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Public health perspectives on testing for colorectal cancer susceptibility genes
Public Health Perspectives on Testing for Colorectal Cancer Susceptibility Genes Steven S. Coughlin, PhD, Daniel S. Miller, MD, MPH Context:
About 131,600 new cases of colorectal cancer will be diagnosed in the United States in 1998. About 27,900 men and 28,600 women will die from colorectal cancer in 1998. Mutations to the hMSH2 gene on chromosome 2p and to the hMLH1 gene on chromosome 3p have been identified as causes of colorectal cancer. These mismatch repair genes, which have recently been cloned, account for most cases of hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer susceptibility syndromes known. The carrier frequency of hMSH2 and hMLH1 gene mutations in the U.S. population is unknown. An adenomatous polyposis coli (APC) gene variant (I1307K allele), which was recently reported in 1 in 17 Ashkenazi Jewish persons, may double the risk for colorectal cancer in that population.
Conclusions: The use of genetic tests for susceptibility to cancer of the colon and other sites needs careful scrutiny. Several issues must be addressed before such tests can be recommended for population-based prevention programs. For example, the screening of population subgroups raises concern about potential discrimination and stigmatization. Before genetic tests for colorectal cancer are incorporated into future programs, the safety, effectiveness, and quality of these tests must be evaluated. Medical Subject Headings (MeSH): cancer genetics, colorectal cancer, genetic testing, germline mutations, prevention effectiveness, screening (Am J Prev Med 1999;16(2): 99 –104) © 1999 American Journal of Preventive Medicine
Introduction
C
olorectal cancer is one of the most common cancers among U.S. men and women. In 1998, an estimated 131,600 new cases will be diagnosed, and 27,900 men and 28,600 women will die from the disease.1 In this review, we consider the public health implications of screening for genetic susceptibility to colorectal cancer. Our interest in these implications stems from new findings in molecular genetics. The discovery of DNA abnormalities associated with genomic instability (referred to as microsatellite instability) in persons with hereditary nonpolyposis colorectal cancer (HNPCC) led to findings of a defect in the DNA mismatch repair system.2 The hMSH2 mismatch repair gene was identified and cloned in 1993,3,4 shortly after a region on chromosome 2p was associated with HNPCC. A second mismatch repair gene associated
From the Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA Address Correspondence and reprint requests to: Steven S. Coughlin, PhD, Epidemiology and Health Services Research Branch, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, NE (K-55), Atlanta, GA 30341.
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with colorectal cancer, hMLH1, was subsequently identified on chromosome 3p.5 HNPCC is now known to be caused by germline mutations of any of four DNA mismatch repair genes (hMSH2, hMLH1, PMS1, PMS2).6 – 8 The first two of these genes account for about 80% to 90% of HNPCC cases,9 and the other two account for only a small fraction of cases.9,10 Linkage and mutational analyses have suggested that hMSH2 is the gene most commonly associated with HNPCC, accounting for 50% to 60% of HNPCC cases; hMLH1 accounts for an additional 30% of HNPCC cases.11 Mutations of these genes have been associated with cancer of the colon, endometrium, ovary, and other sites. These genes code for proteins that normally repair mutations introduced by the DNA polymerase during cell replication. Mismatch repair dysfunction accelerates the accumulation of mutations in tumor suppressor genes and oncogenes (e.g., ras, APC, and p53) thereby speeding the development of malignancy.11–13 A multi-step model of colorectal cancer pathogenesis has been described by Cho and Vogelstein.12 Genetic tests for susceptibility to HNPCC are becoming widely available but are not currently recommended outside of research protocols. These tests include linkage testing, truncated protein testing, and direct mutational testing.14 Identification of truncated
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protein has been successful in some families with a history of HNPCC. Several issues related to screening for hMSH2 and hMLH1 gene mutations must be considered before these tests can be recommended for population-based prevention programs for colorectal cancer.15 These issues include the significance of a positive or negative test result; the public health effect of gene mutations that increase susceptibility to colorectal cancer; available intervention or prevention methods; and the effect, quality, and safety of testing for these mutations. We also provide an overview of selected ethical, legal, and social issues of colorectal cancer genetic testing and screening as they relate to public health practice.
