The Washington Manual of Oncology, 3 Ed.

Genetic Counseling in Oncology

Jennifer Ivanovich

Cancer genetic counseling and risk assessment is the process of identifying and educating individuals and their families who are at increased risk for developing cancer due to their family’s cancer history. Cancer genetic counseling addresses the psychosocial issues associated with hereditary disease and identifies mechanisms for adaptation and personal control (Cancer Genetics Risk Assessment and Counseling (PDQ). www.cancer.gov, 2014; Am J Med Genet C Semin Med Genet 2006;142C:269; J Genet Counsel 2012;21:151; J Genet Counsel 2006;15:77).

A genetic counselor is a health-care provider who is specifically trained in clinical genetics, communication, and family-based risk. While the Master’s level training is directed at the study of general clinical genetics, many genetic counselors have chosen to specialize in cancer genetics. In most settings, genetic counselors work with clinical geneticists, physicians boarded in clinical genetics. However, as the discipline of cancer genetics continues to expand, many genetic counselors now work independently with medical and surgical oncologists.

The intended goal of the cancer genetic counseling process is to educate individuals about their family’s cancer risk in a manner that is useful to them and utilize this information to guide medical care that is reflective of this risk (Fig. 43-1). This objective remains with or without the use of cancer genetic testing. Ideally, the process of assisting a family extends over several years, as new research discoveries transition to clinical care, the family history changes, or family members in the next generation approach an age when medical management will be altered (JAMA 2011;306:172).

Understanding a person’s motivations for and expectations from the assessment, knowledge of cancer genetics, decision-making approach, personal experience with cancer, family communication style, family dynamics, as well as general psychological issues, such as cancer worry, is key to tailoring the education to meet his/her unique needs. This phase of the process has been termed contracting and, at its core, identifies factors that influence an individual’s personal utility of the information to be shared (Cancer J 2012;18:287).

It is estimated 5% to 10% of any cancer type has an inherited genetic component. Data from a twin study conducted by Lichtenstein et al. suggest this proportion may be underestimated, at least for three common cancer types (N Engl J Med 2000;343:78). The authors evaluated the concordance rates of 28 cancer types among 44,788 monozygotic and dizygotic twin pairs from the Swedish, Danish, and Finnish twin registries. They estimated the effect of heritability, the proportion of disease susceptibility accounted for by inherited genetic abnormalities. Statistically significant effects of heritable factors were identified for cancers of the breast (27%), colon (35%), and prostate (42%) (N Engl J Med 2000;343:78). If these data hold true for other populations, the contribution of inherited genetic factors in cancer predisposition may be higher than currently estimated.

Families with hereditary disease have significantly increased cancer risks above the general population. Thorough attention must be directed first to identifying families with increased cancer risks, allowing for intensified surveillance as well as medical and surgical interventions, reflective of their family risk, to be implemented.

 I. ASSESSMENT. Evaluation of both the personal medical history and the family cancer history is necessary to address the basic question does this individual/family have features of hereditary cancer?

 For the personal medical history, special attention is paid to any history of benign and malignant tumors, cancer screening history, birth marks or unusual skin lesions, environmental exposures, reproductive history, and major illnesses (J Genet Counsel 2012;21:151). At present, physical examination adds limited diagnostic value, with some notable exceptions. Mucosal neuromas of the lips and tongue, which characterize the multiple endocrine neoplasia syndrome, type 2B, or the dark brown macules of the lips, mouth, and digits associated with the Peutz–Jeghers syndrome, are two examples (Dig Dis Sci 2007;52:1924; Genet Med 2011;13:755).

 Family history is often a neglected component of the medical intake, making it challenging, if not nearly impossible, to identify individuals with an increased cancer risk due to their family history. It is not unusual to find the following reporting: family history is not contributory. What does this statement mean? Does the clinician imply a thorough family history was obtained and there were no features of hereditary disease? Or consider the following reporting: mother with breast cancer, uncle with lung cancer, cousin with stomach cancer, grandmother with ovarian cancer. This note is not useful either as the biological relationships are not clarified (are the affected individuals all from the same side of the family?), the ages at diagnosis are not recorded, and exposure history such as tobacco use is not documented. The importance of taking a thorough family cancer history cannot be overstated and requires detailed data regarding the family structure and reported cancer diagnoses.

Figure 43-1. Cancer genetic counseling process.

