Supporting Documentation

October 2001 - Vol44, No.10

PRACTICE PARAMETERS FOR THE IDENTIFICATION AND TESTING OF PATIENTS AT RISK FOR DOMINANTLY INHERITED COLORECTAL CANCER - SUPPORTING DOCUMENTATION

Prepared By
The Standards Task Force
The American Society of Colon and Rectal Surgeons

James Church, M.D., For the Collaborative Group, and Ann Lowry, M.D., Clifford Simmang, M.D., For The American Society of Colon and Rectal Surgeons

It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient.

Even though the incidence of colorectal cancer has decreased at an average of 1.6 percent per year from 1985 to 1997,(1) it is still the second leading cause of cancer deaths in the United States. It is eminently preventable. When it does occur, early diagnosis offers an improved chance of cure. Detection of asymptomatic cancers and prevention of cancer by removal of asymptomatic adenomas requires screening, which can be most beneficial for patients at high risk. Guidelines for identification and screening of those at increased risk for colorectal cancer by virtue of their family history are proposed.

The genetic changes associated with the development of sporadic colorectal neoplasia are becoming better understood. An accumulation of inactivating mutations in tumor suppressor genes along with activation of proto-oncogenes produces progressive loss of control of colonocyte growth, death, and differentiation that is manifest histologically as the adenoma-carcinoma sequence.(2,3) In most cases, these mutations are somatic, occurring in the colonocyte as a result of the influences of the colonic environment and the effects of aging. In some patients, germline mutations are inherited from a parent or occur de novo at conception and predispose cells to earlier, faster neoplastic transformation. Syndromes of dominantly inherited colorectal cancer include familial adenomatous polyposis (FAP)(4) and hereditary nonpolyposis colorectal cancer (HNPCC or the Lynch Syndromes I and II).(5) The genetic basis for FAP is a germline mutation of APC, which is also the first tumor suppressor gene involved in the pathway to sporadic colorectal neoplasia.(6,7) HNPCC lies at the end of a different genetic route, involving DNA mismatch repair (MMR).(8,9) Several proteins are involved in the recognition and repair of errors that occur during DNA replication. The genes coding for these proteins in humans include hMSH2, hMSH3, hMSH6, hMLH1, hPMS1 and hPMS2. An inherited inactivating mutation of any one of these genes leads to deficient repair, with hypermutability of the DNA and development of the clinical syndrome known as HNPCC.(5,8,9)

FAP and HNPCC account for less than 5 percent of the 135,400 cases of colorectal cancer expected to be diagnosed this year in the United States.(1) A much less well-defined proportion of cases show clustering of colorectal cancer in a family and may be categorized under the heading of Familial Colorectal Cancer (FCC). In these cases, the family history is not strong enough, and the disease phenotype is not suggestive enough, to fit the clinical definitions of FAP or HNPCC. Although some of these families may harbor a germline APC or MMR gene mutation, most will not. Their members are not candidates for routine clinical genetic testing but they are at increased risk of colorectal cancer. The definition of a family cluster of colorectal cancer varies, but the increased cancer risk associated with at least two affected first-degree relatives (10-12) suggests that this is an appropriate level for inclusion.

Inherited colorectal cancer can therefore be defined as clustering of the disease in a family where at least two first-degree relatives (parents, siblings, and children) are affected. Clinical syndromes fitting this definition include FAP, HNPCC, FCC, and the rarer syndromes of Peutz-Jeghers Polyposis and Juvenile Polyposis. These practice parameters focus on FAP and HNPCC, especially risk recognition and assessment, and testing, screening, and surveillance.

The first clue to the presence of inherited colorectal cancer in a family is usually a strong family history.(13,14) Risk increases with increasing numbers of relatives affected, younger age at diagnosis of affected relatives and closer family relationship to the patient (Table 1).

Table 1.

Guideline 1. Take a Family History

A simple screening question, "have you or any of your relatives ever had colorectal cancer or polyps?" is effective in identifying most high-risk families. If the answer is yes, ask the number of relatives affected, their relationships and their age at diagnosis. An expanded family tree is needed if there are more than two first-degree relatives affected.

