Genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC), or what is now more appropriately known as Lynch syndrome, has become the standard of care for patients with features suggestive of this syndrome and their at-risk relatives.1Giardiello F.M. Brensinger J.D. Petersen G.M. AGA technical review on hereditary colorectal cancer and genetic testing.Gastroenterology. 2001; 121: 198-213Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 2Levin B. Gruber S.B. NCCN colorectal cancer screening practice guidelines.Oncology. 1999; 13: 152-179PubMed Google Scholar, 3Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 4Lynch H.T. de la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (1649) Google Scholar, 5Burke W. Petersen G. Lynch P. Botkin J. Daly M. Garber J. Kahn M.J. McTiernan A. Offit K. Thomson E. Varricchio C. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium.JAMA. 1997; 19 (915–919): 277Google Scholar Lynch syndrome is an autosomal dominant syndrome characterized by high risk of cancers of the colon and rectum, endometrium, stomach, small intestine, hepatobiliary system, upper ureteral tract, ovary, and rarely the brain.6Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Scopus (479) Google Scholar, 7de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Crossref PubMed Scopus (525) Google Scholar, 8Watson P. Riley B. The tumor spectrum in the Lynch syndrome.Fam Cancer. 2005; 4: 245-248Crossref PubMed Scopus (78) Google Scholar This review will highlight recent advances in the clinical recognition and genetic testing of Lynch syndrome. The patttern and lifetime risk of cancers arising within Lynch syndrome are now well established, and the pattern is reasonably close to the first descriptions by Aldred Warthin at the University of Michigan in 19139Warthin A.S. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of The University of Michigan.Arch Intern Med. 1913; : 546-555Crossref Scopus (431) Google Scholar and Henry Lynch’s seminal observations almost 40 years ago.10Lynch H.T. Shaw M.W. Magnuson C.W. Larsen A.L. Krush A.J. Hereditary factors in cancer. Study of two large midwestern kindreds.Arch Intern Med. 1966; 117: 206-212Crossref PubMed Scopus (382) Google Scholar, 11Lynch H.T. Krush A.J. Cancer family “G” revisited 1895-1970.Cancer. 1971; 27: 1505-1511Crossref PubMed Scopus (286) Google Scholar Gastric cancers dominated early pedigrees, but as the incidence of gastric cancer has decreased in population-based registries in Western countries since the 1930s,12Henson D.E. Dittus C. Younes M. Nguyen H. Albores-Saavedra J. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973–2000 increase in the signet ring cell type.Arch Pathol Lab Med. 2004; 128: 765-770PubMed Google Scholar there has been a parallel decrease in the incidence of gastric cancer within Lynch syndrome.13Douglas J.A. Gruber S.B. Meister K.A. Bonner J. Watson P. Krush A.J. Lynch H.T. History and molecular genetics of Lynch syndrome in family G a century later.JAMA. 2005; 294: 2195-2202Crossref PubMed Scopus (60) Google Scholar The lifetime risk of colorectal cancer has been estimated to be as high as 82%,14Aarnio M. Sankila R. Pukkala E. Salovaara R. Aaltonen L.A. de la Chapelle A. Peltomaki P. Mecklin J.P. Jarvinen H.J. Cancer risk in mutation carriers of DNA-mismatch-repair genes.Int J Cancer. 1999; 81: 214-218Crossref PubMed Google Scholar although a more recent population-based study reported a lifetime risk of 68.7% in men and 52.2% in women.15Hampel H. Stephens J.A. Pukkala E. Sankila R. Aaltonen L.A. Mecklin J.P. de la Chapelle A. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome later age of onset.Gastroenterology. 