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Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis.

ABSTRACT: To date, genomewide association studies have identified 10 genetic loci associated with colorectal cancer (CRC) susceptibility. We hypothesized that these loci might also affect cancer survival.To determine whether single-nucleotide polymorphisms tagging these 10 loci influenced all-cause and CRC-specific mortality, we prospectively followed survival outcomes for 2,838 Scottish patients recruited soon after a diagnosis of CRC. Survival analysis was conducted using Cox proportional hazard models adjusted for American Joint Committee on Cancer stage, age, and sex.None of the single-nucleotide polymorphisms were found to be statistically significantly associated with all-cause or CRC-specific mortality.We conclude that none of the 10 common genetic variants thus far shown to be associated with CRC risk are associated with survival from CRC.

SUBMITTER: Tenesa A

PROVIDER: S-EPMC2906703 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis.

Tenesa Albert A Theodoratou Evropi E Din Farhat V N FV Farrington Susan M SM Cetnarskyj Roseanne R Barnetson Rebecca A RA Porteous Mary E ME Campbell Harry H Dunlop Malcolm G MG

Clinical cancer research : an official journal of the American Association for Cancer Research 20100713 14

<h4>Purpose</h4>To date, genomewide association studies have identified 10 genetic loci associated with colorectal cancer (CRC) susceptibility. We hypothesized that these loci might also affect cancer survival.<h4>Experimental design</h4>To determine whether single-nucleotide polymorphisms tagging these 10 loci influenced all-cause and CRC-specific mortality, we prospectively followed survival outcomes for 2,838 Scottish patients recruited soon after a diagnosis of CRC. Survival analysis was con ...[more]

PMID: 20628028

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Project description:A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

Project description:Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data.Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks.The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk.Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.

Dataset Information

Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis.

Publications

Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis.

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