Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for sporadic CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling. Results We identified 13 loci that reached genome-wide significance (P<5×10^-8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.

中文翻译：

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近端和远端结直肠癌的遗传结构部分不同

目的了解大肠癌（CRC）的病因异质性对于提高精确预防至关重要，包括个体化的筛查建议以及发现新的化学靶标和可预防化学用的可替代药物。已知在结肠直肠不同部位出现的肿瘤之间的分子特征和环境危险因素的差异提示了部分不同的致癌机理。尚未检查遗传性遗传危险因素对散发性CRC的贡献程度因原发肿瘤的解剖亚部位而异。 设计为了确定新的解剖亚位特异性风险基因座，我们进行了全基因组关联研究（GWAS）荟萃分析，包括48,214例CRC病例和64,159例欧洲血统对照的数据。我们使用多项式建模来表征CRC风险基因座的效应异质性。 结果我们确定了13个达到全基因组意义的基因座（P <5×10 ^-8），而先前的GWAS并未报告其总体CRC风险。多条证据支持这些基因座中几个基因的候选基因。我们检测到解剖亚位之间的实质异质性。在109个已知和新的风险变体中，只有略超过一半（61）表示没有异质性证据。相反，有22个变体显示与远端CRC（包括直肠癌）的关联，但没有证据表明与远端CRC的关联或减弱的关联。对于两个基因座，有强有力的证据表明其作用仅限于近端结肠癌。 结论近端和远端CRC的遗传结构部分不同。对危险因素和致癌机理以及精确预防策略的研究应考虑肿瘤的解剖亚位。