Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.


BACKGROUND & AIMS Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

DOI: 10.1053/j.gastro.2016.02.076

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@article{Zeng2016IdentificationOS, title={Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.}, author={Chenjie Zeng and Koichi Matsuda and Wei-hua Jia and Jiang Chang and Sun-Seog Kweon and Yong-Bing Xiang and Aesun Shin and Sun Ha Jee and Dong-Hyun Kim and Ben Zhang and Qiuyin Cai and Xingyi Guo and Jirong Long and Nan Wang and Regina Courtney and Zhizhong Pan and Chen Wu and Atsushi Takahashi and Min-Ho Shin and Keitaro Matsuo and Fumihiko Matsuda and Yu-tang Gao and Jae Hwan Oh and Soriul Kim and Keum Ji Jung and Y O Ahn and Zefang Ren and Hong-lan Li and Jie Wu and Jiajun Shi and Wanqing Wen and Gong Yang and Bingshan Li and Bu-tian Ji and Hermann Brenner and Robert E. Schoen and S{\'e}bastien K{\"{u}ry and Stephen B. Gruber and Fredrick R. Schumacher and Stephanie L. Stenzel and Graham R Casey and John L. Hopper and Mark Jenkins and Hyeong Rok Kim and Jinyoung Jeong and Ji Won Park and Kazuo Tajima and Sang-Hee Cho and Michiaki Kubo and Xiao Shu and Dongxin Lin and Yi Zeng and Wei Zheng}, journal={Gastroenterology}, year={2016}, volume={150 7}, pages={1633-1645} }