Jonathan P. Terdiman, M.D., Peggy G. Conrad, M.S., and Marvin H. Sleisenger, M.D.
Colorectal Cancer Program and Cancer Risk Program
Department of Medicine
University of California, San Francisco
San Francisco, California
Acknowledgments: This work was supported in part by a 1997 and 1998 Clinical Research Award from the Glaxo Wellcome Institute for Digestive Health and a grant from the Theodora Betz Foundation. This report is comprised of material published by the American Journal of Gastroenterology, 94:2344-2356, 1999 and is submitted with permission of the publisher.
Corresponding Author: Marvin H. Sleisenger, M.D.
VA Medical Center (11)
4150 Clement St.
San Francisco, CA 94121
Tel: 415/221-4810 ext. 6923
Fax: 415/750-2095
Abstract
Approximately 25% of colorectal cancers occur in younger individuals or those with a personal or family history of the disease, suggesting a heritable susceptibility. The minority of these cases are accounted for by one of the well-described hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). The recent identification and cloning of the genes responsible for FAP and HNPCC, along with other colon cancer susceptibility genes, has led to the widespread availability of genetic testing for hereditary colorectal cancer. Genetic testing raises clinical, ethical, legal and psychosocial questions which must urgently be discussed.
Background
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Each year approximately 150, 000 Americans are diagnosed with the disease and 50, 000 will die of it [1]. The cumulative lifetime risks of colorectal cancer and mortality from CRC are approximately 5-6% and 2.5%, respectively [2]. The majority of colorectal cancers occur in individuals over sixty years old who have no previous personal or family history of the disease. Although the major risk factors for these sporadic cases are advancing age (age > 55) and environmental exposures, most importantly diet [3, 4], approximately 25% of colorectal cancers are in a younger individuals or in those with a personal or family history of cancer, suggesting a heritable susceptibility [5]. First degree relatives of persons with CRC or adenomatous polyps have an approximately twofold risk of developing colorectal cancer, and the risk increases with the number of relatives affected and the earlier the age of onset in the family [6-11]. A family history of extra-colonic cancers (e.g. uterine), or the presence in individual family members of multiple colorectal or other cancers, also increases the risk. About 3% of colorectal cancers are accounted for by two well-defined, highly penetrant, dominant hereditary syndromes for which genetic testing is now available: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) [5, 12]. Based on genetic epidemiological and kindred studies, heredity also plays a causal role in the development of so-called familial colon cancer, an entity distinct from the well-described inherited FAP and HNPCC syndromes, which accounts for approximately 20% of colorectal cancers [11](Figure 1). Candidate genes include minor mutations of the gene responsible for FAP , alleles of genes involved in carcinogen metabolism, and others. Recently a variant of APC, the gene responsible for FAP, has been described that may account for some cases of familial colon cancer in Askenazi Jews [13]. Commercial germ-line genetic testing for this APC variant is now available, and tests for other minor colorectal cancer susceptibility genes are sure to follow in the near future.
Genetic testing for CRC
The recent identification and cloning of a number of genes in which inherited mutations predispose to colorectal cancer has led to the widespread availability of genetic testing in the clinical setting. Genetic predisposition testing promises improved cancer control by leading to scientifically based preventive measures. Such genetic tests raise clinical, ethical, legal and psychosocial questions which must urgently be discussed since the age of genetic testing for colorectal cancer susceptibility has come. Equally imperative in colon cancer prevention is that gastroenterologists must learn of the availability, indications and proper procedures for such genetic testing. This task is formidable given the rapidly expanding body of scientific knowledge of genetic susceptibility, and hence, of colorectal cancer risk.
Genetics of FAP
FAP is caused by a germ-line mutation of the tumor supressor APC gene located on chromosome 5q21 [14, 15]. Normally each individual has two functional copies of the APC gene in all cells. Loss of APC gene function in a colonic epithelial cell by mutation of one gene copy and loss of the other is an early and critical genetic step in the development of most sporadic colorectal neoplasms [16]. Owing to a germ-line mutation of APC, which usually is inherited from a parent but can occur spontaneously in about one-third of cases, individuals with FAP only have one functional copy of the APC gene per cell [17]. Since the colonic epithelial cells have only one functional copy of APC , initiation of colonic neoplasia is far more likely to occur, resulting in a dramatic increase in the number of colorectal adenomas and cancers [18]. Data suggest that in some circumstances mutation of one gene copy alone may be enough to eliminate APC function in a cell because the mutant APC gene product can interfere with the function of the wild-type gene product [19].
