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Genetic Testing for Hereditary Colorectal Cancer: Challenges in Identifying, Counseling, and Managing High-Risk Patients
Mini-Reviews and Perspectives
Genetic Testing for Hereditary Colorectal Cancer: Challenges in Identifying, Counseling, and Managing High-Risk Patients ELENA M. STOFFEL and ANU CHITTENDEN Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts
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wenty years ago, the main clinical application for genetic testing was in the prenatal and pediatric settings. Currently, genetic testing plays an important role in many areas of medicine, including gastroenterology. Genetic testing for cancer predisposition should be offered when a patient has a personal or family history suggestive of a hereditary cancer syndrome and the genetic test will influence their own medical management and/or that of their family members.1 Each year, nearly 140 000 people in the United States will be diagnosed with colorectal cancer (CRC). Although most of these cases will be sporadic, estimates suggest that 5%– 6% of CRCs develop as a result of inherited genetic mutations that are associated with extremely high cancer risks requiring specialized interventions for preventing cancer. Clinicians practicing in the genetics era are expected to (1) identify individuals who may be at risk for hereditary cancer syndromes, (2) ensure they undergo appropriate genetic evaluation, and (3) translate the information obtained from genetic testing into effective clinical care. In this review, we examine indications for genetic testing for hereditary CRC syndromes and highlight some of the challenges involved to reduce cancer mortality for these patients and their families. Clinical genetic testing is available for a number of hereditary gastrointestinal cancer syndromes, including familial adenomatous polyposis (FAP), hereditary nonpolyposis CRC/Lynch syndrome, Peutz-Jeghers syndrome, and juvenile polyposis.2 The sensitivity of the gene tests can vary by syndrome. Approximately 90% of individuals with the classic polyposis phenotype of 100s–1000s of colorectal adenomas have germline mutations in the tumor suppressor gene APC, which can be detected through DNA sequencing and/or deletion/duplication analysis using Southern blot or multiplex ligation-dependent probe amplification. Biallelic mutations in the base-excision repair gene MYH can result in either classic polyposis or a more attenuated phenotype of 10-100 colonic polyps. Because of the variability in clinical presentation, American Gastroenterological Association guidelines recommend that individGASTROENTEROLOGY 2010;139:1436 –1441
uals with a history of ⬎20 adenomas consider genetic evaluation for polyposis3 (Figure 1). However, most cases of hereditary CRC arise not from FAP, but from Lynch syndrome. Lynch syndrome is implicated in 3%–5% of CRC cases and its phenotype of colorectal and endometrial cancers can be subtle, making it challenging to identify at-risk individuals. Genetic testing for Lynch syndrome has been available since the mid 1990s after DNA linkage analysis identified mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1 in families who met the classic Amsterdam Criteria. Although initial studies identified mutations in only 40%– 60% of these families,4 improvements in molecular testing techniques and the recent addition of testing for other genes involved in MMR have increased the yield of genetic testing. Currently available genetic testing for Lynch syndrome includes options for full gene sequencing of MLH1, MSH2, MSH6, and PMS2, with additional testing available for large rearrangements in these genes as well as deletions in TACSTD1/EpCAM, which was recently found to cause epigenetic silencing of MSH2 promotor (Figure 2). Because most patients with Lynchassociated CRC have tumors with pathologic features of defective DNA MMR and do not meet the Amsterdam Criteria, the Bethesda Guidelines5 were developed to specify which CRC tumors should be tested for microsatellite instability (MSI) and/or loss of expression of MMR proteins by immunohistochemistry (IHC), which would prompt further genetic evaluation. The hamartomatous polyposis syndromes are considerably less common than either FAP or the Lynch syndrome. Peutz–Jeghers syndrome is characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyps, and a lifetime cancer risk approaching 80%–90%. Mutations in STK-11 (also called LKB1) are identified in 50%–70% of individuals with Peutz-Jeghers syndrome. Individuals with juvenile polyposis syndrome typically present with multiple juvenile polyps and a family history of gastro© 2010 by the AGA Institute
0016-5085/$36.00 doi:10.1053/j.gastro.2010.09.018
Mini-Reviews and Perspectives continued
Figure 1. Algorithm for genetic testing for FAP. (Adapted with permission from American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer, and Genetic Testing. Gastroenterology 2001;121:195–197.)
intestinal cancer, and mutations in SMAD4 and BMPR1A are found in ⬍50% of individuals with juvenile polyposis syndrome. Cowden syndrome, which is associated with mutations in PTEN, is also characterized by gastrointestinal hamartomas and high risk for thyroid, breast, and uterine cancers. Recent reports suggest that the risk for CRC associated with Cowden syndrome is only moderately increased, if at all, for most individuals with this condition.