 Clinical genetic providers summarize the family history using a pedigree format. The family history can quickly be constructed, and by its very structure, biological relations are defined and patterns of cancer, and other key clinical characteristics, may be visualized. Three generation histories are typically obtained documenting individual family members, their children, and the family ethnic background. Recording extended relatives allows for the scope of at-risk family members to be recognized. The age at diagnosis, cancer type, as well as key exposure history, are solicited. When feasible, self-reported family histories are completed in advance of the genetics evaluation, allowing for family members to be contacted or medical records obtained. Limited research suggests that family history questionnaires completed in advance provide thorough family history information (J Genet Counsel 2009;18:366).

 Consider a 28-year-old man diagnosed with colon cancer (Fig. 43-2). There is no reported family cancer history in the first example (Fig. 43-2A), and the genetics assessment is based solely on the age at diagnosis and tumor characteristics. Minimal changes to the reported family cancer history, as demonstrated in Figure 43-2B, leads to a diagnosis of familial polyposis based on the number of colonic polyps and dominant pattern of inheritance. Slightly different cancer reporting, as noted in Figure 43-2C, also demonstrates dominant inheritance but with a cancer pattern now diagnostic for the Lynch syndrome. Familial polyposis and Lynch syndrome are both hereditary colon cancer predisposition syndromes; however, they result from mutations in different genes, have distinct cancer risks, and consequently the medical recommendations differ. Visualization of the family history provides diagnostic and practical advantages.

Figure 43-2. Example pedigrees.

 There are several personal and family history features suggestive of hereditary disease (Table 43-1). To date, most, but not all, hereditary cancer syndromes are inherited following an autosomal dominant pattern of inheritance. Multiple affected individuals, who are closely related to one another, with more than one generation affected, are characteristics suggestive of any dominant disease. Young age at diagnosis, more than one primary cancer in a single individual, bilaterality of paired organs, the occurrence of rare tumor types, and unusual cancer presentations are key features. Distinct histologic features of specific cancers and specialized tumor genetic studies (e.g., microsatellite instability (MSI) testing) may provide important clues. It is the combination of features, not a single trait, that leads to the suspicion, or diagnosis, of inherited cancer predisposition. More specific clinical criteria, dependent on the predominant cancer in the family, have been developed (J Med Genet 2004;41:81). Independent evaluation of the maternal and paternal side of the family is necessary as the two histories are not additive.

 Clinical assessment of the family cancer history may be hindered by the level of accuracy of reported cancer history, family structure, and the general age of the family. Overreporting the family cancer history may lead to an overestimation of risk with implementation of inappropriate medical interventions. In contrast, underreporting the family cancer history may result in lower cancer risk estimates with consequential underutilization of potentially beneficial surveillance and or prophylactic medical and surgical interventions.

 Several studies have assessed the validity of cancer reporting, using both cancer and general populations, with evaluation of reporting for several different cancer types (J Med Genet 1999;36:309; J Natl Cancer Inst2011;103:788;JAMA 2004;292:1480; Am J Prev Med 2003;24:190). Key findings include the following: (a) cancer reporting for first-degree relatives is more accurate than for second- or third-degree relatives; (b) cancer populations, who may be more motivated to seek family history information and demonstrate higher levels of reporting accuracy than general populations; (c) reporting accuracy varies by cancer site with breast and colon cancer consistently being correctly reported among first degree relatives; and (d) younger informants tend to have higher reporting accuracy (J Med Genet 1999;36:309; J Natl Cancer Inst 2011;103:788; JAMA2004;292:1480; Am J Prev Med2003;24:190).

• Multiple affected individuals who are closely related to one another
• Cancers occurring in multiple generations
• Clusters of the same type of cancer (e.g., brother, father, paternal uncle with prostate cancer)
• Young age at diagnosis (e.g., colon cancer diagnosed at 35 yr)
• Multiple primary cancers in a single individual (e.g., sarcoma and breast cancer)
• Bilaterality in paired organs or multifocal disease (e.g., bilateral renal clear cell cancer)
• Uncommon presentation (e.g., male breast cancer)
• Rare cancer types (e.g., retinoblastoma, paraganglioma)
• Unusual tumor histology (e.g., renal chromophobe histology)
• Tumor genetic studies designed to screen for specific cancer syndromes (e.g., MSI analysis)
• Presentation of unusual skin lesions (e.g., mucocutaneous hyperpigmentation of mouth and lips)
• Combination of cancers suggestive of a known cancer syndrome
• Ethnic background associated with higher incidence of specific gene mutations

 To verify the reported cancer history, medical records and/or death certificates are collected. Pathology, medical, and surgical records are the most informative; however, these records are not always available given the limited time health-care facilities maintain paper records. Widespread implementation of electronic medical record systems will help to address this issue. Death certificates are inexpensive and readily available through a state’s vital statistics office and may confirm a family member’s cancer type and age at diagnosis.