Patients who have a particularly strong family history may be members of a family affected by a dominantly inherited syndrome of colorectal cancer. Criteria suggesting dominant inheritance include:

Vertical transmission of disease(from one genera-tion to another).

Disease occurring at a young age (<50 years).

Multiple affected relatives.

Genetic testing may be indicated to confirm the presence of an inherited mutation in these patients and in their families. It is important to remember that about 30 percent of patients with FAP do not have a family history. Most of these patients represent new mutations. In this case, the parents are unaffected, siblings are not at risk, but offspring are. Other reasons for the lack of a family history include adoption, nonpaternity, loss of contact with family, or denial. A suggestive phenotype in the absence of family history still needs investigation.

Guideline 2. Document a Suspicious Pedigree

When a patient has a family history suggestive of a dominantly inherited syndrome of colorectal cancer, a fully documented pedigree is needed. This means confirming diagnoses with pathology reports, death certificates or other medical records and is best done in the setting of an institutional review board-approved program within a department or registry with a special interest in these syndromes. A preliminary appointment is used to obtain informed consent and signed releases from the proband so that medical records of affected family members may be sought and other family members contacted.

Guideline 3. Identify Criteria for Genetic Testing

If documentation supports the following criteria, genetic testing is discussed with the proband and family.

FAP:(15)

1. More than 100 adenomatous polyps in the colon and rectum.
2. Undiagnosed, at-risk family member in docu-mented FAP kindred.
3. Typical, extracolonic manifestations of FAP (e.g., duodenal neoplasia, abdominal desmoid tumors, congenital hypertrophy of the retinal pigmented (CHRPE), epidermoid cysts, osteomas) with any number of colorectal adenomas.
4. Clinical suspicion of attenuated FAP: pattern of dominantly inherited colorectal cancer; age of onset of cancer relatively late (50s and 60s); smaller number of adenomas (<100).

HNPCC: The Amsterdam Criteria(16) have been used to identify patients and families likely to have HNPCC:

1. At least three affected relatives (with colorectal cancer); two are first-degree relatives of the other one.
2. At least two successive generations affected.
3. Colorectal cancer diagnosed , 50 years in at least one family member.
4. No evidence of FAP.

The Amsterdam Criteria have been criticized as being too rigid in that they fail to account for small families where a dominant pattern of inheritance may not be obvious and for extracolonic cancers that are included in the syndrome of HNPCC. Other sets of clinical criteria for HNPCC genetic testing have been reported: Mt. Sinai Registry (Toronto) Criteria,(17) Japanese Criteria for HNPCC,(18) International Collaborative Group (ICG)-HNPCC Criteria for Amsterdam-negative patients to benefit from MMR testing,(19) and "Modified Amsterdam" criteria.(20) In 1999 the Amsterdam II criteria were published(21) in an attempt to answer some of the criticisms of the original Amsterdam criteria. The Amsterdam II Criteria still require three family members with cancer but allow inclusion of families with three HNPCC-related cancers (endometrial, small bowel, ureteric/renal pelvis) as long as there are two consecutive generations affected, one member is a first-degree relative of the other two, and at least one affected member was diagnosed at or younger than age 50. Use of the original Amsterdam Criteria as an indication for germline mismatch repair gene testing results in detection of a mutation in 40 to 60 percent of families (depending on the particular genetic tests used and whether all mutations or only pathogenic mutations are included). The use of less strict criteria is associated with significantly lower yields (Table 2). Although the pedigrees of families failing to satisfy the original Amsterdam Criteria may be strong enough to arouse suspicion, there is not enough justification yet for routine MMR gene testing. There is, however, a genetic test that looks for microsatellite instability (MSI) in tumors as evidence of MMR deficiency. In a family with a strong history of colorectal or other HNPCC cancers, a microsatellite unstable tumor is highly suggestive of HNPCC.