The Role of Clinicians in Managing Individuals at Risk for Hereditary CRC The diagnosis of a hereditary cancer syndrome has significant implications for the care of patients and their family members. Integrating genetic evaluation into the clinical practice can facilitate identification of patients at risk for hereditary cancer syndromes who require riskreducing interventions, such as specialized screening or prophylactic surgery. Even though genetic testing is expensive (full sequencing for the MMR genes MLH1, MSH2 and MSH6 associated with Lynch Syndrome can cost upwards of $3000), a number of decision analysis studies have supported the cost effectiveness of genetic testing for hereditary CRC,6 – 8 especially because the information gained through genetic testing can benefit both patients and their family members. However, genetic testing is only useful if clinicians can effectively identify and manage these patients at highest risk for cancer.
Challenge #1: Identifying Individuals at Risk for Hereditary CRC Syndromes Although family history assessment is important in identifying individuals at risk for hereditary CRC, there are limitations. A strategy that relies solely on
family history to identify high risk patients depends on physicians to take the time to construct a 3-generation pedigree (including all cancers and ages of diagnosis) and be familiar with diagnostic criteria of hereditary CRC syndromes. Even when perfectly accurate, family history may still not be perfectly sensitive. Approximately 1 in 3 cases of classic FAP have no family history because they arise as the result of a novel APC mutation. Furthermore, nearly 30% of MMR mutation carriers are missed by the Bethesda Guidelines.9 Several risk prediction models (PREMMM1,2,10 MMRPro,11 and MMRPredict12) have been developed using patients’ personal and family history information to calculate a predicted probability that they carry a MMR gene mutation. Although the performance characteristics of these models improve on the Bethesda Guidelines,13,14 the models still depend on clinicians to suspect the possibility of a hereditary syndrome and elicit an accurate family history. Given the limitations of family historyassessment, some have proposed molecular tumor testing as the primary screening strategy for Lynch syndrome.15 Because estimates suggest that as many as 1 in 35 CRC patients may have Lynch syndrome, a number of cancer centers have implemented routine molecular testing for MMR deficiency for all CRC tumors with MSI and/or immunohistochemistry for the MLH1, MSH2, MSH6, and PMS2 proteins. However, it is important to realize that approximately 15% of CRCs are MSI-high and the vast majority of these MSI-high tumors are not associated with Lynch syndrome, but rather with the CpG island methylator phenotype associated with hypermethylation of the MLH1 promoter and somatic mutations in the BRAF gene.16 In short, strategies that rely on physicians to recognize hereditary cancer syndromes by using family history alone identify too few of the individuals truly at 1437
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1438 Figure 2. Algorithm for genetic testing for Lynch syndrome. (Adapted with permission from American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer and Genetic Testing. Gastroenterology 2001;121:195–197.)
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risk, whereas population-based strategies using universal tumor screening would yield too many false positives. Genetic evaluation of all 22 000 patients with MSI-high CRC diagnosed in the United States each year might not be cost effective or even feasible.
Challenge #2: Coordinating Genetic Evaluations Since the publication of the 2001 American Gastroenterological Association Medical Position Statement and Technical Review on Hereditary Colorectal Cancer and Genetic Testing,3 a number of new testing options have made the algorithms for genetic testing for hereditary CRC even more complex (Figures 1 and 2). Genetic testing for hereditary breast and ovarian cancer syndrome provides an interesting case comparison, because testing for mutations in the BRCA1 and BRCA2 genes became commercially available shortly before hereditary CRC testing. Myriad Genetic Laboratories, the company that holds the patent for the BRCA1 and BRCA2 gene tests, has effectively marketed the tests to health care providers in a wide variety of disciplines and offered support with insurance preauthorizations and telephone consultations with genetic counselors. Because the sensitivity of this testing is high, a “negative” test result for a pathogenic mutation in the BRCA1 and BRCA2 genes provides reassurance that the diagnosis of hereditary breast and ovarian cancer syndrome is less likely. To date, genetic testing for hereditary breast and ovarian cancer syndrome is widely available and is usually covered by most medical insurance providers, even at a cost of ⬎$3000 per test. By comparison, genetic testing for hereditary CRC syndromes is less straightforward. In familial CRC, there are a number of different syndromes to consider and unless there has already been a pathogenic gene mutation identified in the family, it is not possible to rule out a hereditary cancer syndrome by ordering a single gene test. Even though most cases of hereditary CRC are associated with Lynch syndrome or the adenomatous polyposis syndromes, it is sometimes difficult to determine which syndrome best fits the clinical picture. Genetic testing for hereditary CRC syndromes can involve a number of different gene tests (5 genes for Lynch syndrome, 2 genes for adenomatous polyposis syndromes, and 4 genes for hamartomatous polyposis syndromes). Before deciding which genetic test to order, the clinician must determine which of the syndromes is most likely, which often requires a review of patient’s family history, pathology reports, and/or tumor blocks. For Lynch syndrome, the first line of testing is often tumor analysis to screen for MSI or abnormal immunohistochemistry of MMR proteins; however, pathology laboratories may vary in their experience analyzing and interpreting results of
