Microsatellite instability in colorectal cancer.

Microsatellite instability (MSI) is a hypermutable phenotype caused by the loss of DNA mismatch repair activity. MSI is detected in about 15% of all colorectal cancers; 3% are of these are associated with Lynch syndrome and the other 12% are caused by sporadic, acquired hypermethylation of the promoter of the MLH1 gene, which occurs in tumors with the CpG island methylator phenotype. Colorectal tumors with MSI have distinctive features, including a tendency to arise in the proximal colon, lymphocytic infiltrate, and a poorly differentiated, mucinous or signet ring appearance. They have a slightly better prognosis than colorectal tumors without MSI and do not have the same response to chemotherapeutics. Discovery of MSI in colorectal tumors has increased awareness of the diversity of colorectal cancers and implications for specialized management of patients.

[1]  M. Marinus,et al.  DNA Mismatch Repair , 2012, EcoSal Plus.

[2]  Sven Diederichs,et al.  The hallmarks of cancer , 2012, RNA biology.

[3]  Mari Mino-Kenudson,et al.  Lymphocytic Reaction to Colorectal Cancer Is Associated with Longer Survival, Independent of Lymph Node Count, Microsatellite Instability, and CpG Island Methylator Phenotype , 2009, Clinical Cancer Research.

[4]  B. Uzzan,et al.  Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. , 2009, European journal of cancer.

[5]  C. Boland,et al.  Promoter Methylation in the Genesis of Gastrointestinal Cancer , 2009, Yonsei medical journal.

[6]  C. Compton,et al.  Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Heather Hampel,et al.  Feasibility of screening for Lynch syndrome among patients with colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  A. Laner,et al.  Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer , 2008, European journal of gastroenterology & hepatology.

[9]  C. Boland,et al.  Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. , 2008, Cancer research.

[10]  Shuji Ogino,et al.  CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer , 2008, Gut.

[11]  J. Mecklin,et al.  The risk of extra‐colonic, extra‐endometrial cancer in the Lynch syndrome , 2008, International journal of cancer.

[12]  J. Shia.  Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. , 2008, The Journal of molecular diagnostics : JMD.

[13]  M. Kloor,et al.  Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. , 2008, Gastroenterology.

[14]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[15]  V. Torri,et al.  Reduced Likelihood of Metastases in Patients with Microsatellite-Unstable Colorectal Cancer , 2007, Clinical Cancer Research.

[16]  Norman Wolmark,et al.  Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  C. Boland.  Clinical uses of microsatellite instability testing in colorectal cancer: an ongoing challenge. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  C. Boland,et al.  Structure and function of the components of the human DNA mismatch repair system , 2006, International journal of cancer.

[19]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[20]  S. Leung,et al.  Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer , 2006, Nature Genetics.

[21]  D. Sargent,et al.  Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. , 2006, Gastroenterology.

[22]  Harry Campbell,et al.  Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. , 2006, The New England journal of medicine.

[23]  F. Waldman,et al.  Regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation in colorectal cancer , 2006, International journal of cancer.

[24]  M. Benito,et al.  Molecular biology in colorectal cancer , 2006, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[25]  R. Gafà,et al.  Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  R. Gafà,et al.  Microsatellite Instability and Colorectal Cancer Prognosis , 2005, Clinical Cancer Research.

[27]  J. Cubiella,et al.  Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer , 2005, Gut.

[28]  Megan Hitchins,et al.  MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. , 2005, Gastroenterology.

[29]  A. Roca,et al.  Differential Features of Colorectal Cancers Fulfilling Amsterdam Criteria without Involvement of the Mutator Pathway , 2005, Clinical Cancer Research.

[30]  P. Møller,et al.  Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC) , 2005, Genes, chromosomes & cancer.

[31]  R. Fishel,et al.  Lynch syndrome: form, function, proteins, and basketball. , 2005, Gastroenterology.

