Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC)

作者：Xicola Rosa M; Bontu Sneha; Doyle Brian J; Rawson Jamie; Garre Pilar; Lee Esther; de la Hoya Miguel; Bessa Xavier; Clofent Joan; Bujanda Luis; Balaguer Francesc; Castellvi Bel Sergi; Alenda Cristina; Jover Rodrigo; Ruiz Ponte Clara; Syngal Sapna; Andreu Montserrat; Carracedo Angel; Castells Antoni; Newcomb Polly A; Lindor Noralane; Potter John D; Baron John A; Ellis Nathan A; Caldes Trinidad^*; LLor Xavier^*

来源：Carcinogenesis, 2016, 37(8): 751-758.

DOI：10.1093/carcin/bgw064

We describe an association between TGFBR1 polymorphism rs868 and mismatch repair proficient hereditary colorectal cancers. This polymorphism results in more binding of TGFBR1 to let-7b-5p miRNA, which would result in lower expression of TGFBR1 and thus higher colorectal cancer risk.The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.

• 出版日期2016-8