Julie Nangia, Annie Su, and Sarah Zentack
Clinical genetics is the specialty that involves the diagnosis and management of hereditary disorders. As an oncologist, recognition of these syndromes is critical in order to provide proper care related to cancer therapy decisions, to increase screening that could detect cancer at early stages (which are more often cured), to identify unaffected family members, and to offer chemoprevention or risk-reducing prophylactic surgeries if indicated. Features of hereditary cancer include the following in an individual patient: multiple primary tumors in the same or different organs, bilateral primary tumors in paired organs, multifocal cancer within a single organ, younger-than-usual age at diagnosis, tumors with rare histology, tumors occurring in the sex not usually affected (i.e., breast cancer in men), and a constellation of tumors associated with a known genetic syndrome.
If a hereditary cancer syndrome is suspected (Table 45.1), a focused exam specific to the syndrome should be done (i.e., dermatologic and head circumference for Cowden syndrome) and genetic counseling with an expanded pedigree detailing the types of cancer, bilaterality, age at diagnosis, and medical record documentation as needed (i.e., pathology reports of primary cancers or carcinogen exposure) should be offered to the patient. Prior to genetic testing, patients must give informed consent with an understanding of the benefits, risks, and limitations of testing as well as the goals for cancer family risk assessment. Options exist for family planning including prenatal diagnosis and assisted reproduction. Patients should be made aware of the Genetic Information Nondiscrimination Act of 2008 (GINA), which prohibits the use of genetic information in health insurance and employment but unfortunately does not apply to life insurance coverage.
In this chapter we will review the most commonly seen and tested hereditary cancer syndromes in adults.
HEREDITARY BREAST CANCER SYNDROMES
Hereditary Breast and Ovarian Cancer Syndrome
Hereditary breast cancer accounts for 5% to 10% of all breast cancers. The most common hereditary breast cancer syndrome involves mutations in the BRCA1/2 genes, tumor suppressor genes that play a role in DNA repair. These mutations account for 65% of hereditary breast cancer and have an autosomal dominant pattern of inheritance. The incidence is 1 in 700 for the general population and 1 in 40 in the Ashkenazi Jewish population.
Mutations in these genes are associated with a very high risk of both breast cancer (up to 87%) and ovarian cancer (up to 44%). The BRCA1 gene is associated with triple-negative breast cancer histology and both genes are associated with ovarian cancer of epithelial origin, often serous histology. Other cancers such as pancreatic cancer, prostate cancer, and melanoma can also be seen, particularly in patients with BRCA2 gene mutations. BRCA1/2testing is recommended in individuals:
■From a family with a known deleterious BRCA1/2 mutation
■With a personal history of breast cancer and one of the following:
•Diagnosed below the age of 45
•Diagnosed below the age of 50 with 1 or more close blood relative with breast cancer younger than 50 and/or 1 or more blood relative with epithelial ovarian cancer at any age
•Two breast primaries when the first breast cancer diagnosis occurred at less than 50 years of age
•Diagnosed below the age of 60 with triple-negative breast cancer
•Diagnosed below the age of 50 with limited family history
•Diagnosed at any age with 2 or more close blood relatives (first-, second-, or third-degree relatives) with breast and/or epithelial ovarian cancer at any age
•Diagnosed at any age with two or more close blood relatives with pancreatic cancer at any age
•Close male blood relative with breast cancer
•Individuals of ethnicity associated with higher mutation frequency (i.e., Ashkenazi Jewish)
■With a personal history of epithelial ovarian cancer
■With a personal history of male breast cancer
■With a personal history of pancreatic cancer at any age with two or more close blood relatives with breast and/or ovarian and/or pancreatic cancer at any age
Testing of unaffected individuals should only be considered when no affected family member is available and family history reveals a first- or second-degree relative meeting the above criteria. In this circumstance, the significant limitations of interpreting results should be discussed since a negative test result in an unaffected individual can be uninformative. Testing consists of full sequencing of the BRCA1/2 genes as well as BART testing (BRCA analysis rearrangement test), which identifies large genomic rearrangements not picked up by routine sequencing.
