title: Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry.
abstract: Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non-Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22-2.16] for first-degree relatives and 1.08 (0.74-1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52-4.71) for first-degree relatives and 4.52 (2.23-10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29-3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non-Lynch syndrome CRCs.
authors.affiliation: Department of Preventive Medicine, Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. ajoanlev@usc.edu
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Tiffany I
authors.initials: TI
authors.lastname: Long
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: McCall
authors.forename: David J
authors.initials: DJ
authors.lastname: Duggan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein