

As Table 12-4 shows, hereditary prostate cancer has enormous genetic heterogeneity.^[148] The first putative gene that was identified, HPC1, emerged after a genomewide scan of 66 high-risk prostatecancer families revealing linkage to 1q24-25. Subsequently, germline RNASEL mutations on chromosome 1q25 were identified in high-risk prostate cancer families.^[149] Analysis of 600 individuals from 91 prostate cancer kindreds revealed linkage to a locus on chromosome 1q24-q25, as did a meta-analysis of 772 prostate cancer kindreds by the International Consortium for Prostate Cancer Genetics. However, it was suggested that this region might be responsible for only a subset of hereditary prostate cancer.^[150] RNASEL polymorphisms have been inconsistently associated with prostate cancer susceptibility; a meta-analysis supported only a modest effect.^[151]

Table 12-4 -- Genetic Heterogeneity of Hereditary Prostate Cancer

Locus Name	Location	Putative Gene
HPC1	1q24-q25	RNASeL
HPC2	17p11	ELAC2
PCAP	1q42-q43	?
CAPB	1p36	EPHB2
HPCX	Xq27-q28	?
HPC20	20q13	?
—	8q24	?
—	7q11-21	?
—	3p26	?

In 2001, Tavtigian and colleagues performed a study of high-risk prostate cancer families from the Utah Population Database, providing evidence for linkage to HPC2 on chromosome 17p.^[152] Common variants of ELAC2 segregated with prostate cancer in two of the pedigrees. Among 266 prostate cancer cases that were unselected for family history and 359 controls, two variants, Ser217Leu and Ala541Thr, were identified in 31.6% and 2.9%, respectively. Interestingly, the Ala541Thr genotype was found only in individuals with the Ser217Leu variant, conferring an elevated prostate cancer risk with an odds ratio of 2.37.^[153] These findings were not supported by a subsequent series of 159 hereditary prostate cancer probands, 249 incident prostate cancer cases, and 222 controls^[154] or by other series. A review of pooled data from various ELAC2 studies that were analyzed by the investigators who originally identified ELAC2 as a prostate cancer susceptibility gene confirmed that this gene does confer increased prostate cancer risk for approximately 2% of prostate cancer cases in the general population. ^{[152] [155]}

Linkage analyses of 360 prostate cancer kindreds from North America, Sweden, and Finland demonstrated significant linkage to HPCX on Xq27-28, estimated to account for up to 16% of hereditary prostate cancer,^[156] a finding that was confirmed by two other studies with no male-to-male transmission. ^{[157] [158]} Another Finnish genomewide linkage analysis identified 3p26 as a major prostate cancer susceptibility locus.^[159] Genomewide linkage studies identified 7q11-21 as a putative region for prostate cancer susceptibility among 36 Ashkenazi Jewish prostate cancer kindreds.^[160] Recently, whole-genome admixture scans in 1597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer,^[161] and subsequent studies have confirmed 8q24 as a locus for up to three prostate cancer susceptibility alleles.^[162] Linkage to HPC20 at 20q13 was implicated in one study of 162 North American kindreds^[163] but not in another study of 172 unrelated prostate caner kindreds.^[164] A French series of 159 affected individuals identified PCAP at 1q42.2-43 as a prostate cancer susceptibility locus among Southern and Western Europeans with prostate cancer diagnosed at age 65 or younger, with no evidence for linkage to the other regions that were analyzed, including HPC1 at 1q24-25, HPCX at Xq27-28, and CAPB at 1p36.^[165]

Prostate cancer with a family history of brain cancer has shown linkage to 1p36.^[166] However, an international collaborative analysis did not confirm linkage to 1p36 with prostate and brain cancer susceptibility exclusively, assessing five brain-prostate cancer kindreds that did show linkage to this region as a chance association.^[167] EPHB2 at 1p36 was biallelically disrupted in prostate cancer lines of brain metastasis origin.^[168]

Other putative prostate cancer susceptibility loci that have been identified by linkage studies include 17q22, 15q11 in late-onset kindreds, and 4q35 with four or more affected family members^[169]; a 79 C➙T polymorphism in the cell cycle gatekeeper/tumor suppressor gene CDKN1B at 12p13^[170]; the polymorphism H6D in MIC-1, a regulator of macrophage activity in inflammatory response^[171]; a tetranucleotide TTTA repeat number polymorphism in the CYP19 estrogen synthesis aromatase gene^[172]; and mutations in the p53 regulator CHEK2. ^{[173] [174] [175]}

Genetic heterogeneity remains the central issue in prostate cancer genetics. A large study of 1233 prostate cancer kindreds found significant positive LOD scores, suggesting linkage to at least nine different regions.^[176] At least two population-based series suggested a recessive mechanism because risk of disease was greater in siblings than in children of those who were affected. ^{[177] [178]}