Background The inherited syndromes of colonic cancer can be roughly divided into those that exhibit colonic polyposis (e.g., familial adenomatous polyposis [FAP]) and those that do not exhibit this phenotype.14,16,17 The nonpolyposis syndromes include hereditary nonpolyposis colorectal cancer (HNPCC). Persons with the nonpolyposis syndromes may have some adenomatous polyps, but these are fewer.14 While the adenomatous polyposis syndromes account for only about 0.5% of colonic cancer cases, the nonpolyposis syndromes may account for 5% or more.14 Familial cases outside of the syndromes may account for 10% to 30% of colonic cancer cases. FAP is an autosomal dominantly inherited disease that occurs in only about 1 in 10,000 persons.14 Persons with this condition develop hundreds to thousands of adenomatous polyps of the colon at a young age,17 and colonic cancer occurs at an average age of 39 years.14 Total colectomy and mucosal proctectomy is recommended because of the extreme risk for colonic cancer.14 FAP is caused by highly penetrant mutations of the adenomatous polyposis coli (APC) tumor suppressor gene on the long arm of chromosome 5. Persons in most families with FAP have distinct mutations of the APC gene, and these mutations are almost always associated with truncation of the APC protein (i.e., frameshift or nonsense mutations).14 Somatic mutations of the APC gene are involved in some cases of sporadic colon cancer.12 HNPCC, which is much more common than FAP, also occurs in an autosomal dominant fashion.16 HNPCC affects about 1 in every 200 to 400 persons in the United States, which makes it one of the most common autosomal dominantly inherited diseases.9 Colonic cancer occurs at an average age of 45 years in these persons.14 The clinical criteria for diagnosis of HNPCC are three family members who have colonic cancer (two of whom are first degree relatives of the third person), colonic cancer cases spanning at least two generations, and at least one case diagnosed before 100
age 50.16 HNPCC has been additionally divided into hereditary site-specific nonpolyposis colonic cancer (Lynch syndrome I) and cancer family syndrome (Lynch syndrome II).16,18 Patients with Lynch syndrome II develop colorectal cancer and endometrial cancer, ovarian cancer, or cancer of other sites. Millions of families in the United States have cancer histories that are indistinguishable from Lynch syndrome II based on the phenotype or cancers that are expressed.19 Nearly all published studies of mutations in the hMSH2 and hMLH1 genes have been in members of families with HNPCC. Therefore, estimates of the cancer risks associated with hMSH2 and hMLH1 mutations are derived from families characterized by an early age of onset and/or multiple tumors and that meet stringent criteria for autosomal dominant inheritance of cancer predisposition.20,21 Persons from families with HNPCC (including persons who test positive for a hMSH2 or hMLH1 gene mutation) may have a cumulative risk for colorectal cancer as high as 35% by age 50 and 80% by age 70.11,20 However, such estimates may be biased upward, because the people selected for study had a family history of cancer. Estimates of the carrier frequency of hMSH2 and hMLH1 gene mutations among persons who do not have a family history of colorectal cancer are currently lacking. About 95% of colonic cancer cases are sporadic and occur outside of the well-described syndromes.14 About 10% of U.S. adults have a first-degree relative with a history of colonic cancer. Such persons have a two- to threefold increased risk of developing colon cancer.17 Because of the heterogeneity of hMSH2 and hMLH1 mutations, laboratory testing for all possible mutations is difficult for persons not from families at high risk for colorectal cancer. False-positive results may occur as a result of missense mutations that are not associated with an increased risk for colorectal cancer. Frameshift or nonsense mutations that result in protein truncation are likely to predispose carriers to disease.22 Falsenegative results may also occur because not all possible hMSH2 and hMLH1 mutations are likely to be detected.
Public Health Impact of hMSH2 and hMLH1 Colorectal Cancer Genes Most people with a family history of colorectal cancer lack the pedigree characteristics of autosomal dominant inheritance of cancer predisposition.14 In addition, colorectal cancer, similar to other chronic diseases, is likely to have multiple causes and no single gene is likely to account for a significant attributable fraction of colorectal cancer cases.15 Although hMSH2 and hMLH1 mutations may account for many hereditary colorectal cancers in the population, other genetic defects, such as APC gene mutations, are likely to
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account for the genetic predisposition to colorectal cancer in other familial cases.14 Estimates of the prevalence of HNPCC are based on imperfect clinical criteria for identifying HNPCC.11 Such criteria likely underestimate the prevalence because they exclude cases in small nuclear families and cases of extracolonic cancers associated with HNPCC.9 The limitations of existing estimates of the prevalence of HNPCC and the need for population studies of the carrier frequency of gene mutations for colorectal cancer susceptibility, have been previously summarized.23 Despite such limitations, HNPCC is a fairly common cancer predisposition syndrome that appears to be responsible for a small yet significant proportion of some of the most prevalent types of cancer in the United States.11
Interaction of hMSH2 and hMLH1 Gene Mutations with Modifiable Risk Factors for Colorectal Cancer Because most nongenetic risk factors for colorectal cancer have low predictive value, the use of genetic tests is likely to improve the predictive value of environmental and behavioral factors for colorectal cancer. Despite an inherited predisposition, colorectal cancer may not develop in the absence of lifestyle factors. The variable age at onset of hereditary colorectal cancer and the fact that some people who have hMSH2 and hMLH1 gene mutations do not develop cancer indicate that other genetic or environmental factors modify the expression of these traits and that their penetrance is incomplete. Data are scant on the role of environmental risk factors for colorectal cancer among people with hMSH2 and hMLH1 gene mutations. Data are lacking about the value of lifestyle modifications, such as a low-fat diet, adequate intake of vegetables and fruit, and regular exercise, in people with hMSH2 and hMLH1 mutations. Even though such lifestyle modifications are unproven to reduce cancer risk and evidence from randomized trials is lacking, these modifications have a broad range of other health benefits, and they pose fewer risks than pharmacologic or surgical interventions.24 Data are also scant on the effect of nonsteroidal anti-inflammatory drugs and calcium among persons with hMSH2 and hMLH1 gene mutations. In contrast to cancer susceptibility genes such as hMSH2 and hMLH1, less penetrant genetic polymorphisms are much more frequent in the population. Therefore, the public health implications may be greater for common genetic polymorphisms, even though they may be associated with only a modest increase in risk for colorectal cancer. Genetic polymorphisms may account for why some people are more sensitive than others to environmental carcinogens or cancer promoters, such as a diet high in red meat and low in fiber.
In the Physicians’ Health Study, for example, men with the homozygous mutation of the gene associated with reduced enzyme activity and lower levels of 5-methyltetrahydrofolate, the primary circulating form of folate, had one half the risk for colorectal cancer than did men with the homozygous normal or heterozygous genotypes.25 When men who have the homozygous normal genotype and who drank little or no alcohol are the reference group, men who have the homozygous mutation and who drank little or no alcohol had an eightfold lower risk (OR 0.12, 95% CI 0.03 to 0.57), and those who were moderate drinkers had a twofold lower risk (OR 0.42, 95% CI 0.15 to 1.2). These results, which await confirmation in future studies, suggest that this gene mutation reduces colorectal cancer risk and that high alcohol consumption or low folate intake may negate some of the protective effect. Polymorphisms in N-acetyltransferase have also been examined in relation to cancer of the colon, rectum, and other sites.26,27 This enzyme catalyzes the formation of mutagenic substances from foods such as cooked meat and fish. People in whom acetylation is fast are at increased risk for colorectal cancer in some but not all studies.28,29 Slow acetylation has been associated with an increased risk for bladder cancer.28
APC Gene I1307K Variant and Risk for Colorectal Cancer in Ashkenazi Jewish Persons An APC gene variant (I1307K allele), recently reported to be present in 1 in 17 Ashkenazi Jewish persons, may be associated with a doubling of colorectal cancer risk in that population.30 This variant, one of the most common cancer-associated genetic mutations known in a specific population, does not directly alter the function of the APC gene but makes it unstable and prone to mutations during cell division. Ten percent of Ashkenazi Jewish persons with colorectal cancer had this gene mutation compared with 6% of Ashkenazi Jewish persons without cancer.30 About 28% of Ashkenazi Jewish persons with colon cancer and a family history of the disease had the I1307K genetic mutation.30 Of 243 people of other ethnic backgrounds, none had this genetic mutation. In a study by Petrukhin et al.,31 the APC I1307K variant was not found to predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. These investigators detected the APC I1307K variant in 7% (11 of 158) of the Ashkenazi Jewish families with breast and/or ovarian cancer and in 5% (12 of 264) of the individuals participating in the studies. Of the 12 individuals who were found to carry the I1307K variant, none was diagnosed with colorectal cancer and none had a known first-, second-, or thirddegree relative diagnosed with colorectal cancer.31 Frayling et al.32 recently found another APC gene variant (E1317Q allele) to be present in 4 of 164 Am J Prev Med 1999;16(2)
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patients with multiple colorectal adenomas and/or carcinoma in Great Britain (2 of 134 patients with multiple adenomas and 2 of 30 colorectal cancer patients). None of the patients found to carry the E1317Q allele were of Ashkenazi Jewish descent. The family histories of the E1317Q carriers varied; the fathers of two patients with colorectal cancer who had the E1317Q allele died of gastrointestinal cancers.32 The E1317Q variant was not present in 80 non-Ashkenazi British controls. Frayling et al.32 also identified three patients with the I1307K allele, all of whom were of Ashkenazi Jewish descent.
The Effect, Quality, and Safety of Testing for hMSH2 and hMLH1 Gene Mutations The introduction of new genetic tests requires the development of standards, regulations, and guidelines to ensure the accuracy and precision of the laboratory procedures.15 All clinical laboratories in the United States that provide information to referring physicians are certified under the Clinical Laboratory Improvement Act Amendments (CLIA) of 1988. The CLIA regulations address cytogenetic testing and other types of genetic tests. Biotechnology companies currently marketing genetic tests for colorectal cancer to physicians are not required to involve the Food and Drug Administration because these companies are using their own reagents and performing the tests in their own laboratories, but they may voluntarily do so.33 Measures of the validity of genetic tests and other laboratory assays include sensitivity, specificity, and positive and negative predictive values.19 The analytic predictive value of a positive test is the proportion of true carriers among those found to have a mutation.19 The analytic sensitivity is the proportion of true carriers of a cancer susceptibility gene mutation who are found to have the mutation, and specificity is the proportion of noncarriers of the mutation whose test result is negative. Interim principles and recommendations on genetic testing developed by the National Institutes of Health’s and Department of Energy’s Task Force on Genetic Testing additionally define and explain these concepts.34 Laboratory quality assurance of genetic testing is also addressed in the Task Force report.34 The adequacy of genetic testing can be evaluated through surveys of health care providers to determine whether the tests are made available to persons likely to benefit and whether they are appropriately counseled before and after testing. The methods used to obtain informed consent and to ensure the confidentiality of results can also be evaluated. For example, one study of 177 persons tested for genetic susceptibility to adenomatous polyposis coli (APC) found that the appropriate strategy for APC gene testing was used in 79% of patients; only 19% had received genetic counseling 102
before the test, and only 17% had provided written informed consent.35 Other ethical issues are considered subsequently.
