Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Abstract

Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately 2-fold (highest versus lowest quintile), and the shape of the dose-response was linear (Ptrend =1.24×10−13 and 3.02×10−14 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (Pinteraction =0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (Ptrend =0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.

Combinations of single nucleotide polymorphisms identified in genome‐wide association studies determine risk for colorectal cancer

“…To date, a moderate number of CRC risk evaluation studies, including GWAS‐identified SNPs, have been reported, but their assessment models were constructed either using a single evaluation method or using only one population . Therefore, the present study has several strengths.…”

“…Several previous genome‐wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with CRC risk . However, few studies have explored the value of these SNPs in evaluating an individual's risk of CRC, particularly in Chinese populations . Therefore, we systematically analyzed 85 GWAS‐identified SNPs (Supporting Information Table S1) using three large‐scale GWAS datasets to determine the potential applications of genetic variants (Supporting Information Table S2).…”

Colorectal cancer susceptibility loci and influence on survival

“…Among previous studies on the role of colorectal cancer susceptibility SNPs in prognosis, several had constructed PRSs . Dai et al observed a cumulative effect for unfavorable genotypes in models including 2 SNPs (rs10749971 and rs961253) for recurrence and 3 SNP (rs961253, rs4464148, and rs6983267) for survival .…”

“…Dai et al observed a cumulative effect for unfavorable genotypes in models including 2 SNPs (rs10749971 and rs961253) for recurrence and 3 SNP (rs961253, rs4464148, and rs6983267) for survival . In a survival analysis, Wang et al used a weighted PRS using 5 SNPs from a literature review (rs1321311, rs6983267, rs4939827, rs10411210, and rs961253) and the number of risk alleles in 2 SNPs (rs6983267 and rs1957636) and found that each SNP was associated with mortality with a linear trend . Phipps et al also observed that the sum of alleles for 3 SNPs (rs4939827, rs10795668, and rs4925386) was associated with survival .…”

“…There have been several studies on the role of colorectal cancer susceptibility SNPs in prognosis, but they have yielded inconclusive results. Some studies have suggested that certain colorectal cancer susceptibility SNPs may also affect disease prognosis, specifically at 1p36.22 ( MTHFR ), 5q33.1 ( GPX3 ), 6p21.2 ( SRSF3 , CDKN1A ), 8q23.3 ( EIF3H ), 8q24 ( SRRM1P1 , POU5F1B , DQ515897 , MYC ), 10p14 ( KRT8P16 , TCEB1P3 , RNA5SP299 , GATA3 ), 11q23.1 ( COLCA2, LOC120376, FLJ45803, C11orf53, POU2AF1 ), 12p12.1 ( SLCO1B1 ), 14q22.2 ( BMP4 ), 15q13.3 ( SCG5 , GREM1 ), 16q22.1 ( CDH1 ), 18q21.1 ( SMAD7 ), 19q13.11 ( RHPN2 ), and 20p12.3 ( BMP2 ) . However, other susceptibility SNPs reported in the same studies show no evidence for associations with colorectal cancer prognosis.…”