Candidate susceptibility alleles for hereditary prostate cancers have also included genes that encode receptors for two steroid hormones that influence cell division within the gland. A case-control study of 57 prostate cancer cases and 169 controls revealed that individuals carrying polymorphisms in the genes encoding the androgen receptor and vitamin D receptors were at increased risk for prostate cancer.^[179] Despite an extensive literature, associations of the CAG repeat number polymorphism in exon 1 of the androgen receptor gene have generally not been confirmed in large cohorts, ^{[180] [181]}emphasizing the importance of ethnic variance and other factors.^[182] In some families, prostate cancer may be associated with already known cancer predisposition syndromes, such as BRCA2 and p53.^{[183] [184] [185]}

Clinical Management

The normal concentration of prostate-specific antigen (PSA) in the serum is 0 to 4ng/mL. Values greater than 10ng/mL are more likely to be associated with cancer. Transrectal ultrasound is performed in the setting of an increased PSA, with transrectal needle biopsy of any suspicious area guided by ultrasound or digital rectal examination. Current recommendations of the American Cancer Society and other professional societies include digital rectal examination and PSA screening for men between the ages of 50 and 70.^[186] Initial evidence for the efficacy of this approach in decreasing mortality was demonstrated in a trial of 45,000 men.^[187]

A study of individuals at increased risk for prostate cancer by virtue of a family history demonstrated the efficacy of intensive screening (PSA, digital rectal examination, transrectal ultrasound, and systematic as well as directed core biopsies).^[188] Additional studies of annual PSA and biopsy for PSA greater than 3.0 targeted to those who are at hereditary risk are in progress.^[189] A future option for hereditary prostate cancer risk reduction may include hormonal chemoprevention.^[190] A large-scale chemoprevention trial of finasteride showed a modest delay in the appearance of prostate cancer but also sexual side effects and an increased risk of high-grade prostatic neoplasms.^[191]

Multiple Endocrine Neoplasia Type 2

Clinical Features

Multiple endocrine neoplasia type 2a (MEN2a) is characterized by multiple endocrine tumors, particularly medullary thyroid carcinoma and pheochromocytoma. There is also hyperplasia of the parathyroid in one quarter of cases. Hypertension is the common presenting symptom, with diagnosis classically made by measurement of urinary VMA and metanephrine. Routine MEN2a screening has been directed to thyroid medullary lesions, with pentagastrin challenge to measure calcitonin response.^[192] Measurement of serum ionized calcium has also been performed in the diagnostic evaluation.

MEN2b has an earlier age of onset than MEN2a; enlarged, nodular lips; a Marfanoid habitus; ganglioneuromatosis of the intestine; and other abnormalities.^[193] This phenotype also includes medullary thyroid carcinoma, which may be more aggressive, and pheochromocytoma. Parathyroid disease is less common than in MEN2a.

Medullary thyroid carcinoma runs in families about 25% of the time, as a syndrome of site-specific familial medullary carcinoma of the thyroid (FMCT) or as MEN2.^[194] Cases usually present in the third and fourth decades and are often bilateral and multifocal. Familial papillary thyroid cancer is distinct from FMCT and is associated with an increased incidence of colorectal cancer.^[195]

Genetics

In 1993, it was observed that RET gene mutations were associated with MEN2a, MEN2b, and FMCT. ^{[196] [197]} Specific RET gene mutations have been associated with MEN2a, MEN2b, and FMCT. ^{[196] [198] [199] [200]} RET testing of sporadic cases of medullary carcinoma of the thyroid will yield a relatively low (5%) rate of diagnosis of MEN2a in the absence of a family history of the disease, C cell hyperplasia, or multifocality. ^{[201] [202]} Nonetheless, RET testing is more sensitive than traditional biochemical screening is. Asymptomatic children with RET mutations and normal plasma calcitonin levels had small foci of medullary carcinoma of the thyroid at time of “prophylactic” surgery.^[203] These findings were confirmed in a large study in the United States.^[204]

A study of 477 MEN2a families showed an association between codon 634 mutations and pheochromocytoma and between mutations at codons 768 and 804 and FMCT, while codon 918 mutation is MEN2b-specific. Rare families with both MEN2 and Hirschsprung disease have MEN2-specific codon mutations.^[205] A 611 codon mutation is associated with a mild form of FMCT with slow progression. The classic M918T mutation in exon 16 is found in MEN2b, and a less common mutation in RET codon 883 has also been reported. ^{[206] [207]}