APC is a large gene containing 15 exons and 2843 codons. The specific location of a mutation may determine in part the disease phenotype [20]. Mutations at either end of the gene (for example proximal to codon 158 or distal to codon 1900) are associated with an attenuated variant of the FAP characterized by sparse polyposis [21, 22], though phenotypic variation occurs in these families, with some family members still demonstrating a classic phenotype [21, 23]. Mutations between codons 1250 and 1330 are linked with profuse polyposis [20]. CHRPE is present in patients in whom the mutation lies downstream to exon 9 but is not seen in individuals with mutations upstream of this exon [24, 25]. Such genotype-phenotype correlation will prove useful in increasing the accuracy and effectiveness of screening, surveillance and treatment [26].
Screening, surveillance and treatment of FAP
Recommendations for cancer detection and prevention in FAP are summarized in Table [5, 11, 14]. The risk of neoplasm in the upper gastrointestinal tract in FAP necessitates screening of the upper tract as well as the colon.
Genetics of HNPCC
The genetic basis of HNPCC is a germ-line mutation in one of a set of genes responsible for DNA mismatch repair (MMR) [27-31]. The growing number of mismatch repair MMR genes include hMSH2, hMLH1, PMS1, PMS2, hMSH3, hMSH6, and others. Over 90 % of the identified mutations are in two genes, hMSH2 and hMLH1, located on chromosome 2p and 3p respectively [32]. Persons with HNPCC have a non-functioning copy of the gene in the germ-line, usually through an inherited, or occasionally spontaneous, germ-line mutation. When the remaining working copy of the gene is inactivated by mutation, loss or other mechanisms, the cell loses the ability to repair the inevitable mismatches of DNA base pairs during DNA replication (e.g. adenine pairing with cytosine rather than thymine). These mismatches can result in mutation in genes important in carcinogenesis.
Particularly vulnerable to mismatch during replication are DNA regions in which nucleotide bases are repeated several or many times. Such DNA repeat sequences are distributed throughout the genome (most commonly An/Tn or CAn/GTn), and are called microsatellites. Greater than 90% of colorectal cancers in HNPCC demonstrate multiple change-of-length mutations of these microsatellites, termed microsatellite instability (MSI) [33-36]. MSI is classified as being absent, low, or high depending on the frequency of microsatellite mutation. The instability of HNPCC tumors is almost always high frequency [37]. Microsatellites are found in the coding regions of genes involved in growth regulation such as the gene for the transforming growth factor b receptor type II and BAX. Mutations of these genes are common in tumors with high frequency microsatellite instability [38-44]. The binding of TGF-b with its receptor is important in inhibition of cellular proliferation as is BAX in the induction of programmed cell death (apoptosis). A simple laboratory assay can detect the presence or absence and degree of MSI in tumor tissue [36, 45].
Genetic testing for HNPCC enables correlation of specific mutations (genotype) with the expression of the syndrome in the individual and family (phenotype). For example, extra-colonic tumors are more common with hMSH2 mutation than hMLH1 mutation [46, 47]. As in FAP, a better understanding of genotype-phenotype correlation will lead to improved HNPCC screening, surveillance and treatment.
Screening, surveillance and treatment
Recommendations for cancer detection and prevention in HNPCC are in evolution [5, 11, 14, 48]. Current recommendations are summarized in Table 2. Colorectal cancer surveillance by colonoscopy will save lives in HNPCC [49, 50].
APC gene polymorphism
FAP and HNPCC do not account for the majority of colorectal cancer in patients with a positive family history of the disease. Since colorectal cancer is common, it is expected that two or more cases of sporadic CRC may occur in a family by chance. However, multiple studies have demonstrated that the risk of colorectal cancer is greater than expected in first degree relatives of those with CRC or adenomas and is not explained by shared diet and environment [6-11]. Investigators have suspected that dominantly inherited, weakly predisposing alleles of a number of genes underlie most cases of familial colorectal cancer. Such an allele of the APC gene, I1307K, was recently described in Ashkenazi Jews [13].