2005; 129: 415-421Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar Endometrial cancer is the second most common malignancy in Lynch syndrome, with an estimated lifetime risk between 40% and 70%.14Aarnio M. Sankila R. Pukkala E. Salovaara R. Aaltonen L.A. de la Chapelle A. Peltomaki P. Mecklin J.P. Jarvinen H.J. Cancer risk in mutation carriers of DNA-mismatch-repair genes.Int J Cancer. 1999; 81: 214-218Crossref PubMed Google Scholar, 16Dunlop M.G. Farrington S.M. Carothers A.D. Wyllie A.H. Sharp L. Burn J. Liu B. Kinzler K.W. Vogelstein B. Cancer risk associated with germline DNA mismatch repair gene mutations.Hum Mol Genet. 1997; 6: 105-110Crossref PubMed Scopus (598) Google Scholar, 17Cederquist K. Emanuelsson M. Wiklund F. Golovleva I. Palmqvist R. Gronberg H. Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.Clin Genet. 2005; 68: 533-541Crossref PubMed Scopus (36) Google Scholar Hampel et al reported a lifetime risk of endometrial cancer of 54%, with an average age of onset at 62 years.15Hampel H. Stephens J.A. Pukkala E. Sankila R. Aaltonen L.A. Mecklin J.P. de la Chapelle A. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome later age of onset.Gastroenterology. 2005; 129: 415-421Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar In some studies, the lifetime risk of endometrial cancer even exceeds the risk of colorectal cancer. Gastric cancer no longer predominates in families with Lynch syndrome and the cumulative risk has been estimated to be 13%.14Aarnio M. Sankila R. Pukkala E. Salovaara R. Aaltonen L.A. de la Chapelle A. Peltomaki P. Mecklin J.P. Jarvinen H.J. Cancer risk in mutation carriers of DNA-mismatch-repair genes.Int J Cancer. 1999; 81: 214-218Crossref PubMed Google Scholar However, the risk of gastric cancer appears to be much higher in China18Cai S.J. Xu Y. Cai G.X. Lian P. Guan Z.Q. Mo S.J. Sun M.H. Cai Q. Shi D.R. Clinical characteristics and diagnosis of patients with hereditary nonpolyposis colorectal cancer.World J Gastroenterol. 2003; 9: 284-287PubMed Google Scholar and in Korea,19Park Y.J. Shin K.H. Park J.G. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea.Clin Cancer Res. 2000; 6: 2994-2998PubMed Google Scholar even exceeding the risk of endometrial cancer. The lifetime risk of ovarian cancer is approximately 10%–12%,14Aarnio M. Sankila R. Pukkala E. Salovaara R. Aaltonen L.A. de la Chapelle A. Peltomaki P. Mecklin J.P. Jarvinen H.J. Cancer risk in mutation carriers of DNA-mismatch-repair genes.Int J Cancer. 1999; 81: 214-218Crossref PubMed Google Scholar, 20Vasen H.F. Stormorken A. Menko F.H. Nagengast F.M. Kleibeuker J.H. Griffioen G. Taal B.G. Moller P. Wijnen J.T. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers a study of hereditary nonpolyposis colorectal cancer families.J Clin Oncol. 2001; 19: 4074-4080PubMed Google Scholar although a study of one large family in Newfoundland estimated a lifetime risk of 36%.21Green J. O’Driscoll M. Barnes A. Maher E.R. Bridge P. Shields K. Parfrey P.S. Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation.Dis Colon Rectum. 2002; 45: 1223-1232Crossref PubMed Scopus (49) Google Scholar Clinical criteria for HNPCC/Lynch syndrome were first established in 1991 to facilitate linkage and positional cloning studies.22Vasen H.F. Mecklin J.P. Khan P.M. Lynch H.T. The international collaborative group on hereditary non- polyposis colorectal cancer (ICG-HNPCC).Dis Colon Rectum. 