tumor immunohistochemistry and MSI. If the tumor shows evidence of defective DNA MMR, the next step may be germline genetic testing for MMR genes or additional tumor testing for mutations in BRAF seen in sporadic MMR-deficient tumors, depending on the clinical history. Once the genetic test result is received, the clinician must interpret the clinical implications and provide patients with recommendations. The expectation is that genetic testing will yield an informative result. The finding of a pathogenic mutation (or “positive” result) provides confirmation of the diagnosis of a hereditary cancer syndrome and makes it possible to offer informative genetic testing to other family members. However, if a positive result has not been identified in the family, a “negative” genetic test result should be interpreted with caution because this could represent several possibilities: (1) the individual could actually be a true negative (he or she did not inherit the familial mutation), (2) the individual could carry a gene mutation that is not detectable by the current technology, or (3) the individual could have a mutation in a different gene which may still be associated with an increased risk for cancer. As many as 80% of individuals tested for MMR mutations receive a test result that is clinically uninformative.10 And although most genetic tests are either positive or negative for a pathogenic mutation, approximately 10% of genetic tests for Lynch syndrome yield a “variant of uncertain significance.” Although some of these variants are reclassified as pathogenic or nonpathogenic with more data, rare variants will probably remain unclassified for a long period of time. In cases in which genetic testing is uninformative, there may be options to pursue additional genetic testing in other affected family members or repeat testing when newer tests become available. Many families with suspected Lynch syndrome who initially tested negative for mutations in MLH1 and MSH2 have subsequently been found to have mutations in MSH6, PMS2, or TACSTD1/ EpCAM, which confirm the clinical diagnosis of a hereditary cancer syndrome. Other families that met the Amsterdam Criteria have undergone additional testing, which demonstrated that the colorectal tumors had normal MSI and immunohistochemistry. Intact DNA MMR alters the diagnosis from Lynch syndrome to familial CRC type X,17 which conveys a lower risk for colorectal and extracolonic tumors than Lynch syndrome and requires less stringent cancer surveillance. The interpretation of uninformative or variant genetic test results is complicated for providers and can be even more confusing for patients. In a well-known study, physicians misinterpreted the clinical implications of an uninformative genetic test result for an individual or family with a clinical diagnosis FAP in approximately 32% of 1439
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cases.18 Our questionnaire study of individuals who underwent genetic testing for Lynch syndrome revealed that nearly half of patients who received an uninformative genetic test result misinterpreted this to mean their risk for CRC was lower than that of other individuals their age.19 Failure to identify a mutation in a family with a clinical diagnosis of Lynch syndrome or an adenomatous polyposis syndrome is not necessarily reassuring, it merely means that genetic testing cannot be used to risk-stratify members of the family. Because the interpretation of genetic test results affects patients’ health behaviors and screening practices, the accuracy of this interpretation is paramount. Most professional societies recommend that genetic testing be performed by a health care professional experienced in cancer genetics and include pre- and posttest counseling as well as discussion of possible risks and benefits of early detection and prevention modalities.1,3 Posttest counseling is associated with reductions in anxiety and cancer worry and remains an important intervention for reinforcing the clinical significance of the genetic test result and the implications for the family. When a mutation is found to explain the family history of cancer, it may be difficult for patients to share this information with at-risk relatives.20,21 Although legal precedents have upheld patients’ rights to disclose or withhold this information, clinicians have an obligation to make the patient aware of the possible consequences the diagnosis of a hereditary cancer syndrome has for the family. Providing patients with written materials to share with their family members can facilitate communication of genetic information to other relatives who are potentially at risk. Referring high-risk patients to a cancer genetics registry may be helpful, because these institutions can often help to coordinate genetic testing for family members, provide updates regarding genetic testing and cancer screening, and facilitate enrollment in research studies.
Challenge 3: Translating Information From Genetic Testing Into Effective Clinical Care The utility of genetic testing for hereditary CRC depends on whether it reduces morbidity and mortality from cancer. Patients at risk for hereditary cancer syndromes require special surveillance22,23 and studies have demonstrated that those who undergo genetic testing are more likely to comply with recommended screening tests.24 –27 In Lynch syndrome, there is evidence to support the effectiveness of intensive colonoscopic surveillance28,29 and prophylactic hysterectomy30 in reducing cancer mortality among MMR mutation carriers to rates similar to those expected in the general population. However, it is important to recognize that many of these data were collected under “ideal” circumstances, through nationally coordinated CRC surveillance programs with 1440
compliance rates of ⬎95%,29 or specialized genetics clinics in which individuals received face-to-face pre- and posttest genetic counseling. Whether these results can be reproduced in the “real world” is still an open question. Several studies have shown that many physicians remain unfamiliar with the management and clinical implications associated with the diagnosis of a hereditary cancer syndrome.31,32 Because care of these patients often involves surveillance for CRC and extracolonic cancers, as well as consideration of risks and benefits of prophylactic surgeries, it is important to ensure effective communication among care teams (including primary care physicians, oncologists, gastroenterologists, surgeons, and gynecologists) and family members.