[32]  A. de la Chapelle,et al.  Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. , 2005, Gastroenterology.

[33]  R. Herrmann,et al.  Prognostic and predictive relevance of microsatellite instability in colorectal cancer. , 2005, Oncology reports.

[34]  W. Frankel,et al.  Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). , 2005, The New England journal of medicine.

[35]  J. Potter,et al.  Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. , 2005, JAMA.

[36]  R. Houlston,et al.  Systematic review of microsatellite instability and colorectal cancer prognosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. Issa.  CpG island methylator phenotype in cancer , 2004, Nature Reviews Cancer.

[38]  P. Møller,et al.  Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. , 2004, Gastroenterology.

[39]  F. Collins,et al.  The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer , 2004, Nature Genetics.

[40]  G. Taylor,et al.  MLPA and MAPH: New techniques for detection of gene deletions , 2004, Human mutation.

[41]  H. Morreau,et al.  Survival after adjuvant 5‐FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer , 2004, International journal of cancer.

[42]  S. Bustin,et al.  Tumour‐infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic , 2004, The British journal of surgery.

[43]  E. Tiret,et al.  Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer , 2004, Gut.

[44]  Leah E. Mechanic,et al.  The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. , 2003, The Journal of clinical investigation.

[45]  L. Aaltonen,et al.  Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability. , 2003, Cancer genetics and cytogenetics.

[46]  W. Foulkes,et al.  MSI‐low, a real phenomenon which varies in frequency among cancer types , 2003, The Journal of pathology.

[47]  M. Ducreux,et al.  Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. , 2003, Cancer research.

[48]  D. Schaid,et al.  BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. , 2003, Cancer research.

[49]  A. Goel,et al.  Role of hMLH1 promoter hypermethylation in drug resistance to 5‐fluorouracil in colorectal cancer cell lines , 2003, International journal of cancer.

[50]  Daniel J Sargent,et al.  Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. , 2003, The New England journal of medicine.

[51]  Richard Fishel,et al.  The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair. , 2003, Molecular cell.

[52]  D. Chang,et al.  Microsatallite Instability and Suppressed DNA Repair Enzyme Expression in Rheumatoid Arthritis , 2003, The Journal of Immunology.

[53]  S. Kakar,et al.  Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age , 2003, Cancer.

[54]  C. Boland,et al.  Identification of frame-shift intermediate mutant cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[55]  A. Duval,et al.  Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. , 2002, Gastroenterology.

[56]  K. Kinzler,et al.  Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status , 2002, Nature.

[57]  M. Loda,et al.  A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. , 2002, Cancer research.

[58]  D. Chang,et al.  Oxidative stress inactivates the human DNA mismatch repair system. , 2002, American journal of physiology. Cell physiology.

[59]  J. Coxhead,et al.  Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[60]  A. Duval,et al.  Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. , 2002, Cancer research.

[61]  J. Herman,et al.  Low-level microsatellite instability in most colorectal carcinomas. , 2002, Cancer research.

[62]  L. Ricciardiello,et al.  Steady-state regulation of the human DNA mismatch repair system , 2001, The Journal of biological chemistry.

[63]  R. Fishel,et al.  The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. , 2001, Cancer research.

[64]  C. Boland,et al.  Oxidative stress increases frameshift mutations in human colorectal cancer cells. , 2001, Cancer research.

[65]  D. Chang,et al.  Microsatellites in the eukaryotic DNA mismatch repair genes as modulators of evolutionary mutation rate. , 2001, Genome research.

[66]  H. Hollema,et al.  Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. , 2001, Gastroenterology.

[67]  I. Tomlinson,et al.  Microsatellite instability and the clinicopathological features of sporadic colorectal cancer , 2001, Gut.

[68]  D. Shibata,et al.  Stepwise deletions of polyA sequences in mismatch repair-deficient colorectal cancers. , 2001, The American journal of pathology.