If a BRCA mutation is found, the following recommendations should be implemented for women: breast self-examination training and education starting at age 18, clinical breast examination every 6 to 12 months starting at age 25, and annual mammography and MRI screening starting at age 25 or individualized based on earliest age of onset in the family. The addition of breast MRI to mammography increased the rate of breast cancer detection from 45% to 95% in one study, and most cancers were detected at stage 0 or 1. Prophylactic mastectomy can reduce the risk of breast cancer by 90% to 100%, and in those who decline surgery, chemoprevention with tamoxifen or raloxifene has been shown to reduce the risk of breast cancer by at least 50% and is a reasonable alternative along with close monitoring. Given the elevated risk for ovarian cancer and the lack of effective screening, risk-reducing salphingo-oopherectomy (RRSO) is recommended between the ages of 35 to 40, or upon completion of childbearing. Until then, a CA125 level and a transvaginal ultrasound should be considered every 6 months starting at age 30 or 5 to 10 years prior to the earliest age of diagnosis of ovarian cancer in the family.
For men, the risk of breast cancer is 2% to 8% and is usually seen after age 50. Breast self-examinations should start at the age of 35 and baseline mammography can be considered at the age of 40 and continued only if gynecomastia or parenchymal/glandular breast density is present. Chemoprevention and prophylactic mastectomies are not offered to men because the incidence of breast cancer is not nearly as high as in women. Male carriers also have a higher risk for both prostate and pancreatic cancer than the general population. Prostate cancer screening should start at age 40 with a baseline digital rectal examination (DRE) and PSA level and repeated per the NCCN guidelines which can be reviewed separately.
For both men and women, annual skin examinations are recommended given the increased risk of melanoma, and the general population screening guidelines for colon cancer prevention should be followed. For pancreatic cancer prevention, alcohol and tobacco use should be avoided. Screening can be offered to individuals with a strong family history with either EUS or MRI every 1 to 3 years and an annual CA 19-9 level. Studies looking at pancreatic cancer screening are limited and the utility of screening is not completely known.
Cowden Syndrome
Cowden syndrome is an autosomal dominant syndrome with an incidence of 1 in 200,000. It is caused by a loss of function in the tumor suppressor PTEN gene and is associated with multiple hamartomas in a variety of tissues, characteristic dermatologic manifestations, and an increased risk of breast, endometrial, thyroid, kidney, melanoma, and colorectal cancers. The lifetime risk of breast cancer is 25% to 50%, although it may be as high as 85%. Thyroid cancer develops in two-third of carriers and can occur in childhood. Pathology is usually follicular, rarely papillary, and never medullary. Renal cell carcinoma (RCC) can be seen in 13% to 34% of carriers. The prevalence of colon polyps is 66% to 93% and they are usually hamartomatous or inflammatory polyps with a lifetime risk of 16% for colon cancer. Neurologic manifestations include dysplastic gangliocytoma of the cerebellar cortex, macrocephaly, and mental retardation/developmental delay/autism. Women commonly have benign abnormalities such as breast hamartomas, uterine fibroids, and ovarian cysts. Men often have lipomatosis of the testes seen as hyperechoic lesions on testicular ultrasound. Both men and women frequently have benign thyroid lesions, such as adenomas and multinodular goiter. Benign esophageal acanthosis can also be seen.
The diagnostic criteria are divided into pathognomic criteria, major criteria, and minor criteria. The pathognomic criteria include mucocutaneous lesions such as facial trichilemmomas (skin tags), acral keratoses (thickened area of skin that may be red, yellow, or brown), or pappilomatous oral lesions (small wart-like growths). The major criteria include breast cancer, thyroid cancer, macrocephaly, endometrial cancer, and dysplastic gangliocytoma of the cerebellar cortex. The minor criteria include benign structural thyroid disease, mental retardation, hamartomatous gastrointestinal (GI) tract polyps, benign cystic breast disease, lipomas or fibromas, and genitourinary tract tumors. Both the NCCN and the International Consortium Cowden Consortium have criteria for testing high-risk individuals and guidelines for the care of carriers. In the absence of family history, Cowden syndrome is diagnosed if any of the following are present: six or more facial papules including at least three trichilemmomas, facial papules and oral pappilomatous, oral pappilomatous and acral keratoses, or six of more acral keratoses on the hands and feet. One major and three minor or four minor criteria are also considered diagnostic. If there is a family history of Cowden syndrome, then one pathognomonic, one major, or two minor criteria are diagnostic. Only 20% to 34% of individuals who meet these criteria have germline PTENmutations. PTEN testing includes sequencing of the entire coding region and deletion/duplication analysis. Mutations have also been reported in the PTEN promoter region and in other genes including succinate dehydrogenase (SDH) subunits B and D.