Challenges for the Future Since the advent of genetic testing for hereditary CRC syndromes, comprehensive clinical testing has become widely available. Federal legislation (the Genetic Information Nondiscrimination Act [GINA] of 200833) has provided some reassurance to patients that the information gained from a genetic test cannot be used by insurers or employers to discriminate against individuals with regard to health coverage or employment. However, many feel that current legislation does not go far enough, as it lacks protections for individuals seeking life insurance and disability insurance. Because the diagnosis of a hereditary cancer syndrome has such an important impact on clinical care of patients and their families, we need to develop effective systems to identify those at high risk for cancer and ensure they receive specialized cancer screening. If we implement tumor screening for defective DNA MMR for all 140 000 CRC cases diagnosed in the United States each year, we should expect to identify approximately 22 000 individuals who will need to undergo additional molecular testing. After additional tumor testing excludes sporadic MLH1 hypermethylation and BRAF mutations, approximately 5000 patients will require comprehensive genetic testing for Lynch syndrome. Before implementing routine tumor testing, it is necessary to ensure that this testing will be covered by patients’ medical insurance and will not jeopardize the family’s ability to obtain insurance coverage in the future. Considering the logistics involved in providing pre and posttest genetic counseling for these patients and their at-risk family members, it is clear we will need more health care providers with knowledge of cancer genetics. The role of genetic counseling for hereditary gastrointestinal cancer syndromes involves more than an explanation of heredity and the recommendations for screening and prevention. It provides a comprehensive evaluation that takes into consideration factors such as family relationships, cultural barriers, fear of genetic discrimination,
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and financial limitations, which may influence patient decision making before genetic testing and after they receive their test result. Twenty years ago, clinical genetic testing was available for only a few conditions. Today, we practice in the era of “personalized medicine,” in which molecular testing offers an opportunity to stratify cancer risk and guide medical management. Hereditary CRC syndromes represent cases in which genetic testing can often be informative and can improve clinical outcomes. In years to come, genetic testing will hopefully offer similar benefit for other gastrointestinal cancer syndromes.
References 1. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21: 2397–2406. 2. Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology 2010;138:2044 –2058. 3. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:195–197. 4. Syngal S, Fox EA, Li C, et al. Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 1999;282:247–253. 5. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96: 261–268.
Supplementary Material Note: The first 5 references associated with this article are available below in print. The remaining references accompanying this article are available online only with the electronic version of the article. To access the remaining references, visit the online version of Gastroenterology at www.gastrojournal.org, and at doi: 10.1053/j.gastro.2010.09.018.
Reprint requests Address requests for reprints to: Elena M. Stoffel, MD, MPH, Division of Population Sciences, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115. e-mail: [email protected]; fax 617-632-4088. Conflicts of interest The authors disclose no conflicts.
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References (Online Only) 6. Ramsey SD, Clarke L, Etzioni R, et al. Cost-effectiveness of microsatellite instability screening as a method for detecting hereditary nonpolyposis cancer. Ann Intern Med 2001;135:577–588. 7. Mvundura M, Grosse SD, Hampel H, et al. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med 2010;12: 93–104. 8. Kievit W, de Bruin JH, Adang EM, et al. Cost effectiveness of a new strategy to identify HNPCC patients. Gut 2005;54:97–102. 9. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788. 10. Balmana J, Stockwell DH, Steyerberg EW, et al. Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 2006;296: 1469 –1478. 11. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479 – 1487. 12. Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006;354:2751–2763. 13. Monzon JG, Cremin C, Armstrong L, et al. Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer. Int J Cancer 2010;126:930 –939. 14. Balmana J, Balaguer F, Castellvi-Bel S, et al. Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J Med Genet 2008;45:557–563. 15. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 2010;28:3380 –3387. 16. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138:2073–2087. 17. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005;293:1979 – 1985. 18. 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– 827. 19. Grover S, Stoffel EM, Mercado RC, et al. Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome. J Clin Oncol 2009;27:3981–3986. 20. Peterson SK, Watts BG, Koehly LM, et al. How families communicate about HNPCC genetic testing: findings from a quali-