Clinical Management

RET testing has been established as the gold standard for MEN2a screening, and prophylactic thyroidectomy has been established as the primary preventive intervention. The age at which surgery is recommended is 3 to 5 years at most centers. Genetic testing should therefore be performed by this age and perhaps even earlier in families with MEN2b, since the thyroid cancers can occur at an earlier age.^[208] Heterozygotes for RET mutations in the setting of MEN2a are screened with abdominal ultrasound and computed tomography (CT), as well as 24-hour urine studies through the adult years, at least to age 35. Plasma screening for the pheochromocytomas has been suggested (see the section on von Hippel Lindau syndrome). The treatment of choice for patients with MEN2a or MEN2b with a unilateral pheochromocytoma is unilateral resection, since substantial morbidity and mortality are associated with the Addisonian state after bilateral adrenalectomy.^[209]

RECENTLY CHARACTERIZED CANCER PREDISPOSITION SYNDROMES

Gorlin Syndrome and Nevoid Basal Cell Carcinoma Syndrome

Basal cell carcinomas (BCCs) are the most common malignancy in humans, with three quarters of a million cases each year. In a small subset of families, BCCs occur at early age and in great numbers. The nevoid basal cell carcinoma syndrome (NBCCS) consists of multiple BCCs, usually presenting after puberty, accompanied by odontogenic jaw cysts, congenital skeletal abnormalities, ectopic calcification of the falx cerebri, and characteristic pits in the skin of the palms and soles. ^{[210] [211]}

A hallmark of the syndrome is the increased susceptibility of the skin to the damaging and tumor-inducing effects of ionizing radiation.^[212] Multiple BCCs have developed within 6 to 36 months following radiation therapy. Unlike Bloom syndrome or ataxia telangiectasia, there is no in vitro evidence of chromosome fragility.

One estimate of the prevalence of the syndrome, 1 in 57,000, comes from a study of a population of 4 million people in northwest England.^[213] As described by Gorlin in 1987, penetrance for the syndrome is virtually 100% over a lifetime.^[211] NBCCS is diagnosed in individuals with two major and one minor criterion or one major and three minor criteria.^[214] Major criteria include bilamellar calcification of the falx cerebri at less than 20 years of age; odontogenic (jaw) keratocyst; palmar/plantar pits (three or more); multiple (more than 2) BCCs or a BCC before the age of 20 years; bifid, fused, or markedly splayed ribs; or a first-degree relative with NBCCS. ^{[215] [216]} Minor criteria include childhood medulloblastoma (also called primitive neuroectodermal tumor); lymphomesenteric or pleural cysts; macrocephaly; cleft lip/palate; vertebral anomalies on X-ray; bifid vertebrae; preaxial or postaxial polydactyly; ovarian/cardiac fibroma; and ocular anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium). One study showed that approximately 5% of Gorlin syndrome patients develop medulloblastoma in the first few years of life and that 10% of patients with medulloblastoma diagnosed at age 2 years or under have Gorlin syndrome.^[217] For diagnostic purposes, it might be salient that one study found that the only histopathologic subtype of medulloblastoma in NBCCS patients is the desmoplastic subtype, which occurs in only 20% of sporadic medulloblastoma cases. The authors suggest that the occurrence of the desmoplastic subtype in a patient younger than 2 years of age is pathognomic.^[218]

Genetics

In 1996, Johnson and coworkers found mutations in exon 15 of the human homolog of the Drosophila patched gene (called PTH or PTCH)^[219] in two of 60 typical NBCCS kindreds. An analysis of 71 unrelated individuals with NBCCS revealed 26 with mutations scattered throughout the 23 exons of the gene. In 86%, the mutations caused a truncated protein.^[220] NBCCS is caused by germline mutations of the gene PTCH mapped to chromosomal locus 9q22.3. The PTCH gene consists of 23 exons and encodes an integral membrane protein with 12 transmembrane regions and two extracellular loops and a putative sterol-sensing domain. Mutations of PTCH are the only known genetic alterations associated with NBCCS.^[221] However, several studies have found no genotype/phenotype correlations, ^{[220] [222] [223]} which suggests that other factors might add to the development of patients’ clinical features. For kindreds with diagnostic clinical findings of NBCCS that test negative for a mutation by sequence analysis, Southern blot analysis may be performed to detect large deletions. About 70% to 80% of probands have inherited the condition from a parent, and about 20% to 30% of probands have a de novo mutation.

