Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 × 10 −10 ), 16q22.1 (rs9929218, CDH1; P = 1.2 × 10 −8 ), 19q13.1 (rs10411210, RHPN2; P = 4.6 × 10 −9 ) and 20p12.3 (rs961253; P = 2.0 × 10 −10 ). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.Whereas inherited susceptibility is responsible for ~35% of all CRC 1 , high-risk germline mutations in APC, the mismatch repair (MMR) genes, MUTYH (MYH), SMAD4, BMPR1A and STK11/LKB1 account for <6% of all cases 2 . Recent GWA studies have validated the hypothesis that part of the heritable risk is caused by common, low-risk variants, identifying CRC susceptibility loci mapping to 8q24 (rs6983267) 3, 4, 8q23.3 (rs16892766, EIF3H)5, 10p14 (rs10795668)5, 11q23 (rs3802842)6, 15q13 (rs4779584)7 and 18q21 (rs4939827, SMAD7) 6,8 .GWA studies are not contingent on prior information concerning candidate genes or pathways, and thereby have the ability to identify important variants in hitherto unstudied genes. However, the effect sizes of individual variants, the need for stringent thresholds for establishing statistical significance, and financial constraints on numbers of variants that can be followed up inevitably constrain study power. We recently published two separate GWA studies for CRC. To augment the power to detect additional CRC risk loci, we have conducted a meta-analysis of data from these studies and followed up the best supported associations in large sample sets. This analysis, in conjunction with a replication study using eight independent case-control series, has enabled us to identify four new loci predisposing to CRC. This brings to ten the number of independent loci conclusively associated with CRC risk, and provides additional insight into the genetic architecture of inherited susceptibility to CRC. RESULTS Meta-analysis of genome-wide association scansThe GWA studies were both conducted by centers in London and Edinburgh, and were both based on designs involving two-phase strategies and using samples from UK populations NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 March 11. Published in final edited form as:Nat Genet. London phase 2 was based on genotyping 2,873 CRC cases and 2,871 controls ascertained through the National Study of Colorectal Cancer Genetics (NSCCG), whereas Edinburgh phase 2 was based on genotyping 2,057 cases and 2,111 controls. For phase 2, the London and Edinburgh samples were genotyped for a common s...

Metastatic Colorectal Cancer: From Improved Survival to Potential Cure

“…Large genome-wide association studies (GWAS) have been performed, and to date 7 GWAS in colorectal cancer have identified 10 risk loci associated with a risk of developing colorectal cancer [144,145,146,147,148,149,150]. These genetic markers may direct screening and preventive therapy approaches, but may also identify unappreciated disease biology.…”

Genetic Copy Number Variations in Colon Mucosa Indicating Risk for Colorectal Cancer

“…In colorectal cancer, 10 risk SNP loci were reported at chromosomal bands 8q24, 18q21 [25], 8q23.3, 10p14 [7], 11q23 [5] [6], 15q13.3 [7], 14q22.2, 16q22.1, 19q13.1 and 20p12.3 [5]. In these studies, large cohorts of colorectal cancer patients and cancer free individuals were screened for novel and confirmed loci and presentation of susceptibility loci should be a step toward blood based screening for colorectal cancer risk [5] [16] [17]. Odds ratios generated in the studies ranged from 1.1 -1.5, which was low even when several DNA loci were combined [16] [17] [26].…”

“…In recent years, it has appeared that CNVs are common and involve a great proportion of the human genome and may be involved in cancer development [2] [3] [9]- [15]. Such findings may be utilized to improve public health care activities [5] [11] [16] [17], where DNA CNVs may provide additional information in screening of phenotypes compared to SNPs [8] [18] [19]. Therefore, the aim of this study was to search for CNVs in colon mucosa, as related to colon cancer, in 60 patients at their primary operation for colorectal cancer.…”

On Track? Using the Human Genome Epidemiology Roadmap

“…This approach was recently applied to multiple GWA studies of colorectal cancer, combining work done by 2 groups in the UK [70]. Another study used this for type 2 diabetes, combining 3 GWA studies in subjects of European descent [71].…”