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tative study. Am J Med Genet C Semin Med Genet 2003; 119:78 – 86. Stoffel EM, Ford B, Mercado RC, et al. Sharing genetic test results in Lynch syndrome: communication with close and distant relatives. Clin Gastroenterol Hepatol 2008;6:333–338. Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006;296:1507– 1517. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in oncology: colorectal cancer screening. Available at: http://www.nccn.org. Hadley DW, Jenkins JF, Dimond E, et al. Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer. J Clin Oncol 2004;22:39 – 44. Wagner A, van Kessel I, Kriege MG, et al. Long term follow-up of HNPCC gene mutation carriers: compliance with screening and satisfaction with counseling and screening procedures. Fam Cancer 2005;4:295–300. Halbert CH, Lynch H, Lynch J, et al. Colon cancer screening practices following genetic testing for hereditary nonpolyposis colon cancer (HNPCC) mutations. Arch Intern Med 2004;164: 1881–1887. Stoffel EM, Mercado RC, Kohlmann W, et al. Prevalence and predictors of appropriate colorectal cancer surveillance in lynch syndrome. Am J Gastroenterol 2010;105:1851–1860. Engel C, Rahner N, Schulmann K, et al. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2010;8:174 –182. Jarvinen HJ, Renkonen-Sinisalo L, Aktan-Collan K, et al. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol 2009;27:4793– 4797. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261–269. Schroy PC, 3rd, Barrison AF, Ling BS, et al. Family history and colorectal cancer screening: a survey of physician knowledge and practice patterns. Am J Gastroenterol 2002;97:1031–1036. Batra S, Valdimarsdottir H, McGovern M, et al. Awareness of genetic testing for colorectal cancer predisposition among specialists in gastroenterology. Am J Gastroenterol 2002;97:729 – 733. United States. Genetic Information Nondiscrimination Act of 2008. 2008. http://thomas.loc.gov/cgi-bin/bdquery/z?d110: HR00493:@@@L&summ2⫽m&.
Genetic Testing for Hereditary Colorectal Cancer: Challenges in Identifying, Counseling, and Managing High-Risk Patients ELENA M. STOFFEL and ANU CHITTENDEN Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts
T
wenty years ago, the main clinical application for genetic testing was in the prenatal and pediatric settings. Currently, genetic testing plays an important role in many areas of medicine, including gastroenterology. Genetic testing for cancer predisposition should be offered when a patient has a personal or family history suggestive of a hereditary cancer syndrome and the genetic test will influence their own medical management and/or that of their family members.1 Each year, nearly 140 000 people in the United States will be diagnosed with colorectal cancer (CRC). Although most of these cases will be sporadic, estimates suggest that 5%– 6% of CRCs develop as a result of inherited genetic mutations that are associated with extremely high cancer risks requiring specialized interventions for preventing cancer. Clinicians practicing in the genetics era are expected to (1) identify individuals who may be at risk for hereditary cancer syndromes, (2) ensure they undergo appropriate genetic evaluation, and (3) translate the information obtained from genetic testing into effective clinical care. In this review, we examine indications for genetic testing for hereditary CRC syndromes and highlight some of the challenges involved to reduce cancer mortality for these patients and their families. Clinical genetic testing is available for a number of hereditary gastrointestinal cancer syndromes, including familial adenomatous polyposis (FAP), hereditary nonpolyposis CRC/Lynch syndrome, Peutz-Jeghers syndrome, and juvenile polyposis.2 The sensitivity of the gene tests can vary by syndrome. Approximately 90% of individuals with the classic polyposis phenotype of 100s–1000s of colorectal adenomas have germline mutations in the tumor suppressor gene APC, which can be detected through DNA sequencing and/or deletion/duplication analysis using Southern blot or multiplex ligation-dependent probe amplification. Biallelic mutations in the base-excision repair gene MYH can result in either classic polyposis or a more attenuated phenotype of 10-100 colonic polyps. Because of the variability in clinical presentation, American Gastroenterological Association guidelines recommend that individGASTROENTEROLOGY 2010;139:1436 –1441
uals with a history of ⬎20 adenomas consider genetic evaluation for polyposis3 (Figure 1). However, most cases of hereditary CRC arise not from FAP, but from Lynch syndrome. Lynch syndrome is implicated in 3%–5% of CRC cases and its phenotype of colorectal and endometrial cancers can be subtle, making it challenging to identify at-risk individuals. Genetic testing for Lynch syndrome has been available since the mid 1990s after DNA linkage analysis identified mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1 in families who met the classic Amsterdam Criteria. Although initial studies identified mutations in only 40%– 60% of these families,4 improvements in molecular testing techniques and the recent addition of testing for other genes involved in MMR have increased the yield of genetic testing. Currently available genetic testing for Lynch syndrome includes options for full gene sequencing of MLH1, MSH2, MSH6, and PMS2, with additional testing available for large rearrangements in these genes as well as deletions in TACSTD1/EpCAM, which was recently found to cause epigenetic silencing of MSH2 promotor (Figure 2). Because most patients with Lynchassociated CRC have tumors with pathologic features of defective DNA MMR and do not meet the Amsterdam Criteria, the Bethesda Guidelines5 were developed to specify which CRC tumors should be tested for microsatellite instability (MSI) and/or loss of expression of MMR proteins by immunohistochemistry (IHC), which would prompt further genetic evaluation. The hamartomatous polyposis syndromes are considerably less common than either FAP or the Lynch syndrome. Peutz–Jeghers syndrome is characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyps, and a lifetime cancer risk approaching 80%–90%. Mutations in STK-11 (also called LKB1) are identified in 50%–70% of individuals with Peutz-Jeghers syndrome. Individuals with juvenile polyposis syndrome typically present with multiple juvenile polyps and a family history of gastro© 2010 by the AGA Institute
0016-5085/$36.00 doi:10.1053/j.gastro.2010.09.018
Mini-Reviews and Perspectives continued
Figure 1. Algorithm for genetic testing for FAP. (Adapted with permission from American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer, and Genetic Testing. Gastroenterology 2001;121:195–197.)