In the original report I1307K was found in 6.1% of all Ashkenazis tested, in 10.4% of those with colorectal cancer, and 28% with CRC and a positive family history of the disease [13]. Other studies have been unable unequivocally to confirm the relationship between carriage of the I1307K allele and colorectal cancer risk [51-54]. A recent large community-based study of Ashkenazi Jews estimated that by age 70, 5.1% of allele carriers will develop CRC compared with 3.1% of non-carriers [55]. It appears that the magnitude of increased risk conferred by carriage of APC I1307K is low to modest [56], and there is no evidence suggests that CRC in those with I1307K appears at an earlier age or differs presentation or prognosis from sporadic. Nevertheless, even a small increase in CRC risk conferred by a gene that is common in a particular population will have important implications for that population.
The I1307K APC allele is only one example of the minor colorectal cancer susceptibility genes that will be identified with increasing frequency in the future. Colorectal cancer resistance genes will be described as well. The particular combination of minor susceptibility and resistance genes a person inherits will prove to be a major determinant of the differing risk of CRC between individuals. The future identification of these genes factors could offer substantial opportunities to better cancer control.
Genetic Tests for Hereditary Colorectal Cancer
Available tests
Genetic tests are commercially available for FAP, HNPCC and the I1307K APC allele. The tests typically are run on DNA extracted from white blood cells obtained from a blood sample. Rarely DNA for testing can be obtained from another source. The commercial and university-affiliated laboratories that provide these tests, the tests themselves, and their costs are constantly changing. An internet reference to laboratories offering testing for patients with heritable disorders is provided by Helix, a computer-based directory funded by the National Center for Biotechnology Information and the National Library of Medicine. The internet address is (http://www.hslib.washington.edu/helix). The National Cancer Institute maintains a directory of individuals and institutions providing professional cancer genetics services. Information about cancer genetics education, counseling and testing often can be obtained by contacting local providers listed in this directory. The Cancer Genetics Services Directory can be accessed on-line at (http://cancernet.nci.nih.gov/wwwprot/genetic/genesrch.shtml).
To circumvent searching for all mutations by sequencing, other techniques for screening mutations are employed and sequencing then used to confirm positives. Single strand conformational polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) rely on the on difference in the movement of a mutated DNA compared with normal DNA during gel electrophoresis. The in-vitro synthesized protein assay (IVSP), also called the protein truncation test (PTT), detects the truncated protein product of a mutated gene. As the majority of APC mutations truncate the gene product, IVSP is the main test for FAP, and its sensitivity is approximately 80%. Techniques used for HNPCC testing include sequencing, SSCP, DGGE, or IVSP. The sensitivity of synthesized protein testing for HNPCC is lower than for FAP as fewer of the mutations result in a truncated protein product. Present commercial testing in HNPCC has been limited to hMSH2 and hMLH1 as the large majority of HNPCC-related mutations occur in these two genes [32]. The sensitivity of HNPCC testing is thereby further limited by testing only two of the mismatch repair genes. To further complicate matters, a recent report indicates that up to a third of all pathogenic hMSH2 mutations, at least in the Dutch population, may be secondary to a germ-line deletion of a large portion or an entire hMSH2 allele. These large deletions will often escape detection by methods such as SSCP, DGGE, IVSP and direct sequencing [57].
Once a particular mutation has been identified in a family, the search for that mutation in other family members can be accomplished rapidly, accurately and inexpensively. The most commonly used technique relies on the detection of hybridization between the DNA to be tested and a DNA sequence that carries the known mutation. The APC I1307K allele also can be detected in this fashion.
In large families that appear to have hereditary colorectal cancer, but in whom the deleterious mutation cannot be found by the direct gene detection methods outlined above, linkage analysis can be employed to determine which individuals carry the deleterious allele [58]. Linkage analysis is based on the simple fact that two regions of DNA that are in close proximity will tend to segregate together (stay linked) during meiosis. DNA microsatellites are chosen that are known to be close to the gene in question. The microsatellites chosen vary with respect to exact nucleotide length between individuals, and this variation (polymorphism) can be easily detected. Individuals in a family that have inherited a mutant copy of the gene in question also inherit particular microsatellite polymorphisms linked to that allele, while those without the mutant allele will inherit different microsatellite variants. By ascertaining the microsatellite variants a particular individual's DNA harbors, and knowing which variants are linked to the mutant gene in the family, one can obtain strong indirect evidence on whether or not the mutant gene was inherited by that individual. In linkage analysis microsatellites are assessed in DNA obtained from blood not tumor. Even though there may be high frequency microsatellite instability in tumor DNA in HNPCC, instability does not occur in germ-line DNA obtained from blood cells. Therefore, linkage analysis is possible in both HNPCC and FAP.