The management guidelines for women with Cowden syndrome include breast self-examination training and education starting at age 18, clinical breast examination every 6 to 12 months starting at age 25, and annual mammography and MRI screening starting at age 25 or individualized based on earliest age of onset in family. There are no specific guidelines for endometrial cancer screening and carriers should be educated and followed closely, with a prompt response to symptoms. Risk-reducing mastectomies and hysterectomy can be considered. Men and women should have an annual physical examination starting at age 18 or 5 years prior to the youngest age of diagnosis of cancer in their family with emphasis on the breast and thyroid examination. Baseline thyroid ultrasound should be done at age 18 and annually after that. Screening colonoscopies starting at age 35, annual dermatologic examinations, and education about the signs and symptoms of cancer can be considered.
Li–Fraumeni Syndrome
Li–Fraumeni syndrome (LFS) is a hereditary syndrome associated with a wide range of cancers that appear at an unusually young age. It has an autosomal dominant pattern of inheritance and is associated with mutations in the p53tumor suppressor gene, which plays a major role in DNA repair. The absence of this gene allows for the survival and proliferation of cells with damaged DNA. The lifetime risk of cancer is nearly 100%, with 90% of individuals diagnosed with cancer by age 60. The classic tumors seen in this syndrome are sarcoma, breast cancer, leukemia, brain tumors, and adrenal gland cancers.
Classic Li–Fraumeni criteria include a proband with sarcoma before the age of 45, a first-degree relative with cancer before the age of 45, and a first- or second-degree relative with cancer before the age of 45 or sarcoma at any age. Chompret criteria include one of the following:
■A proband who has a tumor belonging to the LFS spectrum (sarcoma, premenopausal breast cancer, brain tumor, adrenocorticoid tumor, leukemia, or lung bronchoalveloar cancer) before age 46 and at least one first- or second-degree relative with a tumor in the LFS spectrum before age 56 or with multiple tumors.
■A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS spectrum and the first of which occurred before age 46.
■A proband who is diagnosed with adrenocortical tumor or choroid plexus tumor regardless of age irrespective of family history.
Testing of individuals who meet either of these criteria or women with breast cancer before age 35 who have tested negative for the BRCA1/2 mutations is recommended.
The management guidelines for women with LFS include breast self-examination training and education starting at age 18, clinical breast examination every 6 to 12 months starting at age 25, and annual mammography and MRI screening starting at age 25 or individualized based on earliest age of onset in family. All carriers should have an annual physical examination including skin and neurologic examinations. Radiation therapy should be avoided if possible (i.e., mastectomy instead of lumpectomy for breast cancer) due to the increased risk of radiation-induced malignancies. Colonoscopy screening should start no later than age 25. Other options for screening should be discussed with the patient such as whole-body MRI, abdominal ultrasound, and brain MRI. Targeted surveillance should be based on family history.
HEREDITARY GI SYNDROMES
Lynch Syndrome
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant disorder characterized by germline mutations in DNA mismatch repair (MMR) genes. The absence of these genes results in a significantly increased risk of cancer formation of up to 80%, with the most common carcinomas located in the colon, rectum, and uterus.
Lynch syndrome accounts for 2% to 3% of all colon cancers with a lifetime risk of up to 70%. Compared to those with sporadic colon cancer, HNPCC patients are usually younger in age (45 vs. 65 years old) and have more poorly differentiated, mucinous tumors found in the right colon. Despite these more aggressive histologic features, affected patients have better 5-year survival rates compared to those with common sporadic colorectal cancer, likely due to the lower risk of metastases. Though uncommon, a small subset (10%) of HNPCC patients will have synchronous (two primary tumors) or metachronous (second tumor developing at least 6 months after the first) cancers.