Risk Management Recommendations

Life expectancy in NBCCS is not significantly different from average. The major clinical issues revolve around the cosmetic effects of treating multiple skin tumors and jaw keratocysts, which can recur. The jaw cysts may also undergo malignant transformation.^[224] Interaction with oral and plastic surgeons and dermatologists is important. Because of early-onset disease risk, for example, for medulloblastomas, genetic testing of children is appropriate for this condition. Evaluation of members of NBCCS kindreds includes skin examination; measurement of head circumference; and radiographic examination of the skull, spine, ribs, and jaws.^[225] Ophthalmologic and dental examination and radiographic monitoring of the jaw cysts (oropantomography) may be performed on affected individuals. MRI scans of at-risk children can diagnose medulloblastomas, though it is unclear whether this improves outcome. If no physical or radiographic stigmata are noted by 5 years of age in the child of an affected patient, the chances that the child is a heterozygote are small.^[214] As has been mentioned, radiotherapy for large basal cell cancers should be avoided, because this can lead to the development of thousands of BCCs in the radiation field. ^{[211] [212]} Prenatal testing for NBCCS is possible if the disease-causing mutation has been identified in an affected family member.

Carney Complex

Clinical Features

Carney complex (CNC) is a multiple neoplasia syndrome that is referred to by acronyms such as NAME^[226] and LAMB syndrome in the medical genetics literature. ^{[227] [228]} As described by Carney in 1985,^[229] the complex is characterized by myxomas, skin pigment abnormalities, endocrine tumors, and schwannomas. The median age at diagnosis is 20 years, spotty skin pigmentation and heart myxomas being the most common initial clinical manifestations.^[230] The skin abnormalities involve the lips, the conjunctiva and inner or outer canthi, and the mucosa of the vagina or penis. Atrial myxomas are by far of greatest clinical concern, since they usually result in a decreased life span and account for the major causes of mortality in affected individuals; cardiac myxoma can cause stroke and death.^[230] Ductal breast adenoma has been described as part of the Carney complex, as well as myxoid fibroadenomas and other findings on breast imaging.^[231] In one study of 338 individuals diagnosed with CNC, 34 of 194 (17.5%) females had breast myxomas, often bilateral.^[232] Large-cell calcifying Sertoli cell tumor, a frequent component of CNC in males, detected as early as 2 years of age, has been associated with infertility due to hormonal imbalance.^[233]

Primary pigmented nodular adrenocortical disease occurs most frequently in association with CNC. A study by Stratakis in 1999 showed that for 95% of the patients, primary pigmented nodular adrenocortical disease occurred as a component of CNC, and 14% had Cushing syndrome.^[234] Thus, the diagnosis of primary pigmented nodular adrenocortical disease should prompt screening for CNC. Other organs that are involved in CNC are the thyroid gland and ovaries. Thyroid gland lesions include follicular hyperplasia, follicular adenoma, and follicular and papillary carcinoma. Ultrasonography is useful for screening and diagnosis of these lesions.^[235] Ovarian serous cystadenomas have been described in the literature, suggesting that pelvic ultrasound may be indicated as a part of evaluating women with CNC.^[236]

Diagnostic criteria for CNC^[232] require two or more of the manifestations or one major manifestation and one of the minor criteria. Major criteria are skin pigmentary abnormalities (multiple lentigines of the face, blue nevus, or epithelioid blue nevus); myxoma (cutaneous or mucosal myxomatosis); cardiac myxoma; endocrine tumors/overactivity (primary pigmented nodular adrenocortical disease, a micronodular form of adrenal hyperplasia, growth hormone-producing pituitary adenoma, large-cell calcifying Sertoli cell tumor, or thyroid adenoma or carcinoma); psammomatous melanotic schwannoma; thyroid carcinoma or multiple thyroid nodules on ultrasound in a young patient; multiple breast ductal adenomas; and osteochondromyxoma. To make the diagnosis, an individual must have two of the components listed or one of the manifestations in addition to an affected first-degree relative or have an inactivating mutation of the PRKAR1A gene. A malignant neoplasm is a relatively uncommon finding in affected patients.

Genetics

Mutations in PRKAR1A (17q23-q24) are identified in about 40% of individuals with CNC.^[237] PRKAR1A codes for the RI-α subunit of PKA, a critical cellular component of a number of cyclic nucleotide-dependent signaling pathways.^[238] PRKAR1-a frameshift mutations cause haploinsufficiency of R1-α and manifest as CNC. As predicted by the Knudson “two-hit” hypothesis, loss-of-heterozygosity of the normal allele supports the model that R1-α may have tumor suppression function in the target tissues in this syndrome. The most common mutation in CNC patients, a two-base-pair deletion (TGdel) in exon 5 of PRKAR1, has also been found de novo in several kindreds, suggestive of a mutational hot spot in the gene.^[239] About 17% of diagnosed individuals harbor de novo mutations.

