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Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer.

ABSTRACT: Genome-wide association studies have identified 16 germline single-nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) incidence. We examined the relationship between these SNPs and survival of 2611 individuals with CRC, enrolled in 5 cohort studies. We used Cox regression analysis to associate SNPs with overall and CRC-specific survival times. The minor allele in rs4939827 (SMAD7) was associated with reduced overall survival (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27; P = .002) and disease-specific survival (hazard ratio, 1.17; 95% confidence interval, 1.05-1.30; P = .005). Other SNPs were not associated significantly with survival. Common germline variations might be prognostic factors for patients with CRC. A variant in SMAD7 could affect progression of CRC.

SUBMITTER: Phipps AI

PROVIDER: S-EPMC3579620 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer.

Phipps Amanda I AI Newcomb Polly A PA Garcia-Albeniz Xabier X Hutter Carolyn M CM White Emily E Fuchs Charles S CS Hazra Aditi A Ogino Shuji S Nan Hongmei H Ma Jing J Campbell Peter T PT Figueiredo Jane C JC Peters Ulrike U Chan Andrew T AT

Gastroenterology 20120508 1

Genome-wide association studies have identified 16 germline single-nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) incidence. We examined the relationship between these SNPs and survival of 2611 individuals with CRC, enrolled in 5 cohort studies. We used Cox regression analysis to associate SNPs with overall and CRC-specific survival times. The minor allele in rs4939827 (SMAD7) was associated with reduced overall survival (hazard ratio, 1.16; 95% confidence inter ...[more]

PMID: 22580541

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Project description:BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Project description:Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality.Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

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Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer.

Publications

Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer.

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