Endometrial carcinoma is the most common extracolonic tumor in Lynch syndrome, accounting for about 2% of all uterine cancer and with a reported incidence as high as 70% in female carriers. Similar to colon cancer in Lynch syndrome, women are typically younger in age at diagnosis (50 vs. 60 years old). Other sites at increased risk of cancer development include the ovaries, stomach, small bowel, pancreas, hepatobiliary system, upper urinary tract (renal pelvis and ureter), skin, and brain. The chances of developing cancer in these various organs vary depending on which gene is mutated, but the incidence can be as high as 20%.
Defects in the MMR system, which identifies base-pair mismatches and repairs them, is the hallmark characteristic of Lynch syndrome. The MMR genes affected in Lynch syndrome include MLH1, MSH2, MSH6, and PMS2. A germline deletion in EPCAM, which is not a MMR gene, inactivates MSH2 and also causes Lynch syndrome. In Lynch syndrome, a germline mutation results in a defective allele and is passed from parent to offspring. When the second copy is inactivated through one of several mechanisms (acquired somatic mutation, loss of heterozygosity, promoter hypermethylation), a defective MMR system ensues, resulting in a failure to repair DNA mismatches and an increased rate of mutations (genomic instability). DNA mismatches tend to occur in areas of repeated nucleotide sequences called microsatellites. An accumulation of mutations in these regions leads to expansion or contraction of the microsatellites, termed microsatellite instability. This addition or deletion of nucleotides leads to a change in the DNA reading frame during RNA synthesis, eventually resulting in the substitution of different amino acids into the end protein product or early termination of protein synthesis. Carcinogenesis occurs when a cancer-related gene or protein (i.e., one that regulates cell growth or apoptosis) is affected by these frameshift mutations.
Germline mutations in one of the four MMR genes or EPCAM can lead to the development of Lynch syndrome, although the clinical picture varies depending on which gene is affected. The most common mutations involve MLH1and MSH2. Both genes result in a markedly increased risk of colorectal carcinoma (up to 70%); however in some studies, the risk of extracolonic cancers including endometrial carcinoma is higher in families with MSH2 mutations. Patients with MSH6 mutations have a lower risk and a later age of onset of colorectal cancer as well as a higher risk of endometrial cancer compared to those with MLH1 and MSH2 mutations. Families with PMS2 mutations have an even more attenuated phenotype with a lower overall cancer risk. Biallelic inheritance of mutations in one of these MMR genes causes constitutional mismatch repair-deficiency syndrome (CMMRD) and is associated with the development of Lynch syndrome-associated cancers, as well as childhood cancers, hematologic malignancies, brain tumors, early-onset colorectal cancers, and neurofibromatosis features such as café-au-lait spots.
Patients suspected to have Lynch syndrome can be screened through the detection of either microsatellite instability by polymerase chain reaction (PCR) or the absence of the MMR protein product by immunohistochemistry (IHC). PCR detects microsatellite instability by identifying expansion or contraction of the microsatellite regions. If 30% or more of the markers show instability, then the tumor is considered to have high levels of microsatellite instability (i.e., MSI-H or microsatellite unstable), suggesting a defect in a DNA MMR gene. Patients with low levels of microsatellite instability (i.e., MSI-L or microsatellite stable) are unlikely to carry this genetic defect. IHC uses antibodies to detect MMR proteins. These antibodies specifically recognize the C-terminal end of the MMR protein. The loss of this epitope due to mutations in the MMR gene causing either a truncated or lost protein product results in a negative test. Unlike PCR, IHC has the advantage of identifying the missing protein product, and by proxy, which gene is affected. Confirmation of Lynch syndrome requires germline testing for the MMR gene mutation as guided by the results of IHC.