Clinical Management

Recommendations include annual echocardiography, annual measurement of urinary free cortisol, testicular sonogram in males at their initial visit, thyroid ultrasound at initial visit and as needed thereafter, pelvic ultrasound in female patients at their initial visit, breast imaging, spine MRI, pituitary MRI, and adrenal CT scan.^[239] Children should have echocardiography during the first 6 months of life and annually thereafter to detect potentially lethal myxomas. Children with large-cell calcifying Sertoli cell tumor may require monitoring of growth rate and pubertal status. Bone age determination and further laboratory evaluation might be necessary if gynecomastia is present.^[212]

Cowden Syndrome

Clinical Features

Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Consensus diagnostic criteria for CS establish three diagnostic categories.^[240]

Pathognomonic criteria include mucocutaneous lesions, facial trichilemmomas, acral keratoses, papillomatous lesions, and mucosal lesions. Major criteria include breast cancer, thyroid cancer (especially follicular histology), macrocephaly, Lhermitte-Duclos disease (defined as presence of a cerebellar dysplastic gangliocytoma),^[241] and endometrial carcinoma. Minor criteria include other thyroid lesions (e.g., goiter), mental retardation, hamartomatous intestinal polyps, fibrocystic breast disease, lipomas, fibromas, and GU tumors (e.g., uterine fibroids, renal cell carcinoma) or GU malformation. The diagnosis of CS is made if an individual meets any one of the following criteria: pathognomonic mucocutaneous lesions alone if there are: six or more facial papules, of which three or more must be trichilemmoma, or cutaneous facial papules and oral mucosal papillomatosis; or oral mucosal papillomatosis and acral keratoses; or six or more palmoplantar keratoses. Alternatively, the individual may fulfill two major criteria, but one must have either macrocephaly or Lhermitte-Duclos disease. Alternatively, the individual may have one major and three minor criteria or four minor criteria.

The palmar and plantar hyperkeratotic pits usually become evident later in childhood. Subcutaneous lipomas and cutaneous hemangiomas are seen in CS with low frequency.^[242] An increased risk of early-onset male breast cancer has been noted in mutation carriers.^[243]

Genetics

The gene for CS, PTEN, was mapped to 10q22-23.^[244] PTEN acts as a tumor suppressor by mediating cell cycle arrest, apoptosis, or both.^[245] Full sequencing and molecular testing by Southern blot are available clinically and on a research basis. Heterozygous germline mutations in PTEN cause most cases of CS. Nonsense, missense, and frameshift mutations that are predicted to disrupt normal PTENfunction have been identified in certain families,^[246] including mutations that disrupt the protein tyrosine/dual-specificity phosphatase domain. A PTEN mutation can be detected in about 80% of patients with CS.^[247]

Risk Management Recommendations

Individuals with known germline PTEN mutations should undergo appropriate cancer screening. ^{[228] [248]} Female patients with CS should be screened for breast cancer, starting clinical breast examination at age 25 and annual mammography at age 30 or 5 years younger than the earliest age of breast cancer diagnosis in the family. Men should perform monthly breast self-examination. Female patients should receive endometrial cancer screening beginning around age 35 years or 5 years before the youngest endometrial cancer diagnosis in the family, as well as a comprehensive annual physical examination starting at age 18 years with screening for skin and thyroid lesions, including a baseline thyroid ultrasound. Individuals with CS should undergo a colonoscopy at age 50 years and annual urinalysis to detect renal carcinoma. Finally, prenatal testing for CS can be done if a mutation is described in a parent.

Birt-Hogg-Dubé Syndrome

Clinical Features

Birt-Hogg-Dubé (BHD) cancer predisposition syndrome was recently molecularly characterized, though it was first described in 1977.^[249] This rare genodermatosis comprises an interesting triad of findings: fibrofolliculomas that appear as white or skin-colored papules on the face and upper torso, spontaneous pneumothorax, and kidney tumors.^[250] Approximately 15% to 30% of patients with cutaneous BHD syndrome develop renal tumors. A recent review of 130 solid renal tumors resected from 30 patients with BHD in 19 different families revealed that renal tumors were multiple and bilateral and were noted at an early age (mean: 50.7 years). The vast majority were hybrid oncocytic neoplasms with areas reminiscent of chromophobe renal cell carcinoma and oncocytoma, while a significant number were chromophobe renal cell carcinomas, and a minority were conventional clear cell renal carcinomas. ^{[251] [252]} The cutaneous lesions usually appear in the region of the head, neck, and upper part of the trunk in the third or fourth decade of life, and about 15% to 30% of patients with skin lesions of BHD syndrome develop renal tumors. Khoo and colleagues described an association with colorectal neoplasia in some families with BHD.^[253] However, other reports did not confirm this.^[254] Individuals with BHD syndrome are at markedly increased risk of spontaneous pneumothoraces. In a recent study, 64 of 198 (32%) BHD-affected individuals had a history of spontaneous pneumothorax.^[255] The syndrome is also associated with a progressive flecked chorioretinopathy with constricted visual fields.^[256]

