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Identification of Specific Susceptibility Loci for the Early-Onset Colorectal Cancer
39 Pages Posted: 9 May 2022
More...Abstract
Background: The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the genetic susceptibility of EOCRC remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC.
Methods: Genome-wide association study (GWAS) with two parallel approaches of regression analyses was conducted in 17,789 CRC cases (including 1,490 EOCRC cases) and 19,951 healthy controls. A polygenetic risk score (PRS) model was built based on identified EOCRC specific susceptibility variants and further validated by using the UK Biobank cohort. Furthermore, we interpreted the potential biological mechanisms of the prioritized risk variant.
Findings: We identified 49 independent susceptibility loci that were significantly associated with the risk of EOCRC and the diagnosed age of CRC (both P < 5.00×10-4), and validated 3 previously identified CRC risk loci. Those assigned susceptibility genes were involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Compared to the individuals in low genetic risk group, the individuals in high genetic risk group have a 3.79-fold increased EOCRC risk. These results were replicated in the UKB cohort with a 1.63-fold risk. The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to merely dependent on the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 might contributed to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2.
Interpretation: These findings will broaden the understanding of the etiology for the EOCRC and may facilitate the early screening and individualized prevention.
Funding: This work were supported by Youth Program of National Natural Science Foundation of China (NSFC-82103929) for Jianbo Tian; Youth Program of National Natural Science Foundation of China (NSFC-81402098) for Heng Li; Youth Program of National Natural Science Foundation of China (NSFC-82003547) for Ying Zhu; National Science Fund for Distinguished Young Scholars of China (NSFC-81925032), Key Program of National Natural Science Foundation of China (NSFC-82130098), and Natural Science Foundation of Hubei Province (2019CFA009) for Xiaoping Miao; National Program for Support of Top-notch Young Professionals for Jiang Chang
Declaration of Interest: All authors declare no conflicts of interest.
Ethical Approval: Summary data was used and as such ethical approval was not required.
Keywords: GWAS, Early-onset CRC, Genetic variants, PRS, Early screening
Suggested Citation: Suggested Citation