Ethical, Legal, and Social Issues Genetic testing for colorectal cancer susceptibility raises ethical and social concerns related to the adequacy of informed consent, the availability and quality of pre- and post-test counseling, and the avoidance of genetic discrimination.36 Other ethical and social issues concern the cost of and access to genetic tests for hMSH2 and hMLH1 mutations, especially among persons who are socioeconomically disadvantaged or underinsured. Moreover, the clinical and preventive applications of such testing are currently ill-defined. The disclosure of genetic test results can have psychologic and economic ramifications for the person screened and his or her relatives.37 Some persons who undergo genetic testing for cancer risk may experience anxiety or other adverse psychologic effects or disrupted personal relationships. Reproductive choices may also be affected. Communities may be harmed if stigmatization or genetic discrimination occurs. Therefore, the screening of selected population subgroups raises ethical concerns and fears. The provision of genetic information without proper counseling and follow-up could lead to psychologic distress and impair adherence to recommendations for the early detection and prevention of colorectal cancer.38 However, people who learn that they carry a hMSH2 or hMLH1 gene mutation might be motivated to adhere to colorectal cancer screening guidelines. Such risks may be minimized through the provision of genetic counseling.39 To make an informed decision about whether to receive genetic testing for colorectal cancer, people must understand the potential benefits as well as the risks and limitations, such as the limitations of current options for cancer prevention and early detection. Guidelines for communicating genetic information about colorectal cancer susceptibility and for providing recommendations and follow-up care for people found to carry hMSH2 and hMLH1 gene mutations have recently been provided.24 Current legal and regulatory safeguards are inadequate to prevent problems associated with genetic discrimination, such as loss of employment or insurance.40 The potential for discrimination by health insurers is one of the most serious risks associated with genetic testing. Genetic counselors commonly advise persons who are considering undergoing genetic testing to verify their insurance coverage before undergoing testing. Genetic discrimination and stigmatization may occur if screening programs target specific populations defined by race, ethnicity, or religion.
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Summary and Conclusions
References
Colorectal cancer is one of the most prevalent types of cancer in the western world. Mutations to the hMSH2 and hMLH1 genes are responsible for a small but significant proportion of colorectal cancer, and such genetic mutations have broad clinical and public health implications. Researchers are beginning to address issues such as the carrier frequency of these gene mutations in specific populations and the relationship between sporadic cases of colorectal cancer and cases attributable to hMSH2, hMLH1, and APC gene mutations.41 Studies of the role of genetic polymorphisms in the etiology of colorectal cancer have been undertaken. Population-based research is needed, however, to examine genotype-phenotype relations and to determine optimal screening protocols and recommendations for preventive interventions for people who have these gene mutations. Large-scale genetic screening for colorectal cancer poses technologic and quality assurance challenges and raises ethical, legal, and social questions.19 The clinical and preventive applications of such screening are unclear. The existence of accepted treatment for people with recognized disease, agreement on whom to treat, the existence of adequate facilities for diagnosis and treatment, reasonable cost of case-finding, and acceptability of the test to the target population are among the recognized criteria for evaluating the suitability of population screening.42 Because not all these criteria are currently met, population-based screening for hMSH2, hMLH1, and APC gene mutations outside of research protocols cannot be recommended. Concern continues about risks of such genetic testing, including the potential for genetic discrimination and stigmatization and the quality of informed consent. Nevertheless, tests for APC gene mutations are already being marketed to clinicians, and tests for hereditary colorectal cancer are becoming commercially available. Surveillance programs for genetic testing should be designed and implemented to closely monitor and evaluate testing done outside of research protocols. The determinants, quality, appropriateness, and extent of such testing are currently poorly understood. Research is needed to learn about the comparability and characteristics of genetic tests for colorectal cancer, to ensure that the tests are standardized, and to examine the adequacy of provisions for informed consent and genetic counseling. Before such tests can be widely used, studies are also needed of the clinical and preventive utility. If genetic tests for colorectal cancer are incorporated into population programs, evaluation will be needed to assess whether the screening is available to all persons likely to benefit and whether the genetic testing is having the intended effect.
1. American Cancer Society, Inc. Facts and Figures, 1998. 2. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995; 87:1114 –25. 3. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1027–38. 4. Leach FS, Nicolaides N, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75:1215– 25. 5. Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer. Nature 1994; 368:258 – 61. 6. Aaltonen LA, Peltomaki P. Genes involved in hereditary nonpolyposis colorectal cancer (review). Anticancer Res 1994; 14(4B):1657– 60. 7. Cama A, Genuardi M, Guanti G, et al. Molecular genetics of hereditary non-polyposis colorectal cancer (review). Tumori 1996; 82:122–35. 8. Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371: 75– 80. 9. Han HJ, Yuan Y, Ku JL, et al. Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer (letter). J Natl Cancer Inst 1996; 88:1317–9. 10. Nystrom-Lahti M, Moisio AL, Hofstra RM, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996; 5:763–9. 11. Kolodner RD, Hall NR, Lipford J, et al. Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for MLH1 mutations. Cancer Res 1995; 55:242– 8. 