 Family structure may also impact the evaluation of the family’s cancer history. Consider a woman with a pancreatic neuroendocrine tumor. Each parent was an only child with no siblings. This woman has no biological aunts, uncles, or cousins. Simply put, there are a limited number of people or “data” to evaluate the family history. The relative “age” of a family may also lead to a biased assessment. The parents of the proband in Figure 43-2a are only 50 years of age, and nearly 10 years younger than the average age of diagnosis for many common cancer types. It is important to understand that the family’s cancer history may not have fully expressed itself yet when evaluating a young adult with cancer or a “young” family.

1. HEREDITARY CANCER PREDISPOSITION SYNDROMES. If the personal and family history features are consistent with hereditary disease, then the question is, what is the underlying cancer syndrome in the family?

 The number of cancer predisposition syndromes described continues to grow (Table 43-2) (J Natl Cancer Inst Monogr 2008:1; Fam Cancer 2013;12:1). Overlapping clinical features (cancer risks) may necessitate the consideration of multiple diagnoses for a given family. Diagnostic guidelines have been established for many syndromes to assist in their clinical recognition (Cancer Res 1988;48:5358; Genetic/familial high-risk assessment: breast and ovarian. www.nccn.org, 2013; Gastroenterology 1999;116:1453).

 Most of the cancer syndromes delineated to date are highly penetrant, dominantly inherited disorders. Penetrance is the frequency in which a gene or gene combination manifests itself in a gene carrier. Every person who carries a gene mutation in a disease with 100% penetrance will develop feature(s) of that disease, whereas only 30% of individuals will develop feature(s) in a syndrome with 30% penetrance. For cancer syndromes, high penetrance translates to high risk for certain cancer types. Expressivity is the term used to describe the clinical variability of a specific disease, and in the case of hereditary cancer is the spectrum of benign and malignant tumors associated with that cancer predisposition syndrome. Much of these data are currently derived from highly selected families, which may represent the extreme end of the disease spectrum. The penetrance and expressivity of a given syndrome will be used to determine screening and medical management.

 As the genetic heterogeneity of inherited cancer predisposition is unraveled, more cancer syndromes will be defined, following varying patterns of inheritance, and with low-to-modest penetrance rates. Syndrome recognition will become increasingly more challenging leading to a greater reliance on genetic testing.

 III. GENETIC TESTING. Genetic testing may encompass the analysis of gene(s), exomes, or even the entire genome. Genetic testing conducted to identify germline (inherited) gene mutations is typically performed on a blood, mouthwash, buccal swab, or banked DNA specimen. The purpose of germline genetic testing in the oncology setting is to identify the underlying genetic basis for the cancer predisposition in the family and subsequently use this information to guide treatment, follow-up, and make genetic testing available to at-risk family members.

 In contrast, genetic analysis performed on a malignant tumor is primarily intended to characterize somatic (acquired) genetic aberrations for the purpose of identifying potential therapeutic targets. Tumor genetic testing may be used to screen a tumor for characteristics for a specific syndrome. For example, MSI analysis, performed on colon or endometrial malignancies, is used to screen for the Lynch syndrome (JAMA 2012;308:1555). Follow-up germline genetic testing is absolutely necessary to distinguish if the positive tumor screen resulted from a germline mutation or somatic events.

The efficacy of surveillance or prophylactic interventions on morbidity and mortality has not been evaluated in controlled clinical trials for most of the known hereditary cancer syndromes. Current medical recommendations for families with hereditary cancer are based primarily on expert opinion only. See GeneReviews (www.genereviews.org) and Lindor et al. (2008) for a detailed review of different cancer predisposition syndromes.

 Genetic testing is typically performed using both gene sequencing and a second technique such as multiplex ligation-dependent probe amplification (MLPA). This latter laboratory analysis is necessary to identify large gene deletions and duplications, types of mutations that cannot be detected using gene sequencing. Deletions and duplications comprise a significant portion of the total mutation profile for genes associated with cancer risk. Analysis of these mutation types is a required component of any cancer genetic testing protocol (Hum Mol Genet 2009;18:1545; J Med Genet 2006;43:e18; Cancer Res 2008;68:7006; JAMA 2006;295:1379). Current testing techniques are descriptive analyses that compare the individual’s gene sequence to the reference sequence for a specific gene(s). Functional analyses are often not available and thus interpreting the results of the genetic testing may be challenging.

 The most informative approach to genetic testing is to begin with an affected family member, an individual diagnosed with one of the known associated cancers for the suspected cancer syndrome. When possible, begin genetic testing with a family member who was diagnosed at a young age or one who has a double primary cancer, as their genetic testing is more likely to be informative. If an affected family undergoes testing first and if a gene mutation is discovered, then the underlying genetic basis for the cancer predisposition in the family has been identified, the testing is informative, and other family members may pursue mutation specific analysis. In this same scenario, if a gene mutation is not identified, then the underlying genetic basis for disease has not been identified, the testing is noninformative, and, consequently, predictive genetic testing is not available for other family members (Fig. 43-3).

 Consider a 34-year-old man with a paraganglioma who has a dominant maternal family history of paragangliomas and pheochromocytomas consistent with hereditary disease. His family has hereditary cancer; the question is can genetic testing identify the underlying gene mutation causative for disease? He undergoes genetic testing of the six known genes causative for hereditary paraganglioma/pheochromocytoma (SDHB, SDHD, SDHC, SDHA, SDHAF2, and MAX). There are three possible test results from his genetic testing.

 First, the testing is positive; a deleterious mutation is identified. This test result is informative because the basis for disease predisposition has been identified. At-risk family members may pursue mutation analysis to predict their cancer risk and guide medical follow-up. One example of a deleterious mutation is a truncating mutation that causes a premature stop codon, halting protein synthesis, and inhibiting protein function. The functional consequences are easily predicted from the gene sequence even without functional analysis.

 Second, the testing is negative; no mutation is identified in the six genes analyzed. This test result is noninformative. The test result is not a true negative because the genetic etiology for their cancer predisposition remains unknown. Thus, at-risk family members cannot pursue genetic testing. In this family, all at-risk family members would need to be considered at “high risk” and followed accordingly until a gene mutation is identified and it is possible to use genetic testing to clarify their cancer risk.

 Given the vast majority of genes associated with cancer risk have not been identified, negative genetic testing is common, even for families with clearly defined hereditary disease. Breast cancer susceptibility is exemplar. Despite extensive breast cancer susceptibility research, it is estimated only 20% of inherited breast cancer risk has been explained (Nat Genet 2008;40:17).

 Third, the test result is neither positive nor negative; a variant of unknown clinical significance (VUS) is identified. VUSs are frequently missense gene variants, single nucleotide changes that code for a different amino acid. Given the lack of available functional analyses, prediction of the clinical significance of a VUS, if any, is not possible with the current data sets. This result is noninformative. At-risk family members should not pursue genetic testing as the clinical significance of the presence or absence of the VUS cannot be determined.

 Interpretation of genetic testing should be performed with extreme caution and care. A common mistake is to start genetic testing with an unaffected family member. Incorrect interpretation of noninformative testing or testing that identified a VUS has resulted in misdiagnoses or delays in diagnoses with significant clinical consequences (Cancer J 2012;18:303; N Engl J Med 1997;336:823). In contrast to other medical testing, genetic testing impacts the clinical care of not just a single individual but an entire family.

Figure 43-3. Genetic testing for cancer susceptibility. Modified from Cancer Genetics Risk Assessment and counseling (PDQ); Figure 2; National Cancer Institute.

 IV. MEDICAL AND LONG-TERM FOLLOW-UP. Medical surveillance and treatment recommendations for families with hereditary cancer are typically based only on expert opinion, given the relatively recent time frame in which these syndromes have been described, and lack of clinical trials to evaluate the efficacy of any screening protocol or medical/surgical intervention.

 The recommendations are straightforward for some cancer syndromes based on the extreme nature of disease. The familial adenomatous polyposis syndrome (FAP) presents with 100s–1,000s of colonic polyps beginning in childhood with total colectomy as the only clinical option (Dis Colon Rectum 2003;46:1001). Yet the most appropriate clinical interventions are not always evident or readily accepted by individuals at risk. Consider a family who has a clinical diagnosis of the hereditary diffuse gastric cancer syndrome (HDGC) in which genetic testing of the CDH1 gene is negative (noninformative). Only one-third of families with HDGC currently have an identifiable gene mutation (J Med Genet 2010;47:436). Should at-risk family members consider prophylactic gastrectomy as a means to reduce their very high risk of diffuse gastric cancer, a type of cancer that is not amendable to surveillance, and for which there is no medical intervention? The Li–Fraumeni syndrome is associated with diverse cancer types, presenting in early childhood and throughout adulthood. Despite the syndrome’s early recognition, only limited studies are available to examine the efficacy of a screening regimen, and no studies have examined the long-term effect of such an intensified surveillance on psychological well-being and quality of life (Lancet Oncol 2011;12:559).

