Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome.

BACKGROUND Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. METHODS We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. RESULTS Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). CONCLUSION Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

[1]  D. Greer Medicine in the University , 2015, Perspectives in biology and medicine.

[2]  Aung Ko Win,et al.  Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  G. Marra,et al.  Evidence for breast cancer as an integral part of lynch syndrome , 2012, Genes, chromosomes & cancer.

[4]  D. Easton,et al.  BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients , 2011, British Journal of Cancer.

[5]  Laetitia Huiart,et al.  Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. , 2011, JAMA.

[6]  S. Gruber,et al.  Hereditary prostate cancer as a feature of Lynch Syndrome , 2011, Familial Cancer.

[7]  P. Baade,et al.  The relative risk of second primary cancers in Queensland, Australia: a retrospective cohort study , 2011, BMC Cancer.

[8]  Aung Ko Win,et al.  Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery , 2010, Gut.

[9]  J. Baron,et al.  Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma , 2010, International journal of cancer.

[10]  L. Kiemeney,et al.  Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers , 2010, Journal of Medical Genetics.

[11]  J. Potter,et al.  Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry , 2010, Clinical Cancer Research.

[12]  Finlay Macrae,et al.  Risks of Lynch syndrome cancers for MSH6 mutation carriers. , 2010, Journal of the National Cancer Institute.

[13]  P. Møller,et al.  Germ-Line Mutations in Mismatch Repair Genes Associated with Prostate Cancer , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[14]  J. Kleibeuker,et al.  Small-bowel cancer in Lynch syndrome: is it time for surveillance? , 2008, The Lancet. Oncology.

[15]  J. Potter,et al.  The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. , 2008, Gastroenterology.

[16]  D. Rubin,et al.  Association between colorectal cancer and urologic cancers. , 2008, Archives of internal medicine.

[17]  I. Bernstein,et al.  Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer , 2008, Familial Cancer.

[18]  K. Schulmann,et al.  Small bowel cancer risk in Lynch syndrome , 2008, Gut.

[19]  John D Potter,et al.  Colon Cancer Family Registry: An International Resource for Studies of the Genetic Epidemiology of Colon Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[20]  G. Nicholas,et al.  A Population-Based Analysis of Second Primary Cancers After Irradiation for Rectal Cancer , 2007, American journal of clinical oncology.

[21]  A. Cats,et al.  Is surveillance of the small bowel indicated for Lynch syndrome families? , 2007, Gut.

[22]  Steve Scoppa,et al.  Multiple Cancer Prevalence: A Growing Challenge in Long-term Survivorship , 2007, Cancer Epidemiology Biomarkers & Prevention.

[23]  L. Travis,et al.  The Epidemiology of Second Primary Cancers , 2006, Cancer Epidemiology Biomarkers & Prevention.

[24]  M. Goodman,et al.  Excess risk of subsequent primary cancers among colorectal carcinoma survivors, 1975–2001 , 2006, Cancer.

[25]  G. Giles,et al.  Large genomic alterations in hMSH2 and hMLH1 in early‐onset colorectal cancer: identification of a large complex de novo hMLH1 alteration , 2006, Clinical genetics.

[26]  J. Jass Hereditary Non-Polyposis Colorectal Cancer: the rise and fall of a confusing term. , 2006, World journal of gastroenterology.

[27]  G. Giles,et al.  Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[28]  C. Pui,et al.  Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations. , 2006, Journal of the National Cancer Institute.

[29]  Susan Robinson,et al.  German , 2006 .

[30]  John L Hopper,et al.  Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  H C van Houwelingen,et al.  Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment , 2005, Journal of Medical Genetics.

[32]  C. Luke,et al.  Multiple primary cancers of separate organ sites: implications for research and cancer control (Australia) , 2005, Cancer Causes & Control.

[33]  K. Schulmann,et al.  HNPCC-associated small bowel cancer: clinical and molecular characteristics. , 2005, Gastroenterology.

[34]  M. Ducreux,et al.  An appendix carcinoid tumor in a patient with hereditary nonpolyposis colorectal cancer. , 2004, Human pathology.

[35]  Cheng-Chang Chang,et al.  Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes. , 2004, Cancer genetics and cytogenetics.

[36]  Sudhir Srivastava,et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. , 2004, Journal of the National Cancer Institute.

[37]  C. Seynaeve,et al.  Microsatellite instability in a pleomorphic rhabdomyosarcoma in a patient with hereditary non‐polyposis colorectal cancer , 2003, Histopathology.

[38]  P. Hutter,et al.  Prostate cancer is part of the hereditary non‐polyposis colorectal cancer (HNPCC) tumor spectrum , 2003, American journal of medical genetics. Part A.

[39]  F. Hermoso,et al.  Highly aggressive leiomyosarcoma associated with Lynch II syndrome: increasing the range of extracolonic cancers related with hereditary non-polyposis colonic cancer. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  C. Lewis,et al.  The risk of subsequent primary cancers after colorectal cancer in southeast England , 2002, Gut.