Genetics

BHD is inherited in an autosomal dominant manner. The recently identified BHD gene has been mapped to chromosome 17p11.2^[257] expressing a novel protein folliculin.^[258] The exact function of this protein is not known. Affected individuals exhibit loss of protein function, usually due to a frameshift mutation in the coding sequence. In a recent study, 27 of 52 BHD-affected families had an insertion/deletion in exon 11 of the gene (c.1733insC or c.1733delC). Phenotype manifestations among those with either the insertion or the deletion were similar for fibrofolliculomas and pneumothoraces. However, the incidence of renal tumors was significantly higher among those with the C-insertion compared to the C-deletion (33% versus 6%).^[255]

Risk Management

Patients with BHD syndrome and their relatives should undergo abdominal CT and renal ultrasound screening for renal tumors. Lung cysts are best seen on CT scans. Dermatologic consultation is advised. Ophthalmologic examination should be performed in patients with BHD syndrome owing to the high incidence of chorioretinopathy.

Rhabdoid Predisposition Syndrome

Clinical Features

Rhabdoid predisposition syndrome (RPS) was initially described in 1999 by Sévenet and colleagues.^[259] RPS results in pediatric cancer predisposition, including renal and extrarenal malignant rhabdoid tumors; choroid plexus carcinomas; central, primitive, neuroectodermal tumors; and medulloblastomas. ^{[260] [261]} In the families that have been described with RPS, the penetrance appears to be quite high at a very young age. In the initial study, all of the first cancers occurred before the age of 3 years in mutation carriers, and no mutation carriers were unaffected.^[259] Pediatric brain tumors are emerging as an important component of this syndrome.^[262] The spectrum of cancers that have been observed in RPS overlaps somewhat with Li-Fraumeni syndrome. Pediatric medulloblastomas may also occur in Gorlin syndrome and in compound BRCA2 heterozygotes, as was noted previously.

Genetics

RPS is caused by mutations in hSNF5/INI1 at 22q11.2 (also known as SMARCB1). Most mutations in the hSNF5/INI1 gene are truncating.^[263] The hSNF5/INI1 gene encodes a subunit of the SWI/SNFfamily of chromatin-remodeling complexes. The spectrum of tumors with somatic mutations of hSNF5/INI1 is similar to the tumors that are seen in the hereditary syndrome.^[263] A recent paper^[264]describes a family with two children, one affected with rhabdoid tumor of the kidney and the other with atypical teratoid/rhabdoid tumor. Though both children satisfied the morphologic and clinical features for a diagnosis of RPS, neither of their tumors showed hSNF5/INI1 inactivation, both had normal expression of the gene in nuclei of tumor cells, and haplotype analysis showed that each received a different set of maternal/paternal alleles. This suggests genetic heterogeneity and warrants further molecular studies to determine the etiology of this syndrome.

Risk Management

Since this syndrome has only recently been described, clinical management is still evolving. As with Li-Fraumeni syndrome, screening for component tumors is unproven. The average survival of infants following diagnosis of malignant rhabdoid tumors with abnormalities of chromosome 22q11 is less then 6 weeks.^[265] Fewer than 25% of infants and young children with rhabdoid tumor of the kidney survive. ^{[262] [266] [267]}

Familial Gastric Cancer

Clinical Features

The International Gastric Linkage Consortium specifies criteria for a clinical diagnosis of familial diffuse gastric cancer. These criteria consist of either two or more documented cases of diffuse gastric cancer in first- or second-degree relatives, with at least one diagnosed before age 50, or three or more cases of diffuse gastric cancer in first- or second-degree relatives, independent of age of onset.^[268]

Genetics

Approximately 30% of familial diffuse gastric cancer kindreds have mutations in the E-cadherin (CDH1) gene.^[269] The lifetime penetrance of CDH1 mutations is estimated to be 70% to 80%.^[269]However, diffuse gastric cancer has been diagnosed in affected individuals as young as 14 years of age, and the majority of mutation carriers die younger than age 40. ^{[270] [271]} Clinical consensus is that individuals with diffuse gastric cancer who are younger than 35 years of age should be considered for CDH1 testing.^[271] Because of the early age of onset, similar to that of FAP, and the estimated 10% 5-year survival rate after diffuse gastric cancer diagnosis, individuals who are as young as 13 years and able to give informed consent or assent should be considered for genetic counseling.

Clinical Management

The management options are surveillance upper GI endoscopy or prophylactic gastrectomy. Gastrectomy has a significant effect on quality of life and should be undertaken only after extensive genetic counseling. The long-term morbidity that can result from gastrectomy includes weight loss, lactose intolerance, fat malabsorption and steatorrhea, dumping syndrome, bacterial overgrowth, postprandial fullness, and vitamin deficiencies. On the basis of the experience of Japan, which has population-based upper endoscopy screening programs to detect gastric cancer, early detection of gastric cancer can lead to 5-year survival rates greater than 90%.^[271] Therefore, upper endoscopy surveillance may be a viable approach to management. Clinical consensus is for a 30-minute endoscopy exam every 6 months by experienced practitioners.^[270] Because of the diffuse distribution of the lesions, chromoendoscopy may be more sensitive for early detection, and ultrasound is less likely to be effective. It is currently not well established whether any other sites develop cancer with increased frequency with CDH1 mutations, except for the elevated risk of lobular breast cancer. There are no clear guidelines for additional surveillance, though breast cancer screening 5 to 10 years younger than the earliest breast cancer in the family may be advisable. ^{[272] [273]}

Asian, African, and Caribbean families with Lynch syndrome generally have greater incidence of stomach cancer compared to kindreds from North America, South America, and Europe, where colorectal cancer predominates. ^{[274] [275] [276]} An important clue in this clinical presentation is the existence of both endometrial and stomach cancer in the same family. It has been speculated that the shift in the GI cancer susceptibility to a rostral-caudal axis has reflected changes in food preparation and content. In particular, the decreased use of smoked and cured meats resulting from refrigeration and the high fat content of the modern European-American diet have been proposed as important factors.^[276] The smoking process of meats can introduce heterocyclic amine byproducts, and the curing process involves nitrate salts that cause nitroso-compounds, which may act as potential mutagens. Epidemiologic and animal model studies provide evidence for this model. ^{[277] [278]} The first HNPCC family to be identified was described by a pathologist, Aldred Warthin, in 1913 in Europe and is referred to as Family G. ^{[276] [279]} In the early twentieth century, the GI tumors in Family G and other similar kindreds were distinguished largely by an excess of stomach adenocarcinoma.^[280] In the middle and late twentieth and early twenty-first centuries, the GI cancer susceptibility has shifted to include mostly colorectal cancers.

Hereditary Leiomyomatosis Renal Cell Cancer Syndrome

Clinical Features

The autosomal dominant, hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) predisposes to benign cutaneous and uterine leiomyomas (fibroids), uterine leiomyosarcomas, and papillary type II renal cell cancer or renal collecting duct carcinoma. ^{[281] [282] [283] [284]}

Kidney tumors in HLRCC are aggressive, often single, small lesions of high malignant potential. The age of onset of four cases of kidney cancer in one HLRCC kindred with 11 affected family members ranged from age 33 to 48 years, and all were diagnosed in females. ^{[281] [285]} A Finnish series of 98 HLRCC cases found a standardized incidence ratio of 6.5 for renal cell cancer and 71 for uterine leiomyosarcoma. In a separate series, renal cancer occurred in 62% of 21 patients with HLRCC, and 76% had cutaneous leiomyomas. Uterine leiomyomas occur in 90% to 100% of women with HLRCC.^[286] One series also reports adrenal gland adenoma and kidney cysts as well as breast and bladder carcinoma.^[287] However, a study of 85 breast cancer patients with a family history of HLRCC found no increased breast cancer risk, though a considerably larger sample size could be more informative.^[288] Cutaneous leiomyomas were present in 14 of 16 cases from five kindreds. They arise from the arrector pili, can be red or skin colored, can be evident as only a few to about 100 lesions, and are sensitive to touch and to cold temperature. Cutaneous lesions may be diffuse and symmetric or present in segmental bands along the lines of Blaschko. Of 11 females, 9 had uterine leiomyoma and 9 presented with cutaneous leiomyomas. ^{[289] [290]} Leiomyomas of the uterus resulted in hysterectomy by age 30 in over 44% of women with HLRCC.^[283]

Genetics

The gene that is responsible for hereditary leiomyomatosis and renal cell cancer on 1q42.3-q43 encodes fumarate hydratase (FH), a tricarboxylic acid/Krebs cycle, mitochondrial enzyme. Dominant mutations in fumarate hydratase cause HLRCC in a manner that is consistent with Knudsen's two-hit tumor suppressor model. Germline biallelic mutations in FH cause the mitochondrial encephalomyopathy, fumarate hydratase deficiency, and obligate carriers have presented with HLRCC. ^{[291] [292] [293] [294]} Mutations in the fumarate hydratase gene are detected in about 75% to 100% of patients with multiple cutaneous and uterine leiomyomatosis. ^{[282] [284] [286]} One mutation, R190H, was detected in 11 of 31 unrelated, North American HLRCC kindreds, and the mutation R58X has also been identified in multiple unrelated kindreds.^[286] Additionally, a mutation, 905-1G>A, was found in four Iranian HLRCC kindreds, possibly representing a founder mutation in this population.^[295]Reduced FH activity in lymphoblastoid and fibroblast cells of HLRCC patients may facilitate confirmation of clinical diagnosis via enzymatic testing.^[296]