1991; 34: 424-425Crossref PubMed Scopus (1746) Google Scholar These criteria, first developed by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer at a conference in Amsterdam, were designed to be highly specific in order to reduce misclassification of families. This high degree of specificity was achieved at the expense of sensitivity, and many families with Lynch syndrome do not meet the original “Amsterdam criteria”. Despite limitations, the original criteria (Amsterdam I) have continued to serve as useful tool for identifying families with Lynch syndrome in clinical practice. Sometimes described as the “3-2-1-0 rule”, the original Amsterdam criteria defined HNPCC (as it was known at the time) by 3 or more individuals with pathologically confirmed colorectal cancer where one affected family member is a first-degree relative of the other 2, in at least 2 successive generations, with one person diagnosed below the age of 50, after excluding a diagnosis of familial adenomatous polyposis. Now that the molecular basis of Lynch syndrome is known, the sensitivity and specificity of the Amsterdam I criteria for the detection of families with known mutations have been estimated in several studies, including a recent meta-analysis. The sensitivity of Amsterdam I criteria ranges from 54%–91% and the specificity ranges from 62%–84%.23Kievit W. de Bruin J.H. Adang E.M. Ligtenberg M.J. Nagengast F.M. van Krieken J.H. Hoogerbrugge N. Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate a meta-analysis.Clin Genet. 2004; 65: 308-316Crossref PubMed Scopus (58) Google Scholar The Amsterdam criteria were revised in 1999 to include other recognized cancers within Lynch syndrome.24Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (2089) Google Scholar The Amsterdam II criteria are essentially identical to the Amsterdam I criteria (Table 1), only the revised criteria do not rely exclusively on colorectal cancer as the defining cancer within the family. In addition to colorectal cancer, Lynch syndrome cancers that are considered as part of the Amsterdam II criteria are cancers of the endometrium, small intestine, renal, pelvis, and ureter. The pooled sensitivity of the Amsterdam II criteria is 78%, while the specificity ranges from 46%–68%.23Kievit W. de Bruin J.H. Adang E.M. Ligtenberg M.J. Nagengast F.M. van Krieken J.H. Hoogerbrugge N. Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate a meta-analysis.Clin Genet. 2004; 65: 308-316Crossref PubMed Scopus (58) Google ScholarTable 1Original and Revised Amsterdam Criteria for Hereditary Nonpolyposis Colorectal CancerAmsterdam I Criteria–families must fulfill all criteria 1. At least 3 relatives should have histologically verified colorectal cancer; 1 of them should be a first-degree relative to the other 2. 2. At least 2 successive generations should be affected. 3. In 1 of the relatives, colorectal cancer should be diagnosed under 50 years of age. 4. Familial adenomatous polyposis should be excluded.Amsterdam II criteria–families must fulfill all criteria 1. There should be at least 3 relatives with an HNPCC-associated cancer (CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis) 2. One should be a first-degree relative of the other 2. 3. At least 2 successive generations should be affected. 4. At least 1 should be diagnosed before age 50. 5. Familial adenomatous polyposis should be excluded in the CRC case(s), if any. 6. Tumors should be verified by pathological examination. Open table in a new tab Relying exclusively on the Amsterdam criteria in clinical practice would lead to a profound under-recognition of Lynch syndrome, so other strategies have been developed to help identify these families. In addition to family history, it is also possible to take advantage of other clinical and pathologic features to recognize Lynch syndrome, including young age of diagnosis, presence of multiple primary Lynch syndrome tumors, or histologic clues that suggest a diagnosis of the type of microsatellite instable tumors that arise in Lynch syndrome. The Bethesda Guidelines (Table 2) were developed by a consensus panel in 1996 to improve the efficiency of recognizing Lynch syndrome and to highlight those patients that would be most likely to benefit from a molecular diagnostic work-up, beginning with microsatellite instability testing of the tumor.25Rodriguez-Bigas M.A. Boland