[69]  N. Ahuja,et al.  Accelerated age-related CpG island methylation in ulcerative colitis. , 2001, Cancer research.

[70]  B. Leggett,et al.  Biological significance of microsatellite instability-low (MSI-L) status in colorectal tumors. , 2001, The American journal of pathology.

[71]  T. Kunkel,et al.  Complementation of an hMSH2 defect in human colorectal carcinoma cells by human chromosome 2 transfer , 2000, Molecular carcinogenesis.

[72]  C. Fenoglio-Preiser,et al.  Microsatellite instability and K-ras mutations in patients with ulcerative colitis. , 2000, Human pathology.

[73]  David Joseph,et al.  Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer , 2000, The Lancet.

[74]  J. Jen,et al.  Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer. , 2000, Cancer research.

[75]  James Lyons-Weiler,et al.  Evolutionary origin, diversification and specialization of eukaryotic MutS homolog mismatch repair proteins. , 2000, Nucleic acids research.

[76]  S. Bull,et al.  Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. , 2000, The New England journal of medicine.

[77]  J. Tytell,et al.  Germ-line msh6 mutations in colorectal cancer families. , 1999, Cancer research.

[78]  T. Iwama,et al.  Frequent Mutation of β-Catenin and APC Genes in Primary Colorectal Tumors from Patients with Hereditary Nonpolyposis Colorectal Cancer , 1999 .

[79]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[80]  A. Millar,et al.  Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. , 1999, Cancer research.

[81]  C. Boland,et al.  Mismatch repair proficiency and in vitro response to 5-fluorouracil. , 1999, Gastroenterology.

[82]  T. Prolla,et al.  Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[83]  H T Lynch,et al.  New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. , 1999, Gastroenterology.

[84]  P. Møller,et al.  MSH2 genomic deletions are a frequent cause of HNPCC , 1998, Nature Genetics.

[85]  S Srivastava,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. , 1998, Cancer research.

[86]  L. Kasturi,et al.  Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[87]  T. Smyrk,et al.  Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members , 1998, Cancer.

[88]  R. Kucherlapati,et al.  Mutation in the Mismatch Repair Gene Msh6 Causes Cancer Susceptibility , 1997, Cell.

[89]  M. Koike,et al.  Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer , 1997, Nature Genetics.

[90]  J. Gebert,et al.  Microsatellite instability analysis: a multicenter study for reliability and quality control. , 1997, Cancer research.

[91]  J. Rüschoff,et al.  Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. , 1997, Cancer research.

[92]  J. L. Fink,et al.  Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[93]  T. Kunkel,et al.  Correction of hypermutability, N-methyl-N'-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. , 1997, Cancer research.

[94]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[95]  G. Marsischky,et al.  hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[96]  S. Aebi,et al.  The role of DNA mismatch repair in platinum drug resistance. , 1996, Cancer research.

[97]  S. Baylin,et al.  Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure. , 1996, Cancer research.

[98]  T. Mak,et al.  MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. , 1996, Cancer research.

[99]  C. Boland,et al.  Loss of DNA mismatch repair in acquired resistance to cisplatin. , 1996, Cancer research.

[100]  M. Hawn,et al.  Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. , 1996, The Journal of clinical investigation.

[101]  Asad Umar,et al.  Meiotic Pachytene Arrest in MLH1-Deficient Mice , 1996, Cell.

[102]  M. Perucho,et al.  Microsatellite instability: The mutator that mutates the other mutator , 1996, Nature Medicine.

[103]  Sajeev P. Cherian,et al.  Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. , 1996, Cancer research.

[104]  L. Aaltonen,et al.  Better survival rates in patients with MLH1-associated hereditary colorectal cancer. , 1996, Gastroenterology.

[105]  K. Kinzler,et al.  Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. , 1995, Cancer research.