Microsatellite instability (MSI)
Assays to assess MSI in tumor tissue are commercially available, but the laboratories that provide this service change frequently. The best way to determine who currently is performing MSI testing on tissue is to ask the laboratories that are providing germ-line HNPCC testing, or to contact a local provider of professional cancer genetics services. Because the large majority of HNPCC related tumors (90-100%) demonstrate high frequency instability (MSI-H), MSI testing of tumors is advocated as a way of screening for HNPCC [59, 60]. The MSI assay can be performed on tissues that have been formalin fixed and embedded in paraffin. In unselected colorectal tumors the specificity of MSI-H for HNPCC is low because 10-15% of all colorectal cancers will demonstrate MSI-H but only 10-15% of these are due to a germ-line HNPCC mutation [12, 61]. As the sensitivity of MSI-H in HNPCC-related tumors is not 100%, some investigators caution that germ-line HNPCC testing should not be abandoned if MSI-H is not found when the clinical history is compelling. The exact role of MSI testing in the detection of individuals with HNPCC remains uncertain and will be discussed below.
Consequences of Genetic Testing for Hereditary Colorectal Cancer
Positive consequences
Public interest in genetic testing for colorectal cancer susceptibility is high [62, 63]. Two scenarios best exemplify the potential benefits of genetic testing for hereditary CRC. In the first scenario the clinician encounters a family that clearly has one of the hereditary colorectal cancer syndromes. It will have members with cancer and others not yet affected, but at risk. To increase the chance of early detection and hence decrease cancer associated morbidity and mortality, burdensome screening procedures must be performed on those at risk. Detection of a mutation among one of the affected members of the family permits genetic testing of at-risk relatives. Those free of mutation need no longer participate in the intensive screening program, while those with the mutation must continue screening and be considered for prophylactic surgery. Recommendations concerning screening and treatment may be modified by knowledge of the exact mutation carried. For example carriers of an APC mutation associated with attenuated FAP may require colonoscopic rather than sigmoidoscopic screening. However, after polyps are detected in these individuals, it may be appropriate to perform a total abdominal colectomy with ileorectal anastomosis rather than a proctocolectomy with ileoanal anastomosis. In the future gene carriers may qualify for novel screening and treatment approaches and they may benefit from other preventive measures, such as chemoprevention. Dispelling the uncertainty of cancer risk may reduce anxiety, improve coping, aide in planning for the future, and improve compliance with medical recommendations. Further, when insurance discrimination has occurred based on family history alone, a negative gene test may reverse the situation. Finally, use of genetic testing to guide cancer screening in families with suspected hereditary cancer will save money [64].
A second scenario in which genetic testing may be of benefit is to establish the diagnosis of hereditary cancer in families in which it is uncertain. Genetic diagnosis of familial cancer will save lives since standard screening and treatment recommendations would be appropriately augmented. An example would be the testing of an individual with a possible FAP phenotype, but no family history of FAP, or the testing of an individual for HNPCC who does not meet Amsterdam criteria, but has a very early onset colorectal cancer and a positive family history. Identification of mutations will have profound effects as many family members may be completely unaware that they are even at-risk for hereditary CRC.
Consequences of Testing
Much of the benefit derived of genetic testing for hereditary CRC is its reduction of uncertainty. The tests available for FAP and HNPCC, however, are imperfect, and neither the sensitivity nor specificity is 100%. Hence, results can be ambiguous. The clearest example of this would be the testing of an affected individual from a suspected hereditary CRC family in which a mutation has not previously been identified. Failure to detect a mutation in this case does not rule out hereditary cancer since the individual may still harbor a hereditary CRC mutation that can not be detected by the current tests. Another example of a shortcoming of a test is that detection of a gene alteration does not always indicate whether the alteration is a deleterious mutation. The alteration may be a silent change representing a polymorphism. This occurs frequently in HNPCC testing. Knowledge about the segregation of this altered allele with respect to affected and non-affected individuals can resolve this ambiguity, but this information is often unavailable. For genetic testing to reduce uncertainty, the proper interpretation of positive, negative and non-informative results is essential (Table 2). Alarmingly, a recent study of physicians ordering FAP testing found that almost a third of providers misinterpreted the results [65].