12. Cho KR, Vogelstein B. Genetic alterations in the adenoma-carcinoma sequence. Cancer 1992; 70(6 Suppl):1727–31. 13. Fey MF. P53, myc, APC, hMSH2, ras, etc. in colorectal cancer. Ann Oncol 1995; 6:961–2. 14. Burt RW, Petersen GM. Familial colorectal cancer: diagnosis and management. In: Young GP, Rozen P, Levin B, editors. Prevention and early detection of colorectal cancer. London: Saunders, 1996, pp. 171–94. 15. Khoury MJ. From genes to public health: the applications of genetic technology in disease prevention. Am J Public Health 1996; 86:1717–22. 16. Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). Int J Cancer 1996; 69:38 – 43. 17. Petersen GM. Genetic epidemiology of colorectal cancer. Eur J Cancer 1995; 31A:1047–50. 18. Lynch HT, Smyrk T, Lynch J. An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet 1997; 93:84 –99. 19. Li FP. Translational research on hereditary colon, breast, and ovarian cancers. JNCI Monographs 1995; 17:1– 4. 20. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110:1020 –7. 21. Voskuil DW, Vasen HFA, Kampman E, et al. Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. Int J Cancer 1997; 72:205–9. 22. Collins FS. BRCA1–lots of mutations, lots of dilemmas. N Engl J Med 1996; 334:186 – 8. 23. Kolodner RD, Hall NR, Lipford J, et al. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for MSH2 mutations. Genomics 1994; 24:516 –26. 24. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277:915–9. 25. Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997; 57:1098 –102. 26. Roberts-Thomson IC, Ryan P, Khoo KK, et al. Diet, acetylator phenotype, and risk of colorectal neoplasia. Lancet 1996; 347:1372– 4. 27. Bell DA, Stephens EA, Castranio T, et al. Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. Cancer Res 1995; 55:3537– 42. 28. Feigelson HS, Ross RK, Yu MC, et al. Genetic susceptibility to cancer from exogenous and endogenous exposures. J Cell Biochem 1996; 25 (Suppl): 15–22. 29. Shibuta K, Nakashima T, Abe M, et al. Molecular genotyping for N-
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acetylation polymorphism in Japanese patients with colorectal cancer. Cancer 1994; 74:3108 –12. Laken SJ, Petersen G, Bruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nature Genetics 1997; 17:79 – 83. Petrukhin L, Dangel JE, Vanderveer L, et al. The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. Cancer Res 1997; 57:5480 – 4. Frayling IM, Beck NE, Ilyas M, et al. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci 1998; 95:10722–7. Hubbard R, Lewontin RC. Pitfalls of genetic testing. N Engl J Med 1996; 334:1192– 4. NIH-DOE Working Group on Ethical, Legal, and Social Implications of Human Genome Research Task Force on Genetic Testing. Promoting Safe and Effective Genetic Testing in the United States, http:// ww2.med.jhu.edu/tfgtelsi/promoting. Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpreta-
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tion of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997; 36:823–7. Clayton EW, Steinberg KK, Khoury MJ, et al. Informed consent for genetic research on stored tissue samples. JAMA 1995; 274:1786 –92. Lerman C, Croyle RT. Emotional and behavioral responses to genetic testing for susceptibility to cancer. Oncology 1996; 10:191–9. Lerman C, Croyle RT. Genetic testing for cancer predisposition: behavioral science issues. JNCI Monographs 1995; 17:63– 6. Offit K, Brown K. Quantitating familial cancer risk: a resource for clinical oncologists. J Clin Oncol 1994; 12:1724 –36. Rothenberg KH. Genetic discrimination and health insurance: a call for legislative action. J Am Med Wom Assoc 1997; 52:43– 4. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998; 338:1481-7. Wilson JMG, Jungner F. Principles and practice of screening for disease (Public Health Papers No. 34). WHO, Geneva, 1968.
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About 131,600 new cases of colorectal cancer will be diagnosed in the United States in 1998. About 27,900 men and 28,600 women will die from colorectal cancer in 1998. Mutations to the hMSH2 gene on chromosome 2p and to the hMLH1 gene on chromosome 3p have been identified as causes of colorectal cancer. These mismatch repair genes, which have recently been cloned, account for most cases of hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer susceptibility syndromes known. The carrier frequency of hMSH2 and hMLH1 gene mutations in the U.S. population is unknown. An adenomatous polyposis coli (APC) gene variant (I1307K allele), which was recently reported in 1 in 17 Ashkenazi Jewish persons, may double the risk for colorectal cancer in that population.
Conclusions: The use of genetic tests for susceptibility to cancer of the colon and other sites needs careful scrutiny. Several issues must be addressed before such tests can be recommended for population-based prevention programs. For example, the screening of population subgroups raises concern about potential discrimination and stigmatization. Before genetic tests for colorectal cancer are incorporated into future programs, the safety, effectiveness, and quality of these tests must be evaluated. Medical Subject Headings (MeSH): cancer genetics, colorectal cancer, genetic testing, germline mutations, prevention effectiveness, screening (Am J Prev Med 1999;16(2): 99 –104) © 1999 American Journal of Preventive Medicine
Introduction
C
olorectal cancer is one of the most common cancers among U.S. men and women. In 1998, an estimated 131,600 new cases will be diagnosed, and 27,900 men and 28,600 women will die from the disease.1 In this review, we consider the public health implications of screening for genetic susceptibility to colorectal cancer. Our interest in these implications stems from new findings in molecular genetics. The discovery of DNA abnormalities associated with genomic instability (referred to as microsatellite instability) in persons with hereditary nonpolyposis colorectal cancer (HNPCC) led to findings of a defect in the DNA mismatch repair system.2 The hMSH2 mismatch repair gene was identified and cloned in 1993,3,4 shortly after a region on chromosome 2p was associated with HNPCC. A second mismatch repair gene associated
From the Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA Address Correspondence and reprint requests to: Steven S. Coughlin, PhD, Epidemiology and Health Services Research Branch, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, NE (K-55), Atlanta, GA 30341.
