Potential therapeutic targets for colorectal cancer and its subsites: evidence from the proteome-wide Mendelian randomization analyses.

Abstract

Background: Colorectal cancer (CRC) is the most common malignant tumor of the digestive tract worldwide, however, the potential targets for CRC and its subsites (colon cancer & rectum cancer) are less known. The aim of this study is to explore potential therapeutic targets for CRC.

Methods: A proteome-wide genome-wide association studies (GWAS) in 35,559 Icelanders with 4,907 plasma proteins was used as instrumental variables (P value <5×10^-8). The discovery stage consisted of the CRC GWAS with the largest sample size (CRC: 14,886 cases; colon: 3,793 cases; rectum: 2,091 cases). The significant proteins were further validated in the FinnGen study with 5,458 CRC cases (3,292 colon + 2,017 rectum). We identified relevant protein loci in CRC by two sample Mendelian randomization (MR) [false discovery rate (FDR) <0.05], colocalization analysis was used to further determine the relevance between CRC and plasma proteins, enrichment analysis and drug prediction were used to predict protein function.

Results: A total of 31 proteins were found to be in robust causal associations with CRC and the proteins' effects displayed anatomic site-specificity in MR analysis. The subsequent colocalization analysis pinpointed that CHDRL2 had a shared region with CRC and its two subsites, suggesting the importance of targeting it. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer. Enrichment analysis revealed functions of these proteins in CRC, and DrugBank showed their target drug.

Conclusions: In summary, our study has identified a common protein, CHDRL2, as the drug targets for CRC and its subsites. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer.