A rare variant P507L in TPP1 interrupts TPP1-TIN2 interaction, influences telomere length, and confers colorectal cancer risk in Chinese population
Menée en population chinoise à partir de données portant sur 3 761 patients atteints d'un cancer colorectal et sur 3 839 témoins, puis répliquée sur 6 765 cas et 6 906 témoins complémentaires, cette étude met en évidence le rôle du variant P507L du gène TPP1 dans l'interruption des interactions TPP1-TIN2, dans le raccourcissement de la longueur des télomères et dans le développement de la maladie
Background: Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer (CRC) susceptibility. Methods: In this study, we firstly captured germline mutations in 192 CRC patients by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set 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 experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in CRC development. Results: The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T, p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with CRC risk with the ORs being 2.90 (95% CI:1.04-8.07, P=0.041), 2.50 (95% CI:1.04-6.04, P=0.042), and 2.66 (95%CI:1.36-5.18, P=0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted CRC development. Conclusions: A rare variant P507L in TPP1 confers increased risk of CRC through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. Impact: These findings emphasize the important role of telomere dysfunction in CRC development, and provide new insights about the prevention of this type of cancer.