DNA microsatellites are short repetitive sequences of nucleotide bases found throughout the genome. They may be single base repeats, or repeats of two to five nucleotides. They are polymorphic and subject to change in the number of repeated bases when DNA mismatch repair is defective. A change in the length of any two out of a panel of 5 (or >30 percent of any number of markers) microsatellites in DNA extracted from tumor tissue when compared with normal tissue from the same patient is defined as microsatellite instability.(32) In the context of other phenotypic evidence of HNPCC, such as a suggestive family history, MSI predicts HNPCC. The concept of screening high risk but Amsterdam Criteria-negative families with MSI(33,34) testing deserves formal study. Mutational analysis in families with MSI-positive tumors is likely to have a higher yield of MMR gene mutations than in families with MSI-negative tumors (Table 2). A NCI sponsored symposium developed criteria to identify patients whose tumors may be worth MSI analysis (Bethesda Criteria, see Appendix 1).(32) Modified Bethesda criteria have been used as a basis for germline mutation testing of hMLH1 and hMSH2. Although sensitivity was high, specificity was low (49 percent).(21) Immunohistochemistry is a way of further refining the search for a MMR gene mutation. If hMLH1, hMSH2, or hMSH6 protein is not expressed in tumor tissue from a patient suspected of having deficient DNA mismatch repair, a germline mutation of that gene may be sought.(35)

Table 2.

Guideline 4. Who Should Be Involved with These Families?

Care of patients and families who are likely to have a syndrome of inherited colorectal cancer is highly specialized. Healthcare providers need to be familiar with the genetic concepts involved, with details of the genetic pathways that lead to colorectal cancer, with the information that underlies these guidelines, and with the principles that govern management of families with a dominantly inherited disease. The syndromes of FAP and HNPCC are sufficiently uncommon that such specialized care need not be universally available. Centers with an interest in the syndromes exist, usually based around a registry or a clinical program, where the required level of expertise exists in clinical management, medical genetics, cancer genetics, molecular genetics, genetic counseling, and data management. Patients and families may be referred to such programs without fear that their overall care will be usurped. Collins has supported the team approach.(36) He stated that an educational and evaluative process is needed to establish minimal standards of care for healthcare providers who take part in educational or counseling services related to genetic testing. His comments are supported by data showing that misinterpretation of the relatively straightforward APC genetic testing is common.(37)

Guideline 5. Offer Surveillance to Families for Whom Genetic Testing Is Not Indicated

Families with clustering of colorectal cancer that is strong enough to arouse suspicion of an inherited syndrome, but does not fit criteria for FAP or HNPCC, should be kept under surveillance. Patients can be offered regular endoscopy and updating of their pedigree. It is possible that as time passes and the pedigree matures, the family history will change so that genetic testing becomes appropriate.

Genetic testing is an important step in characterizing a family affected by a dominantly inherited syndrome of colorectal cancer. Its main purpose is to define risk status, separating those who carry the mutation and who are likely to manifest the disease from those who do not carry the mutation and are at background population risk. Genetic testing is important for younger generations as confirmation of a normal genotype, exempting children from the intensive screening recommended for mutation carriers.

Genetic testing has psychological, financial, and insurance-related implications.(38) For this reason, genetic testing must follow a carefully defined protocol:

Guideline 6. Adhere to Protocol for Genetic Testing

Institutional Review Board (IRB) Approval for Program. The IRB is an essential part of protection for patients, families and healthcare workers, as confidentiality of information becomes increasingly important.

Pretest Counseling and Informed Consent. The initial counseling session includes education about the nature of FAP or HNPCC, the meaning of a dominant pattern of inheritance and the implications of this for risk status of the family members.(38,39) The effect of genetic testing in defining risk status and what this means for surveillance and treatment is also covered. Other issues to be discussed include the emotional and financial impact of a positive and negative result, confidentiality of records and test results, costs, and method of payment. Informed consent is then obtained from the patient to enter the patient and the patient's family into the registry, to contact relatives, to obtain medical records, and to bank blood or tissue.