Psychological harm of Testing
Genetic testing can psychologically harm a patient. Members of families with multiple and early-onset cancers have already experienced much grief and suffering. Genetic testing can add to this burden. Positive test results may be accompanied by feelings of anger, anxiety, and depression [66]. Even individuals that have already been diagnosed with cancer may be shocked and saddened to learn that this "trait" may be passed onto their children, or that they are at risk for further cancers. Individuals who test negative may experience relief and joy, they may also experience feelings of guilt and shame (survivor guilt) when dealing with the reality that others in the family carry the deleterious gene . Ambiguous results of tests may lead over time to anxiety and depression greater than a positive result. Individuals with cancer are often looking for an explanation of their cancer, and for a way to protect their children from the same fate. Therefore, ambiguous results can be especially troubling.
Genetic discrimination
The gravest negative consequence of genetic testing for hereditary colorectal cancer is the possibility of genetic discrimination. Discrimination may be purely social, such as with respect to dating and marriage. Genetic testing also may lead to the inability to obtain or keep a job or health, life or disability insurance. In a survey of members of a genetic support group, 25% stated they were refused life insurance, 22% were refused health insurance and 13% were denied or lost employment [67]. In a recent anonymous survey of insurance company presidents, 10% said they would not provide health insurance to HNPCC gene carriers and 20% would increase the premiums to these individuals. Also, one quarter of insurers would either not provide, or provide only at increased premium, life or disability insurance [68].
Confidentiality
The fear of genetic discrimination creates a vexing problem for the clinician with respect to issues of confidentiality. Kenneth Offitt Writes, "Clinicians are left to choose between two bad alternatives: recording genetic data in patient charts (posing insurance risks to patients), or keeping genetic data in separate records (compromising availability of information to be used in making medical decisions)" [69]. When testing is performed in a "research" setting, providers may be able to obtain a certificate of confidentiality issued by the Department of Health and Human Services. The certificate protects the researcher from being compelled to reveal the identity of a research subjects "in any Federal, State or local civil, criminal, administrative, legislative, or other proceedings...". A clear distinction between "research" and "clinical" activity in the area of cancer genetic predisposition testing often is difficult to make. Certificates of confidentiality are not appropriate or available in all situations that involve genetic testing. An even greater problem may confront patients that have been tested. To maintain confidentiality, patients may be put in the unenviable position of having to withhold information about test results if asked by an insurance company.
References
1. Parker SL, Tong T, Bolden S, Wingo PA: Cancer Statistics, 1997. CA-A Cancer Juornal for Clinicians 1997; 47(1): 5-27.
2. SEER Cancer Statistics Review,1973-1995. (http://www-seer.ims.nci.nih.gov/Publications/CSR7394/colorect.pdf) ed: National Cancer Institute, 1999.
3. Sandler RS: Epidemiology and risk factors for colorectal cancer. Gastroenterology Clinics of North America 1996; 25(4): 717-35.
4. Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN: Eating patterns and risk of colon cancer. American Journal of Epidemiology 1998; 148(1): 4-16.
5. Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112(2): 594-642.
6. St. John DJB, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ESR: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993; 118: 785-790.
7. Slattery ML, Kerber RA: Family history of cancer and colon cancer risk: the Utah Population Database. Journal of the National Cancer Institute 1994; 86(21): 1618-26.
8. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC: A prospective study of family history and the risk of colorectal cancer. New England Journal of Medicine 1994; 331(25): 1669-74.
9. Winawer SJ, Zauber AG, Gerdes H, et al.: Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. New England Journal of Medicine 1996; 334(2): 82-7.
10. Ahsan H, Neugut AI, Garbowski GC, et al.: Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Annals of Internal Medicine 1998; 128(11): 900-5.
11. Burt RW: Screening of patients with a positive family history of colorectal cancer. Gastrointestinal Endoscopy Clinics of North America 1997; 7(1): 65-79.
12. Aaltonen LA, Salovaara R, Kristo P, et al.: Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. New England Journal of Medicine 1998; 338(21): 1481-7.
13. Laken SJ, Petersen GM, Gruber SB, et al.: Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nature Genetics 1997; 17(1): 79-83.
14. Kinzler KW, Nilbert MC, Su LK, et al.: Identification of FAP locus genes from chromosome 5q21. Science 1991; 253: 661-665.
15. Groden J, Thliveris A, Samowitz W, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66: 589-600.
16. Powell SM, Zilz N, Beazer-Barclay Y, et al.: APC mutations occur early during colorectal tumorigenesis. Nature 1992; 359(6392): 235-7.