[41]  E. Buiatti,et al.  Multiple primary cancer incidence in Italy. , 2001, European journal of cancer.

[42]  K. Hemminki,et al.  Second primary cancers after sporadic and familial colorectal cancer. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[43]  P. Simpson,et al.  Statistical methods in cancer research , 2001, Journal of surgical oncology.

[44]  H. Hollema,et al.  Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non‐polyposis colorectal cancer , 2000, Genes, chromosomes & cancer.

[45]  C. la Vecchia,et al.  Cancer risk following polyps or cancer of the large bowel in Vaud, Switzerland , 1999, International journal of cancer.

[46]  J. Mecklin,et al.  Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma , 1998, Cancer.

[47]  L. Tanoue,et al.  The National Comprehensive Cancer Network , 1998, Cancer.

[48]  A. Neugut,et al.  The epidemiology of cancer of the small bowel. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[49]  J. Ferlay,et al.  Cancer Incidence in Five Continents , 1997 .

[50]  E. Buiatti,et al.  Incidence of second primary cancers in three Italian population-based cancer registries. , 1997, European journal of cancer.

[51]  M. McCredie,et al.  Second primary cancers after cancers of the colon and rectum in New South Wales, Australia, 1972-1991. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[52]  J. Boyd,et al.  Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome , 1996, Cancer.

[53]  L. Aaltonen,et al.  Life‐time risk of different cancers in hereditary non‐polyposis colorectal cancer (hnpcc) syndrome , 1995, International journal of cancer.

[54]  M. Slattery,et al.  Impact of family history of colon cancer on development of multiple primaries after diagnosis of colon cancer , 1995, Diseases of the colon and rectum.

[55]  J. Gudmundsson,et al.  Identification of a breast tumor with microsatellite instability in a potential carrier of the hereditary non‐polyposis colon cancer trait , 1995, Clinical genetics.

[56]  J. Mecklin,et al.  The International Collaborative Group on HNPCC. , 1994, Anticancer research.

[57]  H. Tsukuma,et al.  Incidence of Second Primary Cancers in Osaka Residents, Japan, with Special Reference to Cumulative and Relative Risks , 1994, Japanese journal of cancer research : Gann.

[58]  C. la Vecchia,et al.  Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974-89. , 1993, British Journal of Cancer.

[59]  Norman E. Breslow,et al.  Statistical Methods in Cancer Research, Vol. II: The Design and Analysis of Cohort Studies. , 1990 .

[60]  C. Muir,et al.  International Classification of Diseases for Oncology , 1990 .

[61]  H. Adami,et al.  The risk of subsequent primary malignant diseases after cancers of the colon and rectum a nationwide cohort study , 1990, Cancer.

[62]  D. Winn,et al.  Second cancer following cancer of the digestive system in Connecticut, 1935-82. , 1985, National Cancer Institute monograph.

[63]  B. Carstensen,et al.  Second cancer following cancer of the digestive system in Denmark, 1943-80. , 1985, National Cancer Institute monograph.

[64]  E. Saxén,et al.  Multiple cancer--an epidemiologic exercise in Finland. , 1985, Journal of the National Cancer Institute.

[65]  J. Stockman Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome , 2013 .

[66]  India,et al.  Cancer Incidence in Five Continents Vol. X , 2013 .

[67]  C. Bonaïti‐pellié,et al.  Cancer risks associated with germline mutations in MLH1, MSH2 and MSH6 genes in Lynch syndrome: results from the large nationwide French ERISCAM study , 2011 .

[68]  J. Stockman,et al.  Risk of Pancreatic Cancer in Families With Lynch Syndrome , 2011 .

[69]  J. Stockman,et al.  Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome , 2008 .

[70]  R. Hoover,et al.  New malignancies among cancer survivors: SEER Cancer Registries, 1973-2000. , 2006 .

[71]  Cancer survivorship--United States, 1971-2001. , 2004, MMWR. Morbidity and mortality weekly report.

[72]  Cancer incidence in five continents. Volume VIII. , 2002, IARC scientific publications.

[73]  Tx Station Stata Statistical Software: Release 7. , 2001 .

[74]  H. Olsson Cancer risks in BRCA2 mutation carriers. , 1999, Journal of the National Cancer Institute.

[75]  F. Levi,et al.  Cancer incidence in five continents, vol. VI , 1993 .

[76]  R. Fitzgibbons,et al.  Hereditary Colorectal Cancer , 1990, Springer Japan.

[77]  Norman E. Breslow,et al.  The design and analysis of cohort studies , 1987 .

[78]  N. Breslow,et al.  Statistical methods in cancer research. Volume II--The design and analysis of cohort studies. , 1987, IARC scientific publications.

[79]  J. Ferlay,et al.  Cancer Incidence in Five Continents , 1970, Union Internationale Contre Le Cancer / International Union against Cancer.