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

Abstract

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 primiR-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.genetic predisposition ͉ microRNA processing ͉ polymorphism ͉ miR-146 ͉ thyroid cancer

Genetic variants within miR-126 and miR-335 are not associated with breast cancer risk

“…MiR-126 inhibits the tumour growth and proliferation, whereas miR-335 suppresses metastatic cell invasion [23]. Mutations and single nucleotide polymorphisms (SNPs) in miRNAs or miRNA target sites have been shown to be associated with the risk of various cancers [15,[24][25][26][27][28]. Some SNPs located in the miRNAs or their flanking regions are reported to have potential impact on the maturation of miRNAs [29].…”

Common genetic variants in pre-microRNAs and risk of gallbladder cancer in North Indian population

“…[9][10][11][12][13] It is possible that association of miRNA polymorphisms may be cancer specific. However, the non-significant results of our study could be explained because of inherent difficulties in validating and replicating association studies with complex traits such as cancer and/or as a consequence of ethnic variation.…”

“…8 Various genetic association studies have explored the function of pre-miRNA polymorphisms in cancers including non-small cell lung cancer (NSCLC), 9 breast cancer, 10 hepatocellular carcinoma, 11 bladder cancer 12 and papillary thyroid carcinoma. 13 However, the function of genetic variants of miRNA genes in GBC is yet to be determined.…”

Single-nucleotide polymorphisms among microRNA: big effects on cancer

“…This SNP reduced both the amount of pre-miR-146a and mature miR-146a, and affected the Drosha/DGCR8 cropping step, and was associated with papillary thyroid carcinoma (PTC), familial/sporadic breast cancer, ovarian cancer, prostate cancer, and hepatocellular carcinoma[91]–[95]. In an association study of 608 PTC patients and 901 controls, Jazdzewski et al [96] found marked differences in genotype distribution of rs2910164 ( P < 0.001).…”