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Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.

ABSTRACT: Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.

SUBMITTER: Zhang B

PROVIDER: S-EPMC4068797 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.

Zhang Ben B Jia Wei-Hua WH Matsuda Koichi K Kweon Sun-Seog SS Matsuo Keitaro K Xiang Yong-Bing YB Shin Aesun A Jee Sun Ha SH Kim Dong-Hyun DH Cai Qiuyin Q Long Jirong J Shi Jiajun J Wen Wanqing W Yang Gong G Zhang Yanfeng Y Li Chun C Li Bingshan B Guo Yan Y Ren Zefang Z Ji Bu-Tian BT Pan Zhi-Zhong ZZ Takahashi Atsushi A Shin Min-Ho MH Matsuda Fumihiko F Gao Yu-Tang YT Oh Jae Hwan JH Kim Soriul S Ahn Yoon-Ok YO Chan Andrew T AT Chang-Claude Jenny J Slattery Martha L ML Gruber Stephen B SB Schumacher Fredrick R FR Stenzel Stephanie L SL Casey Graham G Kim Hyeong-Rok HR Jeong Jin-Young JY Park Ji Won JW Li Hong-Lan HL Hosono Satoyo S Cho Sang-Hee SH Kubo Michiaki M Shu Xiao-Ou XO Zeng Yi-Xin YX Zheng Wei W

Nature genetics 20140518 6

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or ...[more]

PMID: 24836286

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

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Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.

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Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.

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