intestinal cancer, and mutations in SMAD4 and BMPR1A are found in ⬍50% of individuals with juvenile polyposis syndrome. Cowden syndrome, which is associated with mutations in PTEN, is also characterized by gastrointestinal hamartomas and high risk for thyroid, breast, and uterine cancers. Recent reports suggest that the risk for CRC associated with Cowden syndrome is only moderately increased, if at all, for most individuals with this condition.
The Role of Clinicians in Managing Individuals at Risk for Hereditary CRC The diagnosis of a hereditary cancer syndrome has significant implications for the care of patients and their family members. Integrating genetic evaluation into the clinical practice can facilitate identification of patients at risk for hereditary cancer syndromes who require riskreducing interventions, such as specialized screening or prophylactic surgery. Even though genetic testing is expensive (full sequencing for the MMR genes MLH1, MSH2 and MSH6 associated with Lynch Syndrome can cost upwards of $3000), a number of decision analysis studies have supported the cost effectiveness of genetic testing for hereditary CRC,6 – 8 especially because the information gained through genetic testing can benefit both patients and their family members. However, genetic testing is only useful if clinicians can effectively identify and manage these patients at highest risk for cancer.
Challenge #1: Identifying Individuals at Risk for Hereditary CRC Syndromes Although family history assessment is important in identifying individuals at risk for hereditary CRC, there are limitations. A strategy that relies solely on
family history to identify high risk patients depends on physicians to take the time to construct a 3-generation pedigree (including all cancers and ages of diagnosis) and be familiar with diagnostic criteria of hereditary CRC syndromes. Even when perfectly accurate, family history may still not be perfectly sensitive. Approximately 1 in 3 cases of classic FAP have no family history because they arise as the result of a novel APC mutation. Furthermore, nearly 30% of MMR mutation carriers are missed by the Bethesda Guidelines.9 Several risk prediction models (PREMMM1,2,10 MMRPro,11 and MMRPredict12) have been developed using patients’ personal and family history information to calculate a predicted probability that they carry a MMR gene mutation. Although the performance characteristics of these models improve on the Bethesda Guidelines,13,14 the models still depend on clinicians to suspect the possibility of a hereditary syndrome and elicit an accurate family history. Given the limitations of family historyassessment, some have proposed molecular tumor testing as the primary screening strategy for Lynch syndrome.15 Because estimates suggest that as many as 1 in 35 CRC patients may have Lynch syndrome, a number of cancer centers have implemented routine molecular testing for MMR deficiency for all CRC tumors with MSI and/or immunohistochemistry for the MLH1, MSH2, MSH6, and PMS2 proteins. However, it is important to realize that approximately 15% of CRCs are MSI-high and the vast majority of these MSI-high tumors are not associated with Lynch syndrome, but rather with the CpG island methylator phenotype associated with hypermethylation of the MLH1 promoter and somatic mutations in the BRAF gene.16 In short, strategies that rely on physicians to recognize hereditary cancer syndromes by using family history alone identify too few of the individuals truly at 1437
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1438 Figure 2. Algorithm for genetic testing for Lynch syndrome. (Adapted with permission from American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer and Genetic Testing. Gastroenterology 2001;121:195–197.)
Mini-Reviews and Perspectives continued
risk, whereas population-based strategies using universal tumor screening would yield too many false positives. Genetic evaluation of all 22 000 patients with MSI-high CRC diagnosed in the United States each year might not be cost effective or even feasible.