[106]  T. Petes,et al.  Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[107]  Luzhe Sun,et al.  Demonstration That Mutation of the Type II Transforming Growth Factor β Receptor Inactivates Its Tumor Suppressor Activity in Replication Error-positive Colon Carcinoma Cells (*) , 1995, The Journal of Biological Chemistry.

[108]  H. Griesser,et al.  MSH2 deficient mice are viable and susceptible to lymphoid tumours , 1995, Nature Genetics.

[109]  M. Hawn,et al.  Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. , 1995, Cancer research.

[110]  M. Radman,et al.  Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer , 1995, Cell.

[111]  J. Jiricny,et al.  GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. , 1995, Science.

[112]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.

[113]  N. York,et al.  Advances in Brief Microsatellite Instability in Ulcerative Colitis-associated Colorectal Dysplasias and Cancers ' , 2006 .

[114]  G. Aquilina,et al.  A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[115]  R. Fleischmann,et al.  Mutations of two P/WS homologues in hereditary nonpolyposis colon cancer , 1994, Nature.

[116]  Sajeev P. Cherian,et al.  Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. , 1994, Cancer research.

[117]  M. Meuth,et al.  Mutator phenotypes in human colorectal carcinoma cell lines. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[118]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[119]  D. Ward,et al.  Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer , 1994, Nature.

[120]  Bert Vogelstein,et al.  Hypermutability and mismatch repair deficiency in RER+ tumor cells , 1993, Cell.

[121]  Robin J. Leach,et al.  Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer , 1993, Cell.

[122]  L. Aaltonen,et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. , 1993, Cancer research.

[123]  N. Copeland,et al.  The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer , 1993, Cell.

[124]  A. Lindblom,et al.  Genetic mapping of a second locus predisposing to hereditary non–polyposis colon cancer , 1993, Nature Genetics.

[125]  Darryl Shibata,et al.  Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis , 1993, Nature.

[126]  S N Thibodeau,et al.  Microsatellite instability in cancer of the proximal colon. , 1993, Science.

[127]  K. Kinzler,et al.  Clues to the pathogenesis of familial colorectal cancer. , 1993, Science.

[128]  C. Boland,et al.  Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. , 1993, Gastroenterology.

[129]  A. Velázquez,et al.  Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[130]  J. Mecklin,et al.  The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) , 1991, Diseases of the colon and rectum.

[131]  P. Modrich,et al.  Mechanisms of DNA-mismatch correction. , 1990, Mutation research.

[132]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[133]  Y. Nakamura,et al.  Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. , 1989, JAMA.

[134]  M. Leppert,et al.  Allelic Loss in Colorectal Carcinoma , 1989 .

[135]  Y. Nakamura,et al.  Allelotype of colorectal carcinomas. , 1989, Science.

[136]  Suet Yi Leung,et al.  Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1 , 2009, Nature Genetics.

[137]  C. Compton,et al.  The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. , 2007, Gastroenterology.

[138]  D. Chang,et al.  The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch Syndrome: from bench to bedside , 2007, Familial Cancer.

[139]  David I. K. Martin,et al.  Germline epimutation of MLH1 in individuals with multiple cancers , 2004, Nature Genetics.

[140]  H. Vasen,et al.  Clinical Description of the Lynch Syndrome [Hereditary Nonpolyposis Colorectal Cancer (HNPCC)] , 2004, Familial Cancer.

[141]  P. Peltomäki.  Lynch Syndrome Genes , 2004, Familial Cancer.

[142]  C. Boland,et al.  Evolution of the Nomenclature for the Hereditary Colorectal Cancer Syndromes , 2004, Familial Cancer.

[143]  Andreas D. Baxevanis,et al.  MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability , 2000, Nature Genetics.

[144]  T. Iwama,et al.  Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. , 1999, Cancer research.

[145]  J. Mecklin,et al.  Prognosis of colorectal cancer varies in different high-risk conditions. , 1998, Annals of medicine.