Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma

By K. Jażdżewski, Elizabeth L. Murray, K. Franssila, B. Jarzab, Daniel R Schoenberg, A. de la Chapelle. Proceedings of the National Academy of Sciences of the United States of America, 2008

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Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7858194081988d0209224615f67377d435cfa4d0

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Citations in the corpus

Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, positive): “For detecting the miR-146a and miR-146b expression levels, Taqman ‘‘stem-loop’’ real-time RT-PCR was performed as demonstrated previously (Jazdzewski et al., 2008).”
Genetic variation in microRNA networks: the implications for cancer research (2010, positive): “This polymorphism involves a mispairing in the hairpin of the precursor, which leads to altered processing, lower expression of the mature sequence and predisposition to papillary thyroid carcinom”
MicroRNAs in body fluids—the mix of hormones and biomarkers (2011, positive): “The SNP rs2910164 located in the 3′ strand of miR-146a promotes mispairing in the hairpin of the precursor, altering its expression and leading to an increased risk of papillary thyroid carcinoma”