Challenge #2: Coordinating Genetic Evaluations Since the publication of the 2001 American Gastroenterological Association Medical Position Statement and Technical Review on Hereditary Colorectal Cancer and Genetic Testing,3 a number of new testing options have made the algorithms for genetic testing for hereditary CRC even more complex (Figures 1 and 2). Genetic testing for hereditary breast and ovarian cancer syndrome provides an interesting case comparison, because testing for mutations in the BRCA1 and BRCA2 genes became commercially available shortly before hereditary CRC testing. Myriad Genetic Laboratories, the company that holds the patent for the BRCA1 and BRCA2 gene tests, has effectively marketed the tests to health care providers in a wide variety of disciplines and offered support with insurance preauthorizations and telephone consultations with genetic counselors. Because the sensitivity of this testing is high, a “negative” test result for a pathogenic mutation in the BRCA1 and BRCA2 genes provides reassurance that the diagnosis of hereditary breast and ovarian cancer syndrome is less likely. To date, genetic testing for hereditary breast and ovarian cancer syndrome is widely available and is usually covered by most medical insurance providers, even at a cost of ⬎$3000 per test. By comparison, genetic testing for hereditary CRC syndromes is less straightforward. In familial CRC, there are a number of different syndromes to consider and unless there has already been a pathogenic gene mutation identified in the family, it is not possible to rule out a hereditary cancer syndrome by ordering a single gene test. Even though most cases of hereditary CRC are associated with Lynch syndrome or the adenomatous polyposis syndromes, it is sometimes difficult to determine which syndrome best fits the clinical picture. Genetic testing for hereditary CRC syndromes can involve a number of different gene tests (5 genes for Lynch syndrome, 2 genes for adenomatous polyposis syndromes, and 4 genes for hamartomatous polyposis syndromes). Before deciding which genetic test to order, the clinician must determine which of the syndromes is most likely, which often requires a review of patient’s family history, pathology reports, and/or tumor blocks. For Lynch syndrome, the first line of testing is often tumor analysis to screen for MSI or abnormal immunohistochemistry of MMR proteins; however, pathology laboratories may vary in their experience analyzing and interpreting results of
tumor immunohistochemistry and MSI. If the tumor shows evidence of defective DNA MMR, the next step may be germline genetic testing for MMR genes or additional tumor testing for mutations in BRAF seen in sporadic MMR-deficient tumors, depending on the clinical history. Once the genetic test result is received, the clinician must interpret the clinical implications and provide patients with recommendations. The expectation is that genetic testing will yield an informative result. The finding of a pathogenic mutation (or “positive” result) provides confirmation of the diagnosis of a hereditary cancer syndrome and makes it possible to offer informative genetic testing to other family members. However, if a positive result has not been identified in the family, a “negative” genetic test result should be interpreted with caution because this could represent several possibilities: (1) the individual could actually be a true negative (he or she did not inherit the familial mutation), (2) the individual could carry a gene mutation that is not detectable by the current technology, or (3) the individual could have a mutation in a different gene which may still be associated with an increased risk for cancer. As many as 80% of individuals tested for MMR mutations receive a test result that is clinically uninformative.10 And although most genetic tests are either positive or negative for a pathogenic mutation, approximately 10% of genetic tests for Lynch syndrome yield a “variant of uncertain significance.” Although some of these variants are reclassified as pathogenic or nonpathogenic with more data, rare variants will probably remain unclassified for a long period of time. In cases in which genetic testing is uninformative, there may be options to pursue additional genetic testing in other affected family members or repeat testing when newer tests become available. Many families with suspected Lynch syndrome who initially tested negative for mutations in MLH1 and MSH2 have subsequently been found to have mutations in MSH6, PMS2, or TACSTD1/ EpCAM, which confirm the clinical diagnosis of a hereditary cancer syndrome. Other families that met the Amsterdam Criteria have undergone additional testing, which demonstrated that the colorectal tumors had normal MSI and immunohistochemistry. Intact DNA MMR alters the diagnosis from Lynch syndrome to familial CRC type X,17 which conveys a lower risk for colorectal and extracolonic tumors than Lynch syndrome and requires less stringent cancer surveillance. The interpretation of uninformative or variant genetic test results is complicated for providers and can be even more confusing for patients. In a well-known study, physicians misinterpreted the clinical implications of an uninformative genetic test result for an individual or family with a clinical diagnosis FAP in approximately 32% of 1439
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cases.18 Our questionnaire study of individuals who underwent genetic testing for Lynch syndrome revealed that nearly half of patients who received an uninformative genetic test result misinterpreted this to mean their risk for CRC was lower than that of other individuals their age.19 Failure to identify a mutation in a family with a clinical diagnosis of Lynch syndrome or an adenomatous polyposis syndrome is not necessarily reassuring, it merely means that genetic testing cannot be used to risk-stratify members of the family. Because the interpretation of genetic test results affects patients’ health behaviors and screening practices, the accuracy of this interpretation is paramount. Most professional societies recommend that genetic testing be performed by a health care professional experienced in cancer genetics and include pre- and posttest counseling as well as discussion of possible risks and benefits of early detection and prevention modalities.1,3 Posttest counseling is associated with reductions in anxiety and cancer worry and remains an important intervention for reinforcing the clinical significance of the genetic test result and the implications for the family. When a mutation is found to explain the family history of cancer, it may be difficult for patients to share this information with at-risk relatives.20,21 Although legal precedents have upheld patients’ rights to disclose or withhold this information, clinicians have an obligation to make the patient aware of the possible consequences the diagnosis of a hereditary cancer syndrome has for the family. Providing patients with written materials to share with their family members can facilitate communication of genetic information to other relatives who are potentially at risk. Referring high-risk patients to a cancer genetics registry may be helpful, because these institutions can often help to coordinate genetic testing for family members, provide updates regarding genetic testing and cancer screening, and facilitate enrollment in research studies.
