Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC)
Por:
Xicola RM, Bontu S, Doyle BJ, Rawson J, Garre P, Lee E, de la Hoya M, Bessa X, Clofent J, Bujanda L, Balaguer F, Castellvi-Bel S, Alenda C, Jover R, Ruiz-Ponte C, Syngal S, Andreu M, Carracedo A, Castells A, Newcomb PA, Lindor N, Potter JD, Baron JA, Ellis NA, Caldes T and LLor X
Publicada:
1 ago 2016
Resumen:
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.
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