Microsatellite instability is sensitive but not specific for Lynch syndrome. MSI-H can be found in up to 15% of sporadic colorectal cancers, most commonly due to the loss of MLH1 via epigenetic silencing from hypermethylation of the MLH1 promoter region. Acquired loss of MLH1 can be differentiated from germline mutations of MLH1 as seen in Lynch syndrome through the presence of BRAF mutations. For unknown reasons, BRAF mutations are almost universally present in sporadic colorectal cancers but rarely seen in Lynch syndrome. In patients who have microsatellite unstable colorectal tumors with loss of MLH1 on IHC, testing for BRAF mutations or MLH1 methylation should be done to rule out sporadic cases. If these tests are negative, then patients should be offered germline testing. The loss of other MMR genes in colorectal cancer, primarily MSH2 and MSH6, is more specific for Lynch syndrome and these patients should proceed directly to MMR gene testing and genetic counseling.
Identifying patients who are at high risk for having Lynch syndrome remains a challenging task. The Amsterdam criteria and the Bethesda guidelines were created to help identify families at risk; however, the Amsterdam criteria lack sensitivity and both lack specificity. As many as 50% of families who meet the Amsterdam criteria, and 80% of patients meeting the Bethesda guidelines, do not have Lynch syndrome. Nonetheless, families meeting these criteria should be offered genetic counseling, and testing should be done on the youngest living member with colorectal cancer.
Amsterdam criteria—3–2–1 rule (three affected members, two generations, one under age 50)
■Three or more relatives with an HNPCC-associated cancer, one of whom is a first-degree relative of the other two and in whom FAP has been excluded
■Two affected generations
■One or more HNPCC-associated cancer diagnosed before the age of 50
Bethesda guidelines
■Colorectal cancer in a patient younger than 50 years
■Colorectal cancer with MSI-H histology in a patient younger than 60 years
■Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age
■A patient with colorectal cancer who has one or more first-degree relatives with an HNPCC-associated tumor, with one of the cancers diagnosed under the age of 50
■A patient with colorectal cancer who has two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age
Colorectal cancer surveillance with colonoscopies should begin at the age of 20 to 25. Screening for endometrial cancer with endometrial biopsy and ovarian cancer with transvaginal ultrasound and a CA125 level should begin at the age of 30 to 35 years, or 10 years prior to the earliest age of cancer diagnosis in the family, whichever comes first. Controversy exists surrounding the screening of other extracolonic cancers and no firm recommendations have been established except for annual skin surveillance. Primary prophylactic colectomy is generally not recommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered in high-risk patients who are 35 years or older or have finished childbearing.
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by the presence of numerous colorectal adenomatous polyps (typically more than 100), caused by germline mutations in the tumor suppressor adenomatous polyposis coli (APC) gene located on chromosome 5. FAP has a number of associated extracolonic carcinomas, but unlike colorectal cancer which has near complete penetrance, the penetrance for extracolonic tumors is variable.
FAP accounts for less than 1% of all colorectal cancer diagnosed in the United States. Seventy-five percent of FAP cases are due to inherited germline mutations of the APC gene, whereas 25% of patients acquire new or de novo mutations and have no family history of FAP. Inactivating mutations of both copies of the APC gene is required for the development of adenomas and, subsequently, carcinoma. In normal circumstances, APC is involved in the phosphorylation of β-catenin resulting in its degradation by proteolysis. In the absence of APC, β-catenin accumulates within the cell and activates several genes involved in cell growth and division.
Two variants of FAP have been described—classic FAP and attenuated FAP (AFAP). Patients with classic FAP typically have more than 100 adenomatous polyps, often 1,000s, with a nearly 100% risk of developing colorectal carcinoma if left untreated. On the other hand, AFAP patients have fewer adenomas (between 10 and 100) and present at a later age (44 vs. 16 years of age) than those with the classic phenotype. A lower yet still significant risk of colorectal cancer development is seen (up to 80%) with a later age of cancer diagnosis (56 vs. 40 years of age) and a predilection for the right colon (up to 75%).
Although FAP is more infamously known for its risk of colorectal cancer, patients also have an elevated risk of developing extracolonic polyps as well. These polyps can be found in the gastric fundus (i.e., body of the stomach), gastric antrum, duodenum, periampullary region, gallbladder, bile duct, and the small bowel. Risk of cancer progression depends on the location of the polyps, with the highest risk seen in the duodenum and periampullary region.