17. Miyoshi Y, Ando H, Nagase H, et al.: Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proceedings of the National Academy of Sciences 1992; 89: 4452-4456.
18. Gryfe R, Di Nicola N, Gallinger S, Redston M: Somatic instability of the APC I1307K allele in colorectal neoplasia. Cancer Research 1998; 58(18): 4040-3.
19. Polakis P: The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta 1997; 1332(3): F127-47.
20. O'Sullivan MJ, McCarthy TV, Doyle CT: Familial adenomatous polyposis: from bedside to benchside. American Journal of Clinical Pathology 1998; 109(5): 521-6.
21. Giardiello FM, Brensinger JD, Luce MC, et al.: Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene. Annals of Internal Medicine 1997; 126(7): 514-9.
22. Gardner RJ, Kool D, Edkins E, et al.: The clinical correlates of a 3' truncating mutation (codons 1982-1983) in the adenomatous polyposis coli gene. Gastroenterology 1997; 113(1): 326-31.
23. Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 1998; 43(4): 548-52.
24. Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G: Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell 1993; 75(5): 959-68.
25. Wallis YL, Macdonald F, Hult‚n M, et al.: Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis. Human Genetics 1994; 94(5): 543-8.
26. Wu JS, Paul P, McGannon EA, Church JM: APC genotype, polyp number, and surgical options in familial adenomatous polyposis. Annals of Surgery 1998; 227(1): 57-62.
27. Fishel R, Lescoe MK, Rao MR, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1994; 77(1): 167.
28. Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75(6): 1215-25.
29. Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994; 368(6468): 258-61.
30. Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371(6492): 75-80.
31. Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genetics 1997; 17(3): 271-2.
32. Peltom„ki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997; 113(4): 1146-58.
33. Peltom„ki P, Aaltonen LA, Sistonen P, et al.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993; 260(5109): 810-2.
34. Parsons R, Li GM, Longley MJ, et al.: Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 1993; 75(6): 1227-36.
35. Aaltonen LA, Peltomaki P, Mecklin JP, et al.: Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994; 54(7): 1645-8.
36. Boland CR, Thibodeau SN, Hamilton SR, et al.: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Research 1998; 58(22): 5248-57.
37. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, R?schoff J: Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Research 1997; 57(21): 4749-56.
38. Markowitz S, Wang J, Myeroff L, et al.: Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268(5215): 1336-8.
39. Parsons R, Myeroff LL, Liu B, et al.: Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 1995; 55(23): 5548-50.
40. Akiyama Y, Iwanaga R, Saitoh K, et al.: Transforming growth factor beta type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. Gastroenterology 1997; 112(1): 33-9.
41. Rampino N, Yamamoto H, Ionov Y, et al.: Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275(5302): 967-9.
42. Yagi OK, Akiyama Y, Nomizu T, Iwama T, Endo M, Yuasa Y: Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas. Gastroenterology 1998; 114(2): 268-74.
43. Ouyang H, Furukawa T, Abe T, Kato Y, Horii A: The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. Clin Cancer Res 1998; 4(4): 1071-4.
44. Yamamoto H, Sawai H, Weber TK, Rodriguez-Bigas MA, Perucho M: Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer. Cancer Research 1998; 58(5): 997-1003.
45. Bocker T, Diermann J, Friedl W, et al.: Microsatellite instability analysis: a multicenter study for reliability and quality control. Cancer Research 1997; 57(21): 4739-43.
46. Lin KM, Shashidharan M, Thorson AG, et al.: Cumulative incidence of colorectal and extracolonic cancers in MLH1and MSH2 mutation carriers of herditary nonpolyposis colorectal cancer. Journal of Gastrointestinal Surgery 1988; 2: 67-71.
47. Lin KM, Shashidharan M, Ternent CA, et al.: Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Diseases of the Colon and Rectum 1998; 41(4): 428-33.
48. 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. Cancer Genetics Studies Consortium. Jama 1997; 277(11): 915-9.
49. J„rvinen HJ, Mecklin JP, Sistonen P: Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108(5): 1405-11.
50. Syngal S, Weeks JC, Schrag D, Garber JE, Kuntz KM: Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Annals of Internal Medicine 1998; 129(10): 787-796.
51. Petrukhin L, Dangel J, Vanderveer L, et al.: The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. Cancer Research 1997; 57(24): 5480-4.
