Identification Of Functional Variants In Telomere Biology For Colorectal Cancer Susceptibility In Chinese Population

Objective: To identify causal variants in genes involved in telomere maintenance which contributing to colorectal cancer(CRC)susceptibility in Chinese population,and illustrate their functional significance in cancer initiation and progression.Methods: We firstly captured germline mutations in 192 CRC patients by sequencing the coding regions of 13 core components implicated in telomere biology.Candidate variants which predicted to be functional were then genotyped and assessed in a case-control study with 3,761 CRC cases and 3,839 healthy controls.The promising association was replicated in additional 6,765 cases and 6,906 controls.Functional prediction and biological experiments were introduced to further clarify the potential function of the significant variant and uncover the underlying mechanism in CRC development.Results: Eighty-two exonic variants were initially captured by targeted sequencing,and eventually 5 nonsynonymous variants with strong predicted functions were selected as our candidates.The two-stage association studies showed that a rare missense variant rs149418249(c.C1520 T,p.P507L)in the gene TPP1 was consistently and significantly increased CRC risk with the ORs equaling 2.91(95% CI: 1.05-8.08;P = 0.041),2.48(95% CI: 1.03-5.99;P = 0.043),and 2.66(95%CI: 1.36-5.17,P = 0.004)in discovery stage,replication stage,and the combined analyses,respectively.Further functional annotation indicated that the TPP1 P507 L substitution interrupted TPP1-TIN2 interaction,impaired telomerase processivity,and shortened telomere length,which subsequently facilitated cell proliferation and promoted CRC development.In addition,we found that the mRNA expression level of TPP1 was significantly elevated in colotractal tumor samples when comparing with the normal samples.Conclusion: The rare variant P507 L in TPP1 confers increased risk of CRC through interrupting TPP1-TIN2 interaction,impairing telomerase processivity,and shrinking telomere length.The discovery of the pathogenic variant TPP1 ra149418249 in our study highlights the power of rare variants in explaining additional heritability.And the illustration of in-depth mechanisms may provide novel biomarkers for early detection and targets for therapeutics of cancer.