Association Between Colorectal Cancer Susceptibility Loci and Survival Time After Diagnosis With Colorectal Cancer

doi:10.1053/j.gastro.2012.04.052

Gastroenterology

Volume 143, Issue 1, July 2012, Pages 51-54.e4

https://doi.org/10.1053/j.gastro.2012.04.052 Get rights and content

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.

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Acknowledgments

The authors wish to acknowledge Patrice Soule and Hardeep Ranu for genotyping at the Dana-Farber Harvard Cancer Center High Throughput Polymorphism Core, under the supervision of Immaculata Devivo, as well as Carolyn Guo and Haiyan Zhang for programming assistance. The authors also wish to acknowledge Dave Duggan at TGen and Andrew Crenshaw at the Broad Institute for genotyping. The authors also thank the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study,

References (12)

J. Xing
Eur J Cancer
(2011)
A. Tenesa
Nat Rev Genet
(2009)
R.S. Houlston
Nat Genet
(2010)
H.L. McLeod
J Clin Oncol
(2010)
W. Zhang
J Clin Oncol
(2007)
V. Formica
Int J Colorectal Dis
(2011)

There are more references available in the full text version of this article.

Cited by (37)

A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients
2021, European Journal of Cancer
Citation Excerpt :
Other factors thought to influence patient prognosis include lifestyle [2,3], systemic inflammatory response [4], immunologic microenvironment [5] and the patient's germline and the tumour's somatic profile [6,7]. The search for inherited prognostic factors has primarily focussed on candidate genes and single nucleotide polymorphisms (SNPs) that function in pharmacological pathways [8,9], influence tumour progression [10] or alter disease risk [11–16]. However, apart from rs9929218 in CDH1, most reported SNP associations have not been independently replicated [17].
While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome.
We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10⁻⁵), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas.
The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16–1.32, P = 1.9 × 10⁻⁷). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10⁻²) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10⁻⁸). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1–1.9, P = 4.6 × 10⁻²).
Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.
Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants
2020, European Journal of Cancer
Citation Excerpt :
No combinations of SNPs within specific pathways were more significantly associated with survival beyond the single most significant SNP in that pathway alone. Six CRC risk SNPs (rs4939827, rs961253, rs6983267, rs10795668, rs4444235 and rs4925386) have previously been associated with survival [17–22], although none have been independently replicated [30,32,33]. We reviewed published survival data for these SNPs [17,19,22,29–31] and carried out meta-analysis with our data.
Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10⁻⁴ for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10⁻⁵). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10⁻⁶). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10⁻³). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
Colorectal Cancer Risk Prediction Using the rs4939827 Polymorphism of the SMAD7 Gene in the Romanian Population
2024, Diagnostics
Association of several loci of SMAD7 with colorectal cancer: A meta-analysis based on case-control studies
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Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival
2022, Scientific Reports
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: Conflicts of interest The authors disclose the following: Dr Chan has received funding as an ad hoc consultant for Bayer Healthcare, Pfizer, and Millenium Pharmaceuticals.

: Funding This work was supported by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088 to U.P.), and was supported in part by a training grant from the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (R25 CA094880 to E.W., with funding for A.I.P. and C.M.H.). A.T.C. is a Damon Runyon Clinical Investigator. P.A.N. was supported by the National Institutes of Health, National Cancer Institute (K05CA152715). Additional funding support for included individual studies was as follows: the Health Professionals' Follow-up Study was supported by the National Institutes of Health (P01 CA 055075 to C.S.F., R01 137178 to A.T.C., and P50 CA 127003 to C.S.F.); the Nurses' Health Study was supported by the National Institutes of Health (R01 137178 to A.T.C., P50 CA 127003 to C.S.F., and P01 CA 087969 to C.S.F.); the Physicians' Health Study was supported by the National Institutes of Health (CA 42182); the VItamins And Lifestyle Study was supported in part by the National Institutes of Health (K05 CA154337 to E.W.) from the National Cancer Institute and Office of Dietary Supplements; and the Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding for the genome-wide scan of the Women's Health Initiative was provided by the National Cancer Institute, Institutes of Health, US Department of Health and Human Services (R01 CA059045 to U.P.).

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Original ResearchBrief ReportAssociation Between Colorectal Cancer Susceptibility Loci and Survival Time After Diagnosis With Colorectal Cancer

Section snippets

Acknowledgments

Eur J Cancer

Nat Rev Genet

Nat Genet

J Clin Oncol

J Clin Oncol

Int J Colorectal Dis

Original Research
Brief Report
Association Between Colorectal Cancer Susceptibility Loci and Survival Time After Diagnosis With Colorectal Cancer