 The essential question is can we bring about positive change by identifying and instituting intensified medical interventions for families at increased cancer risk? Answering this question will become even more challenging as a greater number of low-penetrant (low-risk) gene mutations are identified. Will clinicians make similar medical recommendations regardless of the level of risk? Without careful distinction, the possibility for overtreatment becomes more likely.

 Ultimately, benefits gained by identifying and educating individuals at increased cancer risk are dependent on an individual’s personal utility. How individuals choose to incorporate medical advice in their care and how they communicate complex information to their extended family are out of the clinician’s hands. What is within the control of the medical community is the will, and recognition of the need, to bring together a team of providers who are knowledgeable of the dynamic medical and psychosocial aspects of hereditary disease. Building an informed infrastructure affords individuals a supportive environment as they address their increased cancer risk.

1. FUTURE DIRECTIONS. It is anticipated whole genome sequencing in cancer care will become routine in the near future. Significant gaps exist in provider and public knowledge of genetics, and limited funding is available to support the investigation of health communication strategies and the identification of the type of information to be conveyed. Significant cultural shifts in medical/public genetics education and current research funding priorities are necessary to fully transition genomic science to oncology care. Expanded integration of the discipline of clinical cancer genetics and genetic counseling in the care of people with cancer will be necessary as the technology advances and the complexity of information increases.

SUGGESTED READINGS

Armel SR, McCuaig J, Finch A, et al. The effectiveness of family history questionnaires in cancer genetic counseling. J Genet Counsel 2009;18:366–378.

Banks KC, Moline JJ, Marvin ML, et al. 10 rare tumors that warrant a genetics referral. Fam Cancer 2013;12:1–18.

Brierley KL, Blouch E, Cogswell W, et al. Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications. Cancer J 2012;18:303–309.

Cancer Genetics Risk Assessment and Counseling (PDQ). www.cancer.gov, 2014.

Church J, Simmang C, Standards Task F, et al. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum 2003;46:1001–1012.

Douglas FS, O’Dair LC, Robinson M, et al. The accuracy of diagnoses as reported in families with cancer: a retrospective study. J Med Genet 1999;36:309–312.

Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010;47:436–444.

Genetic/familial high-risk assessment: breast and ovarian. 2013. www.nccn.org.

Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997;336:823.

Hampel H, Sweet K, Westman JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004;41:81–91.

Li FP, Fraumeni JF Jr., Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:5358–5362.

Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343:78–85.

Lindor NM, McMaster ML, Lindor CJ, et al; National Cancer Institute, DoCPCO, Community Oncology and Prevention Trials Research Group. Concise handbook of familial cancer susceptibility syndromes, 2nd ed. J Natl Cancer Inst Monogr 2008:1–93.

Mai PL, Garceau AO, Graubard BI, et al. Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst 2011;103:788–797.

Mehenni H, Resta N, Guanti G, et al. Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome. Dig Dis Sci 2007;52:1924–1933.

Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med 2011;13:755–764.

Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308:1555–1565.

Murff HJ, Spigel DR, Syngal S. Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA 2004;292:1480–1489.

O’Daniel JM, Lee K. Whole-genome and whole-exome sequencing in hereditary cancer: impact on genetic testing and counseling. Cancer J 2012;18(4):287-292.

Oliveira C, Senz J, Kaurah P, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet 2009;18:1545–1555.

Palma MD, Domchek SM, Stopfer J, et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 2008;68:7006–7014.

Resta RG. Defining and redefining the scope and goals of genetic counseling. Am J Med Genet C Semin Med Genet 2006;142C:269–275.

Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Counsel 2012;21:151–161.

Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet 2008;40:17–22.

Task F, Resta R, Biesecker BB, et al; National Society of Genetic Counselors’ Definition. A new definition of genetic counseling: national society of genetic counselors’ task force report. J Genet Counsel 2006;15:77–83.

Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–1456.

Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12:559–567.

Volikos E, Robinson J, Aittomaki K, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome. J Med Genet 2006;43:e18.

Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006;295:1379–1388.

Ziogas A, Anton-Culver H. Validation of family history data in cancer family registries. Am J Prev Med 2003;24:190–198.

Ziogas A, Horick NK, Kinney AY, et al. Clinically relevant changes in family history of cancer over time. JAMA 2011;306:172–178.