C.R. Hamilton S.R. Henson D.E. Jass J.R. Khan P.M. Lynch H. Perucho M. Smyrk T. Sobin L. Srivastava S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome meeting highlights and Bethesda guidelines.J Natl Cancer Inst. 1997; 89: 1758-1762Crossref PubMed Scopus (943) Google Scholar These guidelines were updated in 2004, following another consensus panel conference.26Umar A. Boland C.R. Terdiman J.P. Syngal S. de la Chapelle A. Ruschoff J. Fishel R. Lindor N.M. Burgart L.J. Hamelin R. Hamilton S.R. Hiatt R.A. Jass J. Lindblom A. Lynch H.T. Peltomaki P. Ramsey S.D. Rodriguez-Bigas M.A. Vasen H.F. Hawk E.T. Barrett J.C. Freedman A.N. Srivastava S. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2487) Google ScholarTable 2Original and Revised Bethesda Guidelines for Microsatellite Instability TestingOriginal Bethesda Guidelines25Rodriguez-Bigas M.A. Boland C.R. Hamilton S.R. Henson D.E. Jass J.R. Khan P.M. Lynch H. Perucho M. Smyrk T. Sobin L. Srivastava S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome meeting highlights and Bethesda guidelines.J Natl Cancer Inst. 1997; 89: 1758-1762Crossref PubMed Scopus (943) Google Scholar–individuals meeting any one of the following: 1. Individuals with cancer in families that meet the Amsterdam criteria. 2. Individuals with 2 HNPCC-related cancers including synchronous and metachronous CRC, or associated extracolonic cancers.aEndometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell carcinoma of the renal pelvis or ureter. 3. Individuals with CRC and a first-degree relative with CRC and/or HNPC related extracolonic cancer and/or a colorectal adenoma; 1 of the cancers diagnosed at age less than 45, the adenoma at age less than 40. 4. Individuals with CRC or endometrial cancer diagnosed at age less than 45. 5. Individuals with right-sided CRC showing undifferentiated pattern on histopathology.bSolid cribriform defined as a poorly undifferentiated carcinoma composed of irregular solid sheets of large eosinophilic cells and containing small gland-like spaces. 6. Individuals with signet ring cell type CRC.cComposed of more than 50% signet ring cells. 7. Individuals with adenomas diagnosed at age less than 40.Revised Bethesda Guidelines26Umar A. Boland C.R. Terdiman J.P. Syngal S. de la Chapelle A. Ruschoff J. Fishel R. Lindor N.M. Burgart L.J. Hamelin R. Hamilton S.R. Hiatt R.A. Jass J. Lindblom A. Lynch H.T. Peltomaki P. Ramsey S.D. Rodriguez-Bigas M.A. Vasen H.F. Hawk E.T. Barrett J.C. Freedman A.N. Srivastava S. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2487) Google Scholar–individuals meeting any one of the following: 1. CRC diagnosed in individual under age 50 years. 2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumorsaEndometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell carcinoma of the renal pelvis or ureter., regardless of age. 3. CRC with the MSI-H histology (presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern), in patient <60 years of age. 4. CRC in 1 or more first-degree relatives with an HNPCC-related tumor, with 1 of the cancers being diagnosed under age 50 years. 5. CRC diagnosed in 2 or more first- or second-degree relatives with HNPCC- related tumors, regardless of age.a Endometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell carcinoma of the renal pelvis or ureter.b Solid cribriform defined as a poorly undifferentiated carcinoma composed of irregular solid sheets of large eosinophilic cells and containing small gland-like spaces.c Composed of more than 50% signet ring cells. Open table in a new tab Unfortunately, even the Bethesda guidelines are extremely difficult to implement in practice. Pathologists usually do not have access to family history data, and clinicians often do not have access to the specific pathologic features that are suggestive of defective