The effect of genetic testing on insurability and insurance premiums remains one of the most controversial areas in the management of families with inherited disease. A U.S. public opinion survey conducted in 1994 for the American Council of Life Insurance showed that 77 percent of those surveyed did not want the results of genetic testing accessible to life insurance companies.(40) Only 27 percent would pay higher premiums to enable a universal rate. Legislation prohibiting insurance discrimination based on genetic testing is endorsed by The American Society of Clinical Oncology,(41) as well as by The American Society of Colon and Rectal Surgeons (ASCRS) and the Collaborative Group of the Americas on Inherited Colorectal Cancer. From an insurance company's view however, determination of risk is key to determining premiums: high-risk clients pay more, whereas lower-risk clients pay less. If a client knows his or her future risk but does not supply this knowledge to an insurance company, calculation of premiums is made in error. Of course, if a genetic test shows a normal genotype in a family where the mutation is known, an individual previously at 50 percent risk becomes at average population risk and should expect low premiums and unhindered insurability. Health insurance is particularly important in countries where public health coverage is limited. In one U.S. study about one-third of FAP patients had difficulties obtaining health insurance coverage because of higher premiums or preexisting disease clauses. This resulted in reluctance to leave a job (job lock), deferment of surveillance or even postponement of surgery.(42) As of 1997, legislation to prohibit insurance companies from requesting genetic testing, or using the results of genetic testing, is in place in 25 states and is under consideration in 5 others.(43) It is recommended that the results of genetic testing done for research purposes be excluded from the patient's clinical record and that the patient not be informed. This is to be specifically stated and agreed to in the pretest consent process. Genetic testing done for clinical purposes is included in the patient's record. This also is stated in the pretest consent.

Test. Clinical testing needs to be done at a laboratory approved by Clinical Laboratory Improvement Amendments, a Health Care Financing Administration program for regulation of laboratory testing.

Posttest Counseling. The same issues covered in the pretest session are covered again, as they relate to the results obtained from testing. Clinical recommendations are explained, and confidentiality of results is discussed.

There are a variety of molecular techniques that can be used to detect mutations, or their effect. The reliability of these tests varies according to the test itself, the mutations that are sought, and the genes under scrutiny.(44) Because of this, testing strategies may differ from one family to another.

First, look for a mutation in an affected family member. Protein truncation testing (PTT) is usually informative, because most APC mutations cause premature stops in protein production. PTT does not identify the actual mutation, however. Genotype/ phenotype relationships may be used in the search as follows:

If polyposis is severe, screen "hot spots" on exon 15G first.(35)

If CHRPE-positive, screen exons 9 to 15G first.

If phenotype is attenuated, screen exons 3 and 4, and 3' end of exon 15 first.

If blood from an affected family member is not available or mutational analysis is not available, use PTT. Once the family mutation has been identified, at-risk relatives can be tested, starting at age 10 or 12 years.

The great majority of MMR gene mutations identified are in hMLH1 or hMSH2. Look for an hMSH2 or hMLH1 mutation in an affected family member. PTT is less effective in HNPCC than in FAP because of the increased number of missense mutations in HNPCC (single base changes that do not shorten the protein). If PTT is negative, gene sequencing is done. If a missense mutation is found on sequencing, look to see if it segregates with disease, or if it has been previously reported as being associated with disease. If a pathologic mutation is identified, test at-risk members in family starting at least ten years younger than the youngest affected. Preliminary immunohistochemistry testing using antibodies against hMLH1, hMSH2, and hMSH6 with tumor tissue that is microsatellite unstable may predict which gene to sequence and streamline the process.

If the mutation associated with disease in the family is identified and an at-risk relative is negative for that mutation, that relative's risk for FAP is no greater than population level. Screening should be as for the average-risk population.

If the at-risk relative has the mutation, surveillance should start immediately with a baseline colonoscopy and continue with flexible sigmoidoscopy every year until adenomas are diagnosed and surgery is performed.

If no mutation can be found in affected relatives and protein truncation is negative, genetic testing is uninformative. Screen all at-risk relatives with yearly flexible sigmoidoscopy beginning at age 10 or 12 years, depending on the severity of the polyposis in affected relatives.

If the mutation associated with disease in the family is identified and an at-risk relative is negative for that mutation, that relative's risk for HNPCC is no greater than population level. Screening should be as for the average-risk population.

