Colorectal cancer (CRC) is one of the most common cancers in United States and many countries in the world. There is an urgent need to better understand its etiology and identify novel biomarkers to facilitate the early detection of CRC. Previous studies either lacked sufficient power to identify novel biomarkers or provided inconsistent results. In the current study, we attempted to uncover novel protein biomarkers for CRC through an integrated analysis of genomics and proteomics data. We first constructed study instruments using genetic variants identified from a large-scale protein quantitative trait loci (pQTL) analysis for over 1,400 circulating proteins. We used beta coefficients and standard errors for these pQTL variants from two large consortia of European-ancestry populations, the Colorectal Transdisciplinary (CORECT) Study (11,895 cases and 14,659 controls) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) (22,974 cases and 14,392 controls) for association analyses for genetically predicted protein levels with CRC risk using an inverse-variance weighted method. The genetically predicted levels of six proteins were associated with CRC risk after accounting for multiple comparisons (Benjamini-Hochberg FDR < 0.05). Among them, genetically predicted levels of VCAM-1, MIP-3b and LPH were inversely associated with CRC risk (VCAM-1: odds ratio [OR] per unit of increase = 0.65, Pmeta = 6.2 ×10-11; MIP-3b: OR = 0.68, Pmeta = 5.5×10-7; LPH: OR = 0.93, Pmeta = 8.0×10-5), while BMP-6, CRDL2 and laminin were positively associated (BMP-6: OR = 1.57, Pmeta = 3.0 ×10-9; CRDL2: OR = 1.36, Pmeta = 3.0 ×10-9; laminin: OR = 1.13, Pmeta = 6.7 ×10-5). Except for VCAM-1 (rs3184504, 12q24.12-SH2B3), other associations are not accounted for by any known CRC susceptibility variants. We observed a possible biological link connecting the genetic variants of LAMC1, LAMC1 expression, and laminin concentrations to CRC risk. Our study identifies potential novel biomarkers for CRC risk and provides novel insight into the disease etiology.

Citation Format: Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Conghui Qu, Stephanie L. Schmit, Chenxu Qu, Sonja I. Berndt, Peter T. Campbell, Andrew T. Chan, Graham G. Giles, Andrea Gsur, Michael Hoffmeister, Mark A. Jenkins, Sanford D. Markowitz, Li Li, Gad Rennert, Kenneth Offit, David Conti, Annika Lindblom, Graham Casey, Stephen B. Gruber, Ulrike Peters, Wei Zheng. Identification of circulating protein biomarkers for colorectal cancer risk: A genetic instrument analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2685.