mismatch repair,27Jass J.R. Do K.A. Simms L.A. Iino H. Wynter C. Pillay S.P. Searle J. Radford-Smith G. Young J. Leggett B. Morphology of sporadic colorectal cancer with DNA replication errors.Gut. 1998; 42: 673-679Crossref PubMed Scopus (407) Google Scholar since features such as the presence of tumor infiltrating lymphocytes,28Greenson J.K. Bonner J.D. Ben Yzhak O. Cohen H.I. Miselevich I. Resnick M.B. Trougouboff P. Tomsho L.D. Kim E. Low M. Almog R. Rennert G. Gruber S.B. Phenotype of microsatellite unstable colorectal carcinomas well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.Am J Surg Pathol. 2003; 27: 563-570Crossref PubMed Scopus (208) Google Scholar Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation,29Jass J.R. Smyrk T.C. Stewart S.M. Lane M.R. Lanspa S.J. Lynch H.T. Pathology of hereditary non-polyposis colorectal cancer.Anticancer Res. 1994; 14: 1631-1634PubMed Google Scholar or medullary growth pattern.29Jass J.R. Smyrk T.C. Stewart S.M. Lane M.R. Lanspa S.J. Lynch H.T. Pathology of hereditary non-polyposis colorectal cancer.Anticancer Res. 1994; 14: 1631-1634PubMed Google Scholar are often not described on pathology reports. For these reasons, simplified criteria for recognizing Lynch syndrome have been studied. A new approach that has been advocated by a group from the Netherlands uses 4 clinical criteria to supplement family history in order to detect Lynch syndrome (Table 3).30Kievit W. de Bruin J.H. Adang E.M. Severens J.L. Kleibeuker J.H. Sijmons R.H. Ruers T.J. Nagengast F.M. Vasen H.F. van Krieken J.H. Ligtenberg M.J. Hoogerbrugge N. Cost effectiveness of a new strategy to identify HNPCC patients.Gut. 2005; 54: 97-102Crossref PubMed Scopus (77) Google Scholar These criteria are: (1) CRC before age 50, (2) second CRC, (3) CRC and HNPCC associated cancer, and (4) adenoma diagnosed before age 40. The new strategy is more expensive to implement since it leads to more testing, but the strategy is more cost-effective than standard approaches used to identify Lynch syndrome since it leads to more targeted use of screening techniques.30Kievit W. de Bruin J.H. Adang E.M. Severens J.L. Kleibeuker J.H. Sijmons R.H. Ruers T.J. Nagengast F.M. Vasen H.F. van Krieken J.H. Ligtenberg M.J. Hoogerbrugge N. Cost effectiveness of a new strategy to identify HNPCC patients.Gut. 2005; 54: 97-102Crossref PubMed Scopus (77) Google Scholar Whether this new approach will achieve widespread clinical use is not yet known, since the new criteria do not specify the strength of the family history that would prompt a work-up in addition to the 4 criteria that are easy to implement.Table 3Kievit Criteria for Microsatellite Instability Testing–for Individuals Meeting any One of the Criteria30Kievit W. de Bruin J.H. Adang E.M. Severens J.L. Kleibeuker J.H. Sijmons R.H. Ruers T.J. Nagengast F.M. Vasen H.F. van Krieken J.H. Ligtenberg M.J. Hoogerbrugge N. Cost effectiveness of a new strategy to identify HNPCC patients.Gut. 2005; 54: 97-102Crossref PubMed Scopus (77) Google Scholar(1) Colorectal cancer diagnosed before age 50(2) Second primary colorectal cancer(3) Colorectal cancer and HNPCC associated cancer (endometrium, ovarian, gastric, hepatobilliary, small bowel cancer, or transitional-cell carcinoma of the renal pelvis or ureter)(4) Adenoma with high-grade dysplasia diagnosed before age 40 Open table in a new tab Another recent clinical development in the genetics of Lynch syndrome reflects the recognition that approximately 70% of families that meet Amsterdam I criteria do not have an identifiable defect in DNA mismatch repair.31Nystrom-Lahti M. Wu Y. Moisio A.L. Hofstra R.M. Osinga J. Mecklin J.P. Jarvinen H.J. Leisti J. Buys C.H. de la Chapelle A. Peltomaki P. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer.Hum Mol Genet. 