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with colorectal cancer, hMLH1, was subsequently identified on chromosome 3p.5 HNPCC is now known to be caused by germline mutations of any of four DNA mismatch repair genes (hMSH2, hMLH1, PMS1, PMS2).6 – 8 The first two of these genes account for about 80% to 90% of HNPCC cases,9 and the other two account for only a small fraction of cases.9,10 Linkage and mutational analyses have suggested that hMSH2 is the gene most commonly associated with HNPCC, accounting for 50% to 60% of HNPCC cases; hMLH1 accounts for an additional 30% of HNPCC cases.11 Mutations of these genes have been associated with cancer of the colon, endometrium, ovary, and other sites. These genes code for proteins that normally repair mutations introduced by the DNA polymerase during cell replication. Mismatch repair dysfunction accelerates the accumulation of mutations in tumor suppressor genes and oncogenes (e.g., ras, APC, and p53) thereby speeding the development of malignancy.11–13 A multi-step model of colorectal cancer pathogenesis has been described by Cho and Vogelstein.12 Genetic tests for susceptibility to HNPCC are becoming widely available but are not currently recommended outside of research protocols. These tests include linkage testing, truncated protein testing, and direct mutational testing.14 Identification of truncated
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protein has been successful in some families with a history of HNPCC. Several issues related to screening for hMSH2 and hMLH1 gene mutations must be considered before these tests can be recommended for population-based prevention programs for colorectal cancer.15 These issues include the significance of a positive or negative test result; the public health effect of gene mutations that increase susceptibility to colorectal cancer; available intervention or prevention methods; and the effect, quality, and safety of testing for these mutations. We also provide an overview of selected ethical, legal, and social issues of colorectal cancer genetic testing and screening as they relate to public health practice.
Background The inherited syndromes of colonic cancer can be roughly divided into those that exhibit colonic polyposis (e.g., familial adenomatous polyposis [FAP]) and those that do not exhibit this phenotype.14,16,17 The nonpolyposis syndromes include hereditary nonpolyposis colorectal cancer (HNPCC). Persons with the nonpolyposis syndromes may have some adenomatous polyps, but these are fewer.14 While the adenomatous polyposis syndromes account for only about 0.5% of colonic cancer cases, the nonpolyposis syndromes may account for 5% or more.14 Familial cases outside of the syndromes may account for 10% to 30% of colonic cancer cases. FAP is an autosomal dominantly inherited disease that occurs in only about 1 in 10,000 persons.14 Persons with this condition develop hundreds to thousands of adenomatous polyps of the colon at a young age,17 and colonic cancer occurs at an average age of 39 years.14 Total colectomy and mucosal proctectomy is recommended because of the extreme risk for colonic cancer.14 FAP is caused by highly penetrant mutations of the adenomatous polyposis coli (APC) tumor suppressor gene on the long arm of chromosome 5. Persons in most families with FAP have distinct mutations of the APC gene, and these mutations are almost always associated with truncation of the APC protein (i.e., frameshift or nonsense mutations).14 Somatic mutations of the APC gene are involved in some cases of sporadic colon cancer.12 HNPCC, which is much more common than FAP, also occurs in an autosomal dominant fashion.16 HNPCC affects about 1 in every 200 to 400 persons in the United States, which makes it one of the most common autosomal dominantly inherited diseases.9 Colonic cancer occurs at an average age of 45 years in these persons.14 The clinical criteria for diagnosis of HNPCC are three family members who have colonic cancer (two of whom are first degree relatives of the third person), colonic cancer cases spanning at least two generations, and at least one case diagnosed before 100
age 50.16 HNPCC has been additionally divided into hereditary site-specific nonpolyposis colonic cancer (Lynch syndrome I) and cancer family syndrome (Lynch syndrome II).16,18 Patients with Lynch syndrome II develop colorectal cancer and endometrial cancer, ovarian cancer, or cancer of other sites. Millions of families in the United States have cancer histories that are indistinguishable from Lynch syndrome II based on the phenotype or cancers that are expressed.19 Nearly all published studies of mutations in the hMSH2 and hMLH1 genes have been in members of families with HNPCC. Therefore, estimates of the cancer risks associated with hMSH2 and hMLH1 mutations are derived from families characterized by an early age of onset and/or multiple tumors and that meet stringent criteria for autosomal dominant inheritance of cancer predisposition.20,21 Persons from families with HNPCC (including persons who test positive for a hMSH2 or hMLH1 gene mutation) may have a cumulative risk for colorectal cancer as high as 35% by age 50 and 80% by age 70.11,20 However, such estimates may be biased upward, because the people selected for study had a family history of cancer. Estimates of the carrier frequency of hMSH2 and hMLH1 gene mutations among persons who do not have a family history of colorectal cancer are currently lacking. About 95% of colonic cancer cases are sporadic and occur outside of the well-described syndromes.14 About 10% of U.S. adults have a first-degree relative with a history of colonic cancer. Such persons have a two- to threefold increased risk of developing colon cancer.17 Because of the heterogeneity of hMSH2 and hMLH1 mutations, laboratory testing for all possible mutations is difficult for persons not from families at high risk for colorectal cancer. False-positive results may occur as a result of missense mutations that are not associated with an increased risk for colorectal cancer. Frameshift or nonsense mutations that result in protein truncation are likely to predispose carriers to disease.22 Falsenegative results may also occur because not all possible hMSH2 and hMLH1 mutations are likely to be detected.