For any relative with the mutation, surveillance should start immediately with a baseline colonoscopy. Recommendations for colonoscopic surveillance programs for HNPCC vary. The American Cancer Society recommends biennial exams from age 21 to age 40, with annual exams after that.(45) The Cancer Genetics Studies Consortium gives colonoscopy at a range of every one to three years starting at age 20 to 25,(46) whereas the recommendations endorsed by multiple societies, including ASCRS, American Cancer Society, American College of Gastroenterology, American Gastroenterological Association, American Society of Gastrointestinal Endoscopy, and Society of American Gastrointestinal Endoscopic Surgeons are colonoscopy every one to two years starting at age 20 to 30 years, with yearly colonoscopy after age 40.(47) There have been no randomized studies comparing different frequencies of colonoscopy, but data from retrospective studies show that interval cancers occur when examinations are performed every three years.(48,49) ASCRS and the Collaborative Group of the Americas on Inherited Colorectal Cancer confirm their endorsement of these last-mentioned guidelines.

If no mutation can be found in the affected relatives, and protein truncation is also negative, the test is uninformative. Screen all at-risk relatives clinically, as described in the endorsed guidelines.

If a missense mutation is identified, check to see if it segregates with disease in the family. If not, treat the test as uninformative. If it does segregate, then at-risk family members can be screened for the mutation.

Extracolonic cancers with an increased incidence in HNPCC include endometrial, ovarian, transitional cell, gastric, and small bowel. Specific screening recommendations for these organs cannot be made on the basis of any sound data, as the Cancer Genetics Studies Consortium pointed out in their consensus statement.(37) However, in some families, there is a pattern of occurrence of one or more of these cancers. There is also some suggestion of a genotype/phenotype association with some extracolonic cancers. For example, families with a mutation in hMSH6 show a very high incidence of uterine cancer and a relatively late onset of colorectal cancer. The clinical pattern of the family or the results of MMR gene testing may therefore be used to tailor a surveillance program.

Surveillance options include yearly PAP smears, pelvic exams, and urine cytology. Yearly esophagogastroduodenoscopy, pelvic ultrasound, and endometrial biopsy can be added in families prone to these cancers.

1. Patients in Amsterdam Criteria-positive families.(10-12,20)
2. Patients with two HNPCC-related cancers, including synchronous/metachronous colorectal cancer or extracolonic cancers*.
3. Individuals with colorectal cancer and a firstdegree relative with colorectal cancer and/or HNPCCrelated extracolonic cancer (1 < 45 years old, and/or colorectal adenoma 1 < 40 years old).
4. Colorectal cancer or endometrial cancer < 45 years.
5. Right-sided colorectal cancer with undifferentiated pattern on pathology.
6. Signet-ring cell colorectal cancer (>50 percent signets).
7. Adenomas < 40 years.
   * Endometrial, ovarian, gastric, hepatobiliary, small bowel, and transitional cell.

The practice parameters set forth in this document have been developed from sources believed to be reliable. The American Society of Colon and Rectal Surgeons makes no warranty, guarantee or representation whatsoever as to the absolute validity or sufficiency of any parameter included in this document, and the Society assumes no responsibility for the use of misuse of the material contained here.

