Introduction
Colorectal polyposis, characterized by more than 10 adenomas, indicates a higher risk of malignancy and necessitates more frequent screening and genetic assessment. However, there are still a large number of polyposis patients with negative genetic test results. This study aimed to explore the risk genetic variants associated with non-hereditary colorectal polyposis through a genome-wide association study (GWAS).
Aims & Methods
Among patients who underwent colonoscopy at a single referral university hospital from January 2012 to September 2021, a total of 638 patients with 10 or more biopsy-proven cumulative polyps on colonoscopies and without genetic mutations or family history related to colorectal polyposis were included in this study. For the control group, a total of 7087 people who underwent colonoscopy for the purpose of health check-up at the Korea Medical Institute and were normal at least twice in a row were included. To find susceptible loci to non-hereditary colorectal polyposis, GWAS was performed and a genome-wide p-value threshold of 5 × 10-7 was set to assess statistical significance.
We compared the genetic differences between two groups of patients with non-hereditary colorectal polyposis: those with 10 or more polyp recurrences observed during follow-up colonoscopies and those without such recurrences. We utilized SNPs that were identified as risk variants for non-hereditary colorectal polyposis in this GWAS. For each SNP, we defined the risk allele as the allele associated with increased risk of non-hereditary colorectal polyposis as identified in this GWAS. Genotypes were coded as 0, 1, or 2 based on the number of risk alleles identified at each SNP. We used a polytomous logistic regression model to identify SNPs that significantly increased the risk of polyp recurrence compared to the group without recurrence. Results of all regression analyses were adjusted for age, sex, BMI, smoking history, alcohol consumption history, family history of cancer, history of cancer other than colorectal cancer, comorbidities, and history of medication use.
Results
A total of 71 risk variants were discovered, which were new single-nucleotide polymorphisms (SNPs) not found in previous GWAS associated with colorectal cancer and polyp (Figure 1). 5 genes (UPF3A, BICRA, CBWD6, PDE4DIP, ABCC4) nearest or overlapped with 7 SNPs (rs566295755, rs2770288, rs1012003, rs201270202, rs71264659, rs1699813, rs149368557) previously reported directly or indirectly related to the development of colorectal cancer were proven to be risk variants significantly associated with non-hereditary colorectal polyposis. In addition, two new genes (CNTN4, CNTNAP3B) that have not previously been reported to be associated with colorectal cancer or polyp were newly identified.
The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-polyposis hereditary colorectal cancer (p-value: 0.049, odds ratio: 2.991, 95% confidence interval: 1.006–8.899).
Conclusion
In this study, we found 71 novel risk variants associated with non-hereditary colorectal polyposis. The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-hereditary colorectal polyposis. The risk variants and genes discovered in this study might be utilized as novel targets to prevent colorectal cancer in the future.