1996; 5: 763-769Crossref PubMed Scopus (202) Google Scholar, 32Lynch H.T. de la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (999) Google Scholar, 33Casey G. Lindor N.M. Papadopoulos N. Thibodeau S.N. Moskow J. Steelman S. Buzin C.H. Sommer S.S. Collins C.E. Butz M. Aronson M. Gallinger S. Barker M.A. Young J.P. Jass J.R. Hopper J.L. Diep A. Bapat B. Salem M. Seminara D. Haile R. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.JAMA. 2005; 293: 799-809Crossref PubMed Scopus (84) Google Scholar This suggests clinical and pathogenetic heterogeneity of families detected by Amsterdam criteria, in addition to the possibility of imperfect detection of mutations of known genes with currently available technology. A recent study of 161 pedigrees that met the Amsterdam I criteria classified families into those with and without evidence of defective mismatch repair by tumor testing.34Lindor N.M. Rabe K. Petersen G.M. Haile R. Casey G. Baron J. Gallinger S. Bapat B. Aronson M. Hopper J. Jass J. LeMarchand L. Grove J. Potter J. Newcomb P. Terdiman J.P. Conrad P. Moslein G. Goldberg R. Ziogas A. Anton-Culver H. de Andrade M. Siegmund K. Thibodeau S.N. Boardman L.A. Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency familial colorectal cancer type X.JAMA. 2005; 293: 1979-1985Crossref PubMed Scopus (486) Google Scholar Those families with evidence of mismatch repair deficiency were considered Lynch syndrome (also called “Hereditary DNA Mismatch Repair Deficiency Syndrome”), while those without defective mismatch repair were described as “Familial Colorectal Cancer Syndrome X” (also described as “Nonpolyposis Familial Colon Cancers Syndrome Not Due to Hereditary DNA Mismatch Repair Gene Mutations”). The risk of specific cancers in these 2 groups differed in important ways. The relative risk of colorectal cancer was 4.3 (95% confidence interval, 3.4–5.3) among the relatives of the population-based sample with Lynch syndrome, compared with 2.0 (95% CI, 1.3–2.7) among the relatives of the population-based sample meeting AC I criteria, but without defective mismatch repair (Familial Colorectal Cancer Syndrome X). In addition to a lower risk of colorectal cancer in the Syndrome X families, there was no evidence of increased risk of uterine cancer in these families, with a relative risk of 0.6 (95% CI, 0.0–1.5). The age of onset of colorectal cancer was also considerably lower in the Lynch syndrome relatives (48.7 years) in comparison to the Syndrome X relatives (60.7 years). Together, these data suggest that screening guidelines for families meeting the original Amsterdam I criteria should be stratified based on whether there is evidence of defective mismatch repair. If mismatch repair is intact, it may be reasonable to begin colonoscopic surveillance 10 years prior to the earliest diagnosis in the family rather than beginning at age 20–25, and to eliminate recommendations for endometrial cancer screening. Understanding the molecular basis of defective mismatch repair facilitates informative genetic testing and the cost-effective management of families with Lynch syndrome.35Ramsey S.D. Clarke L. Etzioni R. Higashi M. Berry K. Urban N. Cost-effectiveness of microsatellite instability screening as a method for detecting hereditary nonpolyposis colorectal cancer.Ann Intern Med. 2001; 135: 577-588Crossref PubMed Google Scholar, 36Vasen H.F. van Ballegooijen M. Buskens E. Kleibeuker J.K. Taal B.G. Griffioen G. Nagengast F.M. Menko F.H. Meera Khan P. A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers.Cancer. 1998; 82: 1632-1637Crossref PubMed Scopus (143) Google Scholar Mutations in hMLH1 and hMSH2 account for the majority of Lynch syndrome (34% and 42%, respectively in a recent comprehensive survey of Amsterdam I families).33Casey G. Lindor N.M. Papadopoulos N. Thibodeau S.N. Moskow J. Steelman S. Buzin C.H. Sommer S.S. Collins C.E. Butz M. Aronson M. Gallinger S. Barker M.A. Young J.P. Jass J.R. Hopper J.L. Diep A. Bapat B. Salem M. Seminara D. Haile R. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.JAMA. 2005; 293: 799-809Crossref PubMed Scopus (84) Google Scholar MSH6 is responsible for a smaller fraction of Lynch syndrome,32Lynch H.T. de la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (999) Google Scholar, 33Casey G. Lindor N.M. Papadopoulos N. Thibodeau S.N. Moskow J. Steelman S. Buzin C.H. Sommer S.S. Collins C.E. Butz M. Aronson M. Gallinger S. Barker M.A. Young J.P. Jass J.R. Hopper J.L. Diep A. Bapat B. Salem M. Seminara D. Haile R. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.JAMA. 2005; 293: 799-809Crossref PubMed Scopus (84) Google Scholar and mutations in MSH6 tend to be more strongly associated with endometrial cancer and a lower degree of microsatellite instability than is observed with mutations of MSH2 or MLH1.37Akiyama Y. Sato H. Yamada T. Nagasaki H. Tsuchiya A. Abe R. Yuasa Y. Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred.Cancer Res. 1997; 57: 3920-3923PubMed Google Scholar, 38Kolodner R.D. Tytell J.D. Schmeits J.L. Kane M.F. Das G. Weger J. Wahlberg S. Fox E.A. Peel D. Ziogas A. Garber J.E. Syngal S. Anton-Culver H. Li F.P. Germ-line msh6 mutations in colorectal cancer families.Cancer Res. 1999; 59: 5068-5074PubMed Google Scholar, 39Berends M.J. Wu Y. Sijmons R.H. Mensink R.G. Van Der S.T. Hordijk-Hos J.M. de Vries E.G. Hollema H. Karrenbeld A. Buys C.H. Der Zee A.G. Hofstra R.M. Kleibeuker J.H. Molecular and clinical characteristics of MSH6 variants an analysis of 25 index carriers of a germline variant.Am J Hum Genet. 2002; 70: 26-37Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Mutations in PMS2 are a rare cause of Lynch syndrome,40Hamilton S.R. Liu B. Parsons R.E. Papadopoulos N. Jen J. Powell S.M. Krush A.J. Berk T. Cohen Z. Tetu B. et al.The molecular basis of Turcot’s syndrome.N Engl J Med. 1995; 332: 839-847Crossref PubMed Scopus (915) Google Scholar and the early evidence that PMS1 causes Lynch syndrome is not compelling, since another pathogenic mutation has been found in the first family found with a PMS1 mutation.41Liu T. Yan H. Kuismanen S. Percesepe A. Bisgaard M.L. Pedroni M. Benatti P. Kinzler K.W. Vogelstein B. Ponz D.L. Peltomaki P. Lindblom A. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.Cancer Res. 2001; 61: 7798-7802PubMed Google Scholar These genes cooperatively participate to repair errors arising in DNA replication called insertion-deletion loop errors; these errors lead to nucleotide mismatches, and deficiencies in any one of the repair genes can lead to Lynch syndrome. A detailed discussion of the molecular genetics of mismatch repair is beyond the scope of this review, but it is worthwhile to highlight some of the key features. Fishel described the relationship between the homologues of mismatch repair genes found in bacteria (Escherichia coli), yeast (S cerevisiae) and humans.42Fishel R. Lescoe M.K. Rao M.R. Copeland N.G. Jenkins N.A. Garber J. Kane M. Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.Cell. 1993; 75 ([published erratum appears in Cell 1994;77:167]): 1027-1038Abstract Full Text PDF PubMed Scopus (2603) Google Scholar The MutS gene in E coli has a homologue in S cerevisiae called Mut S homologue 2 (or MSH2). The corresponding human gene, hMSH2, was shown to play a critical role DNA repair and was associated with Lynch syndrome. At the same time, Leach et al cloned hMSH2 using a positional cloning approach and identified mutations in this gene as the cause of Lynch syndrome in several HNPCC families.43Leach F.S. Nicolaides N.C. Papadopoulos N. Liu B. Jen J. Parsons R. Peltomaki P. Sistonen P. Aaltonen L.A. 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