Although the molecular mechanisms underlying HLRCC have yet to be fully characterized, glycolysis dependence appears to be a contributing factor.^[297] The genes HIF-1α and HIF-2a target GLUT1, all of which are elevated in HLRCC tumors. This pathway is being explored for chemotherapeutic intervention, including the agent bevacizumab, as are Hsp90 inhibitors. NAD(P)H dehydrogenase quinone 1-mediated 17-AAG antitumor activity is also under exploration in treating HLRCC related cancers.^[283]

Clinical Management

Screening at regular intervals for renal lesions utilizing CT with contrast is indicated in patients with fumarate hydratase mutations. MRI is recommended for uterine leiomyoma screening, and ultrasound can also be utilized.^[298]

Chemodectoma and Paraganglionoma Syndromes

Clinical Features

Chemodectomas are also known as glomus tumors or paragangliomas of the head and neck. These tumors are formed from neuroectodermal and mesodermal origins and most frequently are observed in the carotid, aortic, jugular, or vagal bodies. Of 30 cases reviewed in one series, about half were bilateral, with a family history of chemodectoma in about one third of these cases. ^{[299] [300]} Most of the familial cases presented with multiple tumors. The remarkable feature about hereditary chemodectomas is the evidence of imprinting; children of affected fathers develop chemodectomas, but the children of affected mothers do not.^[301]

Genetics

In paraganglioma syndromes, mitochondrial succinate dehydrogenase gene complex (SDH-A, -B, -C, and -D) has been implicated, given the oxygen sensor function of the carotid body, a common site for chemodectomas.^[302] Mutations in SDH-D exhibit autosomal dominant inheritance, with an imprinting mechanism,^[302] whereas SDH-B and SDH-C mutations do not appear to be imprinting genes. Although maternally derived SDH-D cases have been reported, further analysis revealed that a paternal mutation on an 11p15.5 allele was also necessary to result in paraganglioma.^[303] SDH-D mutations give rise to more frequent head and neck tumors, whereas SDH-B mutations exhibit a greater propensity for malignancy and also are associated with renal cell cancers.^[304]

Of 271 paraganglioma and/or pheochromocytoma patients with no family history, germline mutations were identified in 66 patients (24%), with SDH-D and SDH-B mutations accounting for 23 cases. Of the remaining 43 germline mutation cases, 30 were attributed to von Hippel Lindau syndrome mutations, and 13 were caused by mutations in the RET gene.^[305] Given the high frequency of germline mutations in paraganglioma cases, diagnosis should prompt consideration of genetic testing to be offered to these patients.^[306]

Clinical Management

Treatment for paraganglioma is surgical. Minimal morbidity occurs with small tumors, but once the size is greater than 5 cm, cranial nerve loss and baroreceptor failure may be postoperative sequelae. Screening for pheochromocytoma is by serum and/or urinary metanephrines. Screening for renal cancers is unproven, but abdominal/pelvic imaging seems reasonable.

OTHER FAMILIAL NEOPLASMS

Familial aggregations of individuals affected by Wilms’ tumors, leukemias, lymphomas, gastric cancer, testicular cancer, and lung cancer as well as other malignancies have been described. A group of autosomal recessive disorders, including Bloom syndrome, Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, are associated with an increased susceptibility to a variety of neoplasms. A number of additional hereditary syndromes are characterized by both nonmalignant (congenital) features as well as a predisposition to cancer.^[1] With the identification of genes associated with many of these syndromes, presymptomatic testing and counseling will be available.

The highly penetrant susceptibility alleles associated with the syndromes reviewed in this chapter account for a minority of human cancers. Nonetheless, the number of molecularly characterized highly penetrant cancer syndromes continues to grow. A larger proportion of human cancers may be associated with genetic polymorphisms that confer a lesser cancer risk. It was predicted on the basis of the Utah genealogies^[307] that inherited susceptibility to environmental carcinogens would emerge as a major focus for the next era of research in oncogenetics. Recent completion of whole-genome association studies for breast cancer, ^{[37] [38]} prostate cancer, ^{[161] [162]} and other common malignancies have begun to lay the foundation for genomic approaches to low-penetrance cancer predisposition. Integrating these new markers of significant but lesser cancer risk into clinical practice looms as the next challenge in preventive oncology.

ACKNOWLEDGMENTS

The authors are indebted to Colleen-Anne Campbell, who assisted in research and referencing of recently described cancer predisposition syndromes.

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