1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics 2001. CA Cancer J Clin 2001;51:15-36.
2. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525-32.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.
4. Church J. Familial adenomatous polyposis: a review. Perspect Colon Rectal Surg 1995;8:203-25.
5. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104:1535-49.
6. Groden J, Thilveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589-601.
7. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal carcinoma patients. Science 1991;253:665-9.
8. Peltomaki P, de la Chapelle A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res 1997;71:93-119.
9. Hirsch B. DNA repair and its malfunction. Semin Colon Rectal Surg 1998;9:21-9.
10. Lovett E. Family studies in cancer of the colon and rectum. Br J Surg 1976;63:13-8.
11. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and risk of colorectal cancer. N Engl J Med 1994;331:1669-74.
12. St. John JB, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993;118:785-90.
13. David KL, Steiner-Grossman P. The potential use of tumor registry data in the recognition and prevention of hereditary and familial cancer. N Y State Med J 1991;91:150-2.
14. Lynch HT, Follett KL, Lynch PM, Albano WA, Mailliard JL, Pierson RL. Family history in an oncology clinic: implications for cancer genetics. JAMA 1979;242: 1268-72.
15. Spigelman AD, Thomson JP. Introduction, history and registries. In: Phillips RK, Spigelman AD, Thomson JP, eds. Familial adenomatous polyposis and other polyposis syndromes. London: Edward Arnold, 1995:6-15.
16. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:424-5.
17. Soravia C, Santos CD, Berk T, et al. Genetic testing of atypical families with hereditary predisposition to colorectal cancer [abstract]. Int J Colorectal Dis 1997;12:349.
18. Baba S. New strategies for treatment of hereditary colorectal cancer. Tokyo: Churchill Livingstone, 1996: 137-52.
19. Park J-G, Vasen HF, Peltomaki P, et al. The genetic diagnosis of suspected HNPCC: interim report [abstract]. Int J Colorectal Dis 1997;12:347.
20. Syngal S, Fox EA, Eng C, Kolodner R, Garber J. Sensitivity and specificity of clinical criteria for hereditary nonpolyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 2000;37:641-5.
21. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the Intern a t i o n a l C o l l a b o r a t i v e g r o u p o n H N P C C . Gastroenterology 1999;116:453- 6.
22. Lamberti C, Ruelfs C, Kruse R, et al. HNPCC: microsaellite instability and germline mutations in the hMSH2 and hMLH1 genes [abstract]. Int J Colorectal Dis 1997; 12:345.
23. Moisio AL, Nystrom-Lahti M, Holmberg M, et al. Mutation and haplotype analysis in Finnish HNPCC kindreds [abstract]. Int J Colorectal Dis 1997;12:345.
24. Wijnen J, Meera Khan P, Vasen H, et al. Genotypes and phenotypes in families with non-polyposis colorectal cancer [abstract]. Int J Colorectal Dis 1997;12:346.
25. Dunlop M. Penetrance of germline DNA mismatch repair gene mutations [abstract]. Int J Colorectal Dis 1997; 12:347.
26. Shomrat R, Orr-Urteger DI, Kedmi M, et al. Molecular diagnosis of hMSH2 and hMLH1 genes in Israeli families with hereditary nonpolyposis colon cancer [abstract]. Int J Colorectal Dis 1997;12:355.
27. Genuardi M, Viel A, Capozzi E, et al. Germline hMLH1 and hMSH2 mutations in hereditary nonpolyposis colorectal cancer (HNPCC) and "suspected" HNPCC [abstract]. Int J Colorectal Dis 1997;12:357.
28. Jass JR, Cottier DS, Jeevaratnam P, et al. Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet 1995;346:1200-01.
29. Brassett C, Joyce JA, Froggatt NJ, et al. Microsatellite instability in early onset and familial colorectal cancer. J Med Genet 1996;33:981-5.
30. Baba S. Hereditary nonpolyposis colorectal cancer: an update. Dis Colon Rectum 1997;40(Suppl):S86-S95.
31. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 1997;57:4749 -56.
32. 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. J Natl Cancer Inst 1997; 89:1758 - 62.
33. Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 1996;56:4836-40.
34. Cunningham JM, Boardman LA, Burgart LJ, Thibodeau SN. Molecular abnormalities in colorectal cancer: microsatellite instability pathway. Semin Colon Rectal Surg 1998;9:38- 48.
35. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260:812-6.
36. Collins F, on behalf of National Action Plan on Breast Cancer. Comment on statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. J Clin Oncol 1996;14:1738-40.
37. Giardiello F, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997;336: 823-7.
38. Petersen GM. Genetic counselling and predictive genetic testing in familial adenomatous polyposis. Semin Colon Rectal Surg 1995;6:55- 60.
39. Giardiello FM. Genetic testing in hereditary colorectal cancer. JAMA 1997;278:1278-81.
40. Masood E. Gene tests: who benefits from risk? Nature 1996;379:389-92. 41. Anonymous. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, adopted on February 20, 1996. J Clin Oncol 1996;14: 1730-6.
41. Church J, Kulikowski K, McGannon E. Familial adenomatous polyposis and insurance: the struggle for coverage and its effect on disease management [abstract]. Int J Colorectal Dis 1997;12:360.
42. Offit K. Psychological, ethical and legal issues in cancer risk counselling. In: Clinical cancer genetics: risk counselling and management. New York: Wiley-Liss, 1998: 287-316.
43. Church J, Williams BR, Casey G. Molecular genetics of colorectal neoplasia: a primer for the clinician. Tokyo: Igaku-Shoin, 1996:18-23.
44. Byers T, Levin B, Rothenberger D, Dodd GD, Smith RA. American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. CA Cancer J Clin 1997; 47:154 - 60.
45. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. 1. Hereditary Nonpolyposis Colon Cancer. JAMA 1997;277:915-9.
46. Ransohoff DF, Lang CA, Young GP. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594-642.
47. Vasen HF, Nagengast FM, Khan PM. Interval cancers in hereditary nonpolyposis colorectal cancer. Lancet 1995; 345:1183-4.
48. Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108:1405-11.

The Collaborative Group of the Americas on Inherited Colorectal Cancer

The Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA) is a group including healthcare professionals who are involved in the care of patients with strong family histories of colorectal cancer and scientists who perform research about the disease. The mission of the group is threefold:

To educate healthcare professionals in the molecular genetics and clinical management of inherited colorectal cancer.

To be a resource for institutions and individuals interested in starting a registry of families with inherited colorectal cancer syndromes.

To provide a forum for presentation of data, for discussion of controversial issues involved in the care of patients and their families, and for the facilitation of collaborative studies.

Why have an Americas Group?

There are two international collaborative groups concerned with inherited syndromes of colorectal cancer; the Leeds Castle Polyposis Group and the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer. Each group has made significant contributions to the clinical management and basic understanding of the syndromes with which they are concerned: familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. Both groups are based in Europe, however, making meetings sponsored by these groups relatively inaccessible and collaborative studies difficult to pursue. The CGA aims to sponsor yearly local scientific meetings and to focus on issues of particular concern to registries, patients, clinicians, and scientists in North and South America.

One of the unique facets of groups concerned with inherited diseases is that many areas of interest are represented. In colorectal cancer, clinicians may include surgeons, gastroenterologists, psychologists, clinical geneticists, pathologists, gynecologists, and oncologists. Basic scientists are usually from the field of molecular genetics, but there are also computer programmers, epidemiologists, statisticians, counselors, social workers, and registry coordinators. The interaction of all these specialists is a major attraction of the Inherited Colorectal Cancer Groups. All these specialists are eligible to join the CGA, as long as they have an interest in inherited colorectal cancer and practice in North or South America. Individual and institutional memberships exist. Annual dues are $100.00 per institution or $25 per individual.

CGA was formed four years ago by a group of interested individuals from a variety of specialties. It met in St. Louis in 1995, Buffalo in 1996, Cleveland in 1997, St. Louis again in 1998, Minneapolis in 1999, and Philadelphia in 2000. The 2001 meeting is planned for San Diego on October 12 and 13. The CGA was incorporated in 1998 and has been supported since its inception by The American Society of Colorectal Surgeons. The article preceding this Commentary was written jointly with the Standards Committee of The American Society of Colorectal Surgeons.

The current Council of CGA is
President: Dr. Patrick Lynch.
Past President: Terri Berk.
Vice President: Dr. Jose Guillem.
Members at Large: Drs. Raoul Cutait, Marty Luchtefeld, Miguel Rodriguez-Bigas, Bruce Boman, Tom Webber, and John King.

Membership of CGA is open to any individual or institution concerned with the care of patients or families affected with inherited colorectal cancer. Those interested in membership should contact Administrative Director James Church, Department of Colorectal Surgery, Cleveland Clinic, 9500 Euclid Avenue, Desk A30, Cleveland, Ohio 44195. (Fax: 216-445-8627. E-mail: churchj@ccf.org.)

James Church, M.D.
Cleveland, Ohio