title: DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, -149 bp from the transcription start site, is reported to greatly increase promoter activity and is associated with increased risk for lung cancer and decreased postsurgical survival in patients with small cell carcinoma of the head and neck. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 146 mismatch repair mutation carriers from 72 families. Of these, 74 participants had colorectal cancer. The participants were genotyped by single-strand conformational polymorphism analysis and DNA sequencing. We tested the association between age of onset and DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test, Wilcoxon's test, and Fleming-Harrington test and estimating the strength and direction of the association using the Cox proportional hazards regression model adjusting for potential demographic and genetic confounding factors. HNPCC patients carrying one or two copies of the DNMT3b variant T allele developed their colorectal cancer significantly earlier than HNPCC patients who were homozygous for the wild-type DNMT3b allele. Combining knowledge of an individual's DNMT3b genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Unit 189, 1515 Holcombe Boulevard, Houston, TX 77030, USA. jonesbeach1@hotmail.com
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Jones
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Mala
authors.initials: M
authors.lastname: Pande
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Gu
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Imelda M
authors.initials: IM
authors.lastname: Campos
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Miguel
authors.initials: M
authors.lastname: Rodriguez-Bigas
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D020137:Base Pair Mismatch; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B