52. Abrahamson J, Moslehi R, Vesprini D, et al.: No association of the I1307K APC allele with ovarian cancer risk in Ashkenazi Jews. Cancer Research 1998; 58(14): 2919-22.
53. 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. Proceedings of the National Academy of Sciences of the United States of America 1998; 95(18): 10722-7.
54. White RL: Excess risk of colon cancer associated with a polymorphism of the APC gene? Cancer Research 1998; 58(18): 4038-9.
55. Woodage T, King SM, Wacholder S, et al.: The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nature Genetics 1998; 20(1): 62-5.
56. Rozen P, Shomrat R, Strul H, et al.: Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Gastroenterology 1999; 116(1): 54-7.
57. Wijnen J, van der Klift H, Vasen H, et al.: MSH2 genomic deletions are a frequent cause of HNPCC. Nature Genetics 1998; 20: 326-328.
58. Piepoli A, Santoro R, Cristofaro G, et al.: Linkage analysis identifies gene carriers among members of families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1996; 110(5): 1404-9.
59. Jass JR, Cottier DS, Jeevaratnam P, et al.: Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet 1995; 346(8984): 1200-1.
60. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. Journal of the National Cancer Institute 1997; 89(23): 1758-62.
61. Liu B, Nicolaides NC, Markowitz S, et al.: Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genetics 1995; 9(1): 48-55.
62. Smith KR, Croyle RT: Attitudes toward genetic testing for colon cancer risk. American Journal of Public Health 1995; 85(10): 1435-8.
63. Lerman C, Marshall J, Audrain J, Gomez-Caminero A: Genetic testing for colon cancer susceptibility: Anticipated reactions of patients and challenges to providers. International Journal of Cancer 1996; 69(1): 58-61.
64. Cromwell DM, Moore RD, Brensinger JD, Petersen GM, Bass EB, Giardiello FM: Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis. Gastroenterology 1998; 114(5): 893-901.
65. Giardiello FM, Brensinger JD, Petersen GM, et al.: The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. New England Journal of Medicine 1997; 336(12): 823-7.
66. Vernon SW, Gritz ER, Peterson SK, et al.: Correlates of psychologic distress in colorectal cancer patients undergoing genetic testing for hereditary colon cancer. Health Psychology 1997; 16(1): 73-86.
67. Lapham EV, Kozma C, Weiss JO: Genetic discrimination: perspectives of consumers. Science 1996; 274(5287): 621-4.
68. Rodriguez-Bigas MA, Vasen HF, O'Malley L, et al.: Health, life, and disability insurance and hereditary nonpolyposis colorectal cancer. American Journal of Human Genetics 1998; 62(3): 736-7.
69. Offitt K: Clinical Cancer Genetics. New York: Wiley-Liss, 1998.
Table 1. Options for Cancer Surveillance and Prevention for FAP and HNPCC in Known or Suspected Gene Mutation Carriers*
FAP
+ Annual flexible sigmoidoscopy beginning by age 10-12
+ Annual colonoscopy, beginning by age 20, when attenuated FAP suspected
+ Prophylactic colectomy in teen years or when polyps detected at endoscopy
+ Endoscopic surveillance every 4-6 months after ileorectal anastomosis and annually after ileoanal anastomosis
+ Upper endoscopy, including duodenoscopy, every 6 months to 3 years starting by age 20
HNPCC
+ Colonoscopy every 1-3 years beginning at age 20-25 or 10 years before the earliest diagnosis of colorectal cancer in the family, whichever comes first_
+ Consider total colectomy at diagnosis of cancer
+ Consider of prophylactic colectomy in known gene carriers
+ Transvaginal ultrasound (with color Doppler) annually beginning at age 25-35__
+ Consider prophylactic hysterectomy and oopherectomy in known gene carriers
_Some experts recommend colonoscopy every 1-2 years until age 40 and every year thereafter
__Alternate strategy would employ yearly endometrial aspirate
*References (5, 11, 48, 69)
Table 2. Appropriate Interpretation of Genetic Test Results
| Proband Result | Family member result | Interpretation |
| Positive | Positive | Positive |
| Positive | Negative | Negative |
| Ambiguous | Do not test | Not informative* |
* Must assume that family member carries the deleterious gene given the inability to prove otherwise because of the negative test in the proband. Proceed with cancer screening appropriate for a gene carrier in the family member.