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Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.

ABSTRACT: Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck carcinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse.The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed.A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050).If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk.

SUBMITTER: Zee RY

PROVIDER: S-EPMC3582777 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.

Zee Robert Y L RY Rose Lynda L Chasman Daniel I DI Ridker Paul M PM

Clinica chimica acta; international journal of clinical chemistry 20121228

<h4>Objective</h4>Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck carcinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse.<h4>Methods</h4>The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MT ...[more]

PMID: 23276522

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Project description:ImportanceCase-control studies show a possible relationship between oral bacteria and head and neck squamous cell cancer (HNSCC). Prospective studies are needed to examine the temporal relationship between oral microbiome and subsequent risk of HNSCC.ObjectiveTo prospectively examine associations between the oral microbiome and incident HNSCC.Design, setting, and participantsThis nested case-control study was carried out in 2 prospective cohort studies: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Among 122 004 participants, 129 incident patient cases of HNSCC were identified during an average 3.9 years of follow-up. Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. All participants provided mouthwash samples and were cancer-free at baseline.ExposuresOral microbiome composition and specific bacterial abundances were determined through bacterial 16S rRNA gene sequencing. Overall oral microbiome composition and specific taxa abundances were compared for the case group and the control group, using PERMANOVA and negative binomial generalized linear models, respectively, controlling for age, sex, race, cohort, smoking, alcohol, and oral human papillomavirus-16 status. Taxa with a 2-sided false discovery rate (FDR)-adjusted P-value (q-value) <.10 were considered significant.Main outcomes and measuresIncident HNSCC.ResultsThe study included 58 patient cases from CPS-II (mean [SD] age, 71.0 [6.4] years; 16 [27.6%] women) and 71 patient cases from PLCO (mean [SD] age, 62.7 [4.8] years; 13 [18.3%] women). Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. Head and neck squamous cell cancer cases and controls were similar with respect to age, sex, and race. Patients in the case group were more often current tobacco smokers, tended to have greater alcohol consumption (among drinkers), and to be positive for oral carriage of papillomavirus-16. Overall microbiome composition was not associated with risk of HNSCC. Greater abundance of genera Corynebacterium (fold change [FC], 0.58; 95% confidence interval [CI], 0.41-0.80; q = .06) and Kingella (FC, 0.63; 95% CI, 0.46-0.86; q = .08) were associated with decreased risk of HNSCC, potentially owing to carcinogen metabolism capacity. These findings were consistent for both cohorts and by cohort follow-up time. The observed relationships tended to be stronger for larynx cancer and for individuals with a history of tobacco use.Conclusions and relevanceThis study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.

Dataset Information

Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.

Publications

Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.

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