Public Health Impact of hMSH2 and hMLH1 Colorectal Cancer Genes Most people with a family history of colorectal cancer lack the pedigree characteristics of autosomal dominant inheritance of cancer predisposition.14 In addition, colorectal cancer, similar to other chronic diseases, is likely to have multiple causes and no single gene is likely to account for a significant attributable fraction of colorectal cancer cases.15 Although hMSH2 and hMLH1 mutations may account for many hereditary colorectal cancers in the population, other genetic defects, such as APC gene mutations, are likely to
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account for the genetic predisposition to colorectal cancer in other familial cases.14 Estimates of the prevalence of HNPCC are based on imperfect clinical criteria for identifying HNPCC.11 Such criteria likely underestimate the prevalence because they exclude cases in small nuclear families and cases of extracolonic cancers associated with HNPCC.9 The limitations of existing estimates of the prevalence of HNPCC and the need for population studies of the carrier frequency of gene mutations for colorectal cancer susceptibility, have been previously summarized.23 Despite such limitations, HNPCC is a fairly common cancer predisposition syndrome that appears to be responsible for a small yet significant proportion of some of the most prevalent types of cancer in the United States.11
Interaction of hMSH2 and hMLH1 Gene Mutations with Modifiable Risk Factors for Colorectal Cancer Because most nongenetic risk factors for colorectal cancer have low predictive value, the use of genetic tests is likely to improve the predictive value of environmental and behavioral factors for colorectal cancer. Despite an inherited predisposition, colorectal cancer may not develop in the absence of lifestyle factors. The variable age at onset of hereditary colorectal cancer and the fact that some people who have hMSH2 and hMLH1 gene mutations do not develop cancer indicate that other genetic or environmental factors modify the expression of these traits and that their penetrance is incomplete. Data are scant on the role of environmental risk factors for colorectal cancer among people with hMSH2 and hMLH1 gene mutations. Data are lacking about the value of lifestyle modifications, such as a low-fat diet, adequate intake of vegetables and fruit, and regular exercise, in people with hMSH2 and hMLH1 mutations. Even though such lifestyle modifications are unproven to reduce cancer risk and evidence from randomized trials is lacking, these modifications have a broad range of other health benefits, and they pose fewer risks than pharmacologic or surgical interventions.24 Data are also scant on the effect of nonsteroidal anti-inflammatory drugs and calcium among persons with hMSH2 and hMLH1 gene mutations. In contrast to cancer susceptibility genes such as hMSH2 and hMLH1, less penetrant genetic polymorphisms are much more frequent in the population. Therefore, the public health implications may be greater for common genetic polymorphisms, even though they may be associated with only a modest increase in risk for colorectal cancer. Genetic polymorphisms may account for why some people are more sensitive than others to environmental carcinogens or cancer promoters, such as a diet high in red meat and low in fiber.
In the Physicians’ Health Study, for example, men with the homozygous mutation of the gene associated with reduced enzyme activity and lower levels of 5-methyltetrahydrofolate, the primary circulating form of folate, had one half the risk for colorectal cancer than did men with the homozygous normal or heterozygous genotypes.25 When men who have the homozygous normal genotype and who drank little or no alcohol are the reference group, men who have the homozygous mutation and who drank little or no alcohol had an eightfold lower risk (OR 0.12, 95% CI 0.03 to 0.57), and those who were moderate drinkers had a twofold lower risk (OR 0.42, 95% CI 0.15 to 1.2). These results, which await confirmation in future studies, suggest that this gene mutation reduces colorectal cancer risk and that high alcohol consumption or low folate intake may negate some of the protective effect. Polymorphisms in N-acetyltransferase have also been examined in relation to cancer of the colon, rectum, and other sites.26,27 This enzyme catalyzes the formation of mutagenic substances from foods such as cooked meat and fish. People in whom acetylation is fast are at increased risk for colorectal cancer in some but not all studies.28,29 Slow acetylation has been associated with an increased risk for bladder cancer.28
APC Gene I1307K Variant and Risk for Colorectal Cancer in Ashkenazi Jewish Persons An APC gene variant (I1307K allele), recently reported to be present in 1 in 17 Ashkenazi Jewish persons, may be associated with a doubling of colorectal cancer risk in that population.30 This variant, one of the most common cancer-associated genetic mutations known in a specific population, does not directly alter the function of the APC gene but makes it unstable and prone to mutations during cell division. Ten percent of Ashkenazi Jewish persons with colorectal cancer had this gene mutation compared with 6% of Ashkenazi Jewish persons without cancer.30 About 28% of Ashkenazi Jewish persons with colon cancer and a family history of the disease had the I1307K genetic mutation.30 Of 243 people of other ethnic backgrounds, none had this genetic mutation. In a study by Petrukhin et al.,31 the APC I1307K variant was not found to predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. These investigators detected the APC I1307K variant in 7% (11 of 158) of the Ashkenazi Jewish families with breast and/or ovarian cancer and in 5% (12 of 264) of the individuals participating in the studies. Of the 12 individuals who were found to carry the I1307K variant, none was diagnosed with colorectal cancer and none had a known first-, second-, or thirddegree relative diagnosed with colorectal cancer.31 Frayling et al.32 recently found another APC gene variant (E1317Q allele) to be present in 4 of 164 Am J Prev Med 1999;16(2)
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patients with multiple colorectal adenomas and/or carcinoma in Great Britain (2 of 134 patients with multiple adenomas and 2 of 30 colorectal cancer patients). None of the patients found to carry the E1317Q allele were of Ashkenazi Jewish descent. The family histories of the E1317Q carriers varied; the fathers of two patients with colorectal cancer who had the E1317Q allele died of gastrointestinal cancers.32 The E1317Q variant was not present in 80 non-Ashkenazi British controls. Frayling et al.32 also identified three patients with the I1307K allele, all of whom were of Ashkenazi Jewish descent.
The Effect, Quality, and Safety of Testing for hMSH2 and hMLH1 Gene Mutations The introduction of new genetic tests requires the development of standards, regulations, and guidelines to ensure the accuracy and precision of the laboratory procedures.15 All clinical laboratories in the United States that provide information to referring physicians are certified under the Clinical Laboratory Improvement Act Amendments (CLIA) of 1988. The CLIA regulations address cytogenetic testing and other types of genetic tests. Biotechnology companies currently marketing genetic tests for colorectal cancer to physicians are not required to involve the Food and Drug Administration because these companies are using their own reagents and performing the tests in their own laboratories, but they may voluntarily do so.33 Measures of the validity of genetic tests and other laboratory assays include sensitivity, specificity, and positive and negative predictive values.19 The analytic predictive value of a positive test is the proportion of true carriers among those found to have a mutation.19 The analytic sensitivity is the proportion of true carriers of a cancer susceptibility gene mutation who are found to have the mutation, and specificity is the proportion of noncarriers of the mutation whose test result is negative. Interim principles and recommendations on genetic testing developed by the National Institutes of Health’s and Department of Energy’s Task Force on Genetic Testing additionally define and explain these concepts.34 Laboratory quality assurance of genetic testing is also addressed in the Task Force report.34 The adequacy of genetic testing can be evaluated through surveys of health care providers to determine whether the tests are made available to persons likely to benefit and whether they are appropriately counseled before and after testing. The methods used to obtain informed consent and to ensure the confidentiality of results can also be evaluated. For example, one study of 177 persons tested for genetic susceptibility to adenomatous polyposis coli (APC) found that the appropriate strategy for APC gene testing was used in 79% of patients; only 19% had received genetic counseling 102
before the test, and only 17% had provided written informed consent.35 Other ethical issues are considered subsequently.
Ethical, Legal, and Social Issues Genetic testing for colorectal cancer susceptibility raises ethical and social concerns related to the adequacy of informed consent, the availability and quality of pre- and post-test counseling, and the avoidance of genetic discrimination.36 Other ethical and social issues concern the cost of and access to genetic tests for hMSH2 and hMLH1 mutations, especially among persons who are socioeconomically disadvantaged or underinsured. Moreover, the clinical and preventive applications of such testing are currently ill-defined. The disclosure of genetic test results can have psychologic and economic ramifications for the person screened and his or her relatives.37 Some persons who undergo genetic testing for cancer risk may experience anxiety or other adverse psychologic effects or disrupted personal relationships. Reproductive choices may also be affected. Communities may be harmed if stigmatization or genetic discrimination occurs. Therefore, the screening of selected population subgroups raises ethical concerns and fears. The provision of genetic information without proper counseling and follow-up could lead to psychologic distress and impair adherence to recommendations for the early detection and prevention of colorectal cancer.38 However, people who learn that they carry a hMSH2 or hMLH1 gene mutation might be motivated to adhere to colorectal cancer screening guidelines. Such risks may be minimized through the provision of genetic counseling.39 To make an informed decision about whether to receive genetic testing for colorectal cancer, people must understand the potential benefits as well as the risks and limitations, such as the limitations of current options for cancer prevention and early detection. Guidelines for communicating genetic information about colorectal cancer susceptibility and for providing recommendations and follow-up care for people found to carry hMSH2 and hMLH1 gene mutations have recently been provided.24 Current legal and regulatory safeguards are inadequate to prevent problems associated with genetic discrimination, such as loss of employment or insurance.40 The potential for discrimination by health insurers is one of the most serious risks associated with genetic testing. Genetic counselors commonly advise persons who are considering undergoing genetic testing to verify their insurance coverage before undergoing testing. Genetic discrimination and stigmatization may occur if screening programs target specific populations defined by race, ethnicity, or religion.
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Summary and Conclusions
References
Colorectal cancer is one of the most prevalent types of cancer in the western world. Mutations to the hMSH2 and hMLH1 genes are responsible for a small but significant proportion of colorectal cancer, and such genetic mutations have broad clinical and public health implications. Researchers are beginning to address issues such as the carrier frequency of these gene mutations in specific populations and the relationship between sporadic cases of colorectal cancer and cases attributable to hMSH2, hMLH1, and APC gene mutations.41 Studies of the role of genetic polymorphisms in the etiology of colorectal cancer have been undertaken. Population-based research is needed, however, to examine genotype-phenotype relations and to determine optimal screening protocols and recommendations for preventive interventions for people who have these gene mutations. Large-scale genetic screening for colorectal cancer poses technologic and quality assurance challenges and raises ethical, legal, and social questions.19 The clinical and preventive applications of such screening are unclear. The existence of accepted treatment for people with recognized disease, agreement on whom to treat, the existence of adequate facilities for diagnosis and treatment, reasonable cost of case-finding, and acceptability of the test to the target population are among the recognized criteria for evaluating the suitability of population screening.42 Because not all these criteria are currently met, population-based screening for hMSH2, hMLH1, and APC gene mutations outside of research protocols cannot be recommended. Concern continues about risks of such genetic testing, including the potential for genetic discrimination and stigmatization and the quality of informed consent. Nevertheless, tests for APC gene mutations are already being marketed to clinicians, and tests for hereditary colorectal cancer are becoming commercially available. Surveillance programs for genetic testing should be designed and implemented to closely monitor and evaluate testing done outside of research protocols. The determinants, quality, appropriateness, and extent of such testing are currently poorly understood. Research is needed to learn about the comparability and characteristics of genetic tests for colorectal cancer, to ensure that the tests are standardized, and to examine the adequacy of provisions for informed consent and genetic counseling. Before such tests can be widely used, studies are also needed of the clinical and preventive utility. If genetic tests for colorectal cancer are incorporated into population programs, evaluation will be needed to assess whether the screening is available to all persons likely to benefit and whether the genetic testing is having the intended effect.
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