Challenge 3: Translating Information From Genetic Testing Into Effective Clinical Care The utility of genetic testing for hereditary CRC depends on whether it reduces morbidity and mortality from cancer. Patients at risk for hereditary cancer syndromes require special surveillance22,23 and studies have demonstrated that those who undergo genetic testing are more likely to comply with recommended screening tests.24 –27 In Lynch syndrome, there is evidence to support the effectiveness of intensive colonoscopic surveillance28,29 and prophylactic hysterectomy30 in reducing cancer mortality among MMR mutation carriers to rates similar to those expected in the general population. However, it is important to recognize that many of these data were collected under “ideal” circumstances, through nationally coordinated CRC surveillance programs with 1440
compliance rates of ⬎95%,29 or specialized genetics clinics in which individuals received face-to-face pre- and posttest genetic counseling. Whether these results can be reproduced in the “real world” is still an open question. Several studies have shown that many physicians remain unfamiliar with the management and clinical implications associated with the diagnosis of a hereditary cancer syndrome.31,32 Because care of these patients often involves surveillance for CRC and extracolonic cancers, as well as consideration of risks and benefits of prophylactic surgeries, it is important to ensure effective communication among care teams (including primary care physicians, oncologists, gastroenterologists, surgeons, and gynecologists) and family members.
Challenges for the Future Since the advent of genetic testing for hereditary CRC syndromes, comprehensive clinical testing has become widely available. Federal legislation (the Genetic Information Nondiscrimination Act [GINA] of 200833) has provided some reassurance to patients that the information gained from a genetic test cannot be used by insurers or employers to discriminate against individuals with regard to health coverage or employment. However, many feel that current legislation does not go far enough, as it lacks protections for individuals seeking life insurance and disability insurance. Because the diagnosis of a hereditary cancer syndrome has such an important impact on clinical care of patients and their families, we need to develop effective systems to identify those at high risk for cancer and ensure they receive specialized cancer screening. If we implement tumor screening for defective DNA MMR for all 140 000 CRC cases diagnosed in the United States each year, we should expect to identify approximately 22 000 individuals who will need to undergo additional molecular testing. After additional tumor testing excludes sporadic MLH1 hypermethylation and BRAF mutations, approximately 5000 patients will require comprehensive genetic testing for Lynch syndrome. Before implementing routine tumor testing, it is necessary to ensure that this testing will be covered by patients’ medical insurance and will not jeopardize the family’s ability to obtain insurance coverage in the future. Considering the logistics involved in providing pre and posttest genetic counseling for these patients and their at-risk family members, it is clear we will need more health care providers with knowledge of cancer genetics. The role of genetic counseling for hereditary gastrointestinal cancer syndromes involves more than an explanation of heredity and the recommendations for screening and prevention. It provides a comprehensive evaluation that takes into consideration factors such as family relationships, cultural barriers, fear of genetic discrimination,
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and financial limitations, which may influence patient decision making before genetic testing and after they receive their test result. Twenty years ago, clinical genetic testing was available for only a few conditions. Today, we practice in the era of “personalized medicine,” in which molecular testing offers an opportunity to stratify cancer risk and guide medical management. Hereditary CRC syndromes represent cases in which genetic testing can often be informative and can improve clinical outcomes. In years to come, genetic testing will hopefully offer similar benefit for other gastrointestinal cancer syndromes.
References 1. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21: 2397–2406. 2. Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology 2010;138:2044 –2058. 3. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:195–197. 4. Syngal S, Fox EA, Li C, et al. Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 1999;282:247–253. 5. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96: 261–268.
Supplementary Material Note: The first 5 references associated with this article are available below in print. The remaining references accompanying this article are available online only with the electronic version of the article. To access the remaining references, visit the online version of Gastroenterology at www.gastrojournal.org, and at doi: 10.1053/j.gastro.2010.09.018.
Reprint requests Address requests for reprints to: Elena M. Stoffel, MD, MPH, Division of Population Sciences, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115. e-mail: [email protected]; fax 617-632-4088. Conflicts of interest The authors disclose no conflicts.
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