Further functional annotation indicated that the TPP1P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development.<b>Conclusions:</b> A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length.<b>Impact:</b> These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer.
To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8.