Extraintestinal manifestations, both malignant and benign, are also seen in families with FAP. Malignant extraintestinal tumors are rare (1% to 3% lifetime risk) and include follicular or papillary thyroid cancer, childhood hepatoblastoma, and central nervous system (CNS) tumors. Benign findings include desmoid tumors, sebaceous or epidermoid cysts, lipomas, osteomas, fibromas, dental abnormalities, adrenal adenomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE). Turcot syndrome refers to the association of familial colon cancer with CNS tumors, primarily medulloblastomas in FAP and gliomas in Lynch syndrome. No single gene mutation is characteristic of Turcot syndrome. Gardner syndrome refers to families with FAP who also have osteomas and soft tissue tumors. The APCgene is the same culprit in both Gardner syndrome and FAP.
FAP should be suspected in any patient with 10 or more colorectal adenomas, and genetic counseling and testing for germline mutation of the APC gene should be offered to these patients as well as all first-degree relatives of affected patients. Commercial genetic testing detects most mutations in the APC gene. A negative test in the setting of high clinical suspicion does not rule out the diagnosis as there are other genes that can cause polyposis and all at-risk patients should undergo surveillance regardless of the results. Testing for MUTYH-associated polyposis which is a recessive syndrome caused by mutation in the MUTYH gene should also be considered in those who test negative for a mutation in the APC gene.
Surveillance of the colon involves either flexible sigmoidoscopy or full colonoscopy depending on the FAP subtype. Patients with classic FAP typically have rectosigmoid involvement; therefore, flexible sigmoidoscopy alone should be sufficient. AFAP patients, on the other hand, more commonly develop tumors in the right colon and should proceed directly to full colonoscopies. Screening should start no earlier than age 10 in families with classic FAP and age 20 to 25 with attenuated phenotypes given the later age of initial polyp presentation and cancer diagnosis. Patients found to have profuse polyposis, multiple large (>1 cm) adenomas, or adenomas with villous histology or high-grade dysplasia should be treated with colectomy followed by routine surveillance of the ileal pouch. AFAP patients with less disease burden can undergo polypectomy followed by continued annual surveillance. Screening for extracolonic cancers remains controversial. No consensus guidelines have been firmly established and data has yet to show a clear benefit for routine surveillance.
Hereditary Diffuse Gastric Cancer
Hereditary diffuse gastric cancer is an autosomal dominant disorder caused by germline mutations in the CDH1 gene that codes for E-cadherin, a cell-adhesion protein that allows cells to interact with each other and is critical for cell development, differentiation, and architecture. Individuals who harbor these germline mutations have a greater than 80% lifetime risk of developing diffuse gastric cancer by age 80 with a median age of onset of 38. These gastric cancers form beneath an intact mucosal surface, causing gastric wall thickening rather than the formation of a discrete mass. Because they are only visible late in the disease process, early detection is extremely challenging. Therefore, screening of high-risk individuals should begin at the age of 16 to 18, and in those who are found to be carriers, prophylactic gastrectomy is recommended after the age of 20.
Like diffuse gastric cancer, the absence of E-cadherin expression is also the key underlying defect in lobular breast carcinoma. Female carriers therefore have a 60% lifetime risk of developing lobular breast carcinoma by age 80. Optimal breast cancer screening has not been clearly established.
The International Gastric Cancer Linkage Consortium (IGCLC) clinical criteria are as follows:
■Two cases of gastric cancer in first-degree relatives, with one confirmed diffuse gastric cancer case diagnosed before the age of 50
■Three confirmed diffuse gastric cancer cases in first- or second-degree relatives, independent of age
■Diffuse gastric cancer before the age of 40 years without a family history
■Families with both diffuse gastric cancer and lobular breast cancer, with one diagnosed before the age of 50 years
Peutz–Jeghers Syndrome
Peutz–Jeghers syndrome (PJS) is a rare, autosomal dominant disorder characterized by multiple GI hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of malignancies. Diagnosis is made clinically but the detection of STK11 gene mutations can help solidify the diagnosis. A negative genetic test however does not exclude the diagnosis since up to 20% of patients with a clinical diagnosis of PJS do not have identifiable mutations. Diagnosis requires any one of the following:
■Two or more histologically confirmed PJ polyps
■PJ polyps and a family history of PJS
■Characteristic mucocutaneous pigmentation and a family history of PJS
■PJ polyps in an individual with characteristic mucocutaneous pigmentation
Skin lesions seen in PJS resemble freckles. They are small (1 to 5 mm in size), flat, blue-gray to brown spots, and are commonly found around the mouth and nose, in the buccal mucosa, hands and feet, perianal areas and genitals. Malignant transformation is rare. GI polyps frequently occur in the small intestine, colon/rectum, and stomach. They can be found as early as the first decade of life but cause problems later, between the ages of 10 and 30. About half of PJS patients present with obstruction from intussusception, abdominal pain, and bleeding, while the other half are asymptomatic and diagnosed based on family history. Malignancies are also commonly seen in PJS and affected patients carry up to an 80% to 90% lifetime risk of developing cancer. The most common malignancies occur in the colon and rectum, but an increased risk is also seen in the breast, stomach, small bowel, pancreas, lung, cervix, ovaries, and testicles.
OTHER GENETIC SYNDROMES
Von Hippel–Lindau Disease
Von Hippel–Lindau disease is an autosomal dominant disorder involving germline mutations of the VHL gene found on chromosome 3. A variety of benign and malignant conditions are associated with VHL disease, including hemangioblastomas of the CNS (cerebellum and spine) and retina, clear cell RCCs, pheochromocytomas, pancreatic cysts and neuroendocrine tumors, endolymphatic sac tumors of the middle ear, and epididymal and broad ligament cysts. Unlike sporadic cases, VHL-associated tumors tend to occur in younger patients (mean age of initial presentation of 26 years) and are more often multifocal and bilateral in nature. Diagnosis of VHL disease is based on the detection of germline mutations in the VHL gene in patients with one or more VHL-associated tumors.
Multiple Endocrine Neoplasia 1 and 2
Multiple endocrine neoplasia (MEN) syndromes are rare with an incidence of 1 in 30,000. MEN1 occurs when tumors are found in two of the three main endocrine glands (parathyroid, pituitary, and pacreatico-duodenum). Nearly 100% of individuals with MEN1 will have primary hyperparathyroidism by age 50, 10% to 20% will have pituitary tumors (prolactinoma, growth hormone-secreting, corticotrophin-secreting, or nonhormone secreting), and 60% to 70% will have pancreatic or extrapancreatic tumors (gastrinoma, insulinoma, vasoactive-intestinal polypeptide-secreting, glucagonoma, pancreatic polypeptide-secreting, or nonhormone secreting).
MEN2 is subdivided into three distinct subtypes: MEN2A, MEN2B, and familial medullary thyroid cancer. The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10. MEN2A is characterized by >90% of individuals having medullary thyroid cancer, 40% to 50% with pheochromocytoma, 10% to 20% with parathyroid hyperplasia, and cutaneous lichen amyloidosis. MEN2B is characterized by medullary thyroid cancer, pheochromocytomas, and other features such as mucosal neuromas, intestinal ganglioneuromas, and marfanois habitus. There is also a variant of MEN2A characterized by familial medullary thyroid cancer. DNA testing for the MEN1 and RET genes is available commercially.
Hereditary Pheochromocytoma/Paraganglioma Syndrome
Pheochromocytomas and paragangliomas are a component of an inherited syndrome in 10% to 50% of cases. Tumors are commonly seen in the head and neck region but can be seen in the thorax, abdomen/pelvis, or urinary bladder. They are often associated with mutations in the SDH subunits (D, B, and C have all been described). Individuals diagnosed with a pheochromocytoma or paraganglioma should be evaluated for a hereditary syndrome.
Dermatologic Syndromes
Approximately 10% of melanomas are hereditary and can be linked to several genes, most commonly the p16 gene. Genetic testing should be considered in individuals with melanoma who have a family history of melanoma and/or pancreatic cancer, multiple primary melanomas, and young age at diagnosis.
Nevoid basal cell carcinoma syndrome (NBCCS) also known as Gorlin syndrome is a rare multisystem disorder due to mutations in the PTCH gene with an incidence of 1 in 57,000 to 164,000 and autosomal dominant pattern of inheritance. Affected individuals have multiple developmental abnormalities, early onset of multiple nevoid basal cell carcinomas (BCC), and a variety of other cysts and tumors including medulloblastomas by age 35. Radiation should be avoided in these individuals as it can induce the formation of several aggressive BCCs.
Renal Syndromes
There are several hereditary RCC syndromes. Hereditary leiomyomatosis has an autosomal dominant pattern of inheritance and is caused by mutations in the fumarate hydratase (FH) gene; it is associated with both cutaneous and uterine leiomyomatosis and papillary type 2 RCC. Birt Hogg Dube syndrome has an autosomal dominant pattern of inheritance and is caused by mutations in the folliculin gene (FLCN); it is associated with the development of RCC, pulmonary cysts often causing pneumothorax, and skin lesions such as fibrofolliculomas. Familial papillary renal cancer has an autosomal dominant pattern of inheritance caused by mutations in the MET gene and is associated with the development of type 1 papillary RCC which are often multifocal or bilateral.
Fanconi Anemia
Fanconi anemia (FA) is an autosomal recessive disorder with an incidence of 1 in 350,000 characterized by congenital abnormalities (café-au-lait spots, short stature, abnormality of thumbs, microcephaly or hydrocephaly, hypogonadism and developmental delay), progressive bone marrow failure, and an increased incidence of malignancies. Patients are usually diagnosed in childhood, but it is important to recognize the syndrome in adults who present with solid malignancies since this would affect therapy decisions (i.e., avoiding radiation and chemotherapy if possible).
REVIEW QUESTIONS
1.A 28-year-old woman is diagnosed with a small triple-negative breast cancer. There is no family history of breast cancer. Her father was an only child and is healthy. What genetic testing do you recommend initially?
A.None—there is not family history of cancer
B.BRCA1/2 sequencing including BART
C.p53 testing
D.PTEN testing
E.STK11 testing
2.Which of the following is NOT in the Chompert tumor spectrum for LFS?
A.Breast cancer
B.Sarcoma
C.Leukemia
D.Colon cancer
E.Brain tumors
3.Which of the following cancers is NOT seen with Cowden syndrome?
A.Breast
B.Lung cancer
C.Endometrial
D.Thyroid
E.Kidney
4.A 45-year-old male comes to you for a second opinion. He was diagnosed with colon cancer a month ago after presenting with fatigue, dyspnea on exertion, and right upper quadrant abdominal pain. Colonoscopy revealed a large nonobstructing tumor at the hepatic flexure and biopsy showed a poorly differentiated, mucinous-producing colon adenocarcinoma. Staging studies showed local extension into the liver capsule but no intrahepatic lesions or widespread metastatic disease was seen. His family history is significant for a mother diagnosed with uterine carcinoma at the age of 47, a maternal aunt with ovarian cancer diagnosed in her 50s, and her daughter who was recently found to have a brain tumor. His maternal grandfather died when the patient was very young from what he thinks was either stomach or pancreatic cancer. What gene mutation does this patient likely harbor?
A.Germline mutation of the APC gene on chromosome 5
B.Somatic mutation of the CDH1 gene and subsequent loss of E-cadherin
C.Germline mutation of MSH2
D.Germline STK11 gene mutation
5.A surgeon refers a 30-year-old patient to you for preoperative clearance. The patient was found to have a hemangioblastoma of the cervical spine causing progressively worsening radiculopathy and weakness of her right arm. She has hypertension for which she takes amlodipine and family history is significant for kidney cancer and a “slow-growing” tumor in the pancreas on her father’s side. Before the patient undergoes surgery to resect the hemangioblastoma, what condition must be ruled out first?
A.Metastatic breast cancer with leptomeningeal spread
B.Pheochromocytoma
C.Malignant melanoma
D.Pancreatic adenocarcinoma with liver metastases
Suggested Readings
1.GeneReview. http://www.ncbi.nlm.nih.gov/books/NBK1116/
2.National Center for Biotechnology Information. Gene Tests. http://www.ncbi.nlm.nih.gov/sites/GeneTests
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