The first evidence of a potential role for microRNAs in papillary thyroid carcinoma (PTC) was an overexpression of several miRs in tumor tissue compared with unaffected tissue of the thyroid gland. The list of highly upregulated miRs (up to 19.3 fold) included miR-146, miR-221/222, miR-155, miR-34, and miR-181 and was soon confirmed. This finding suggests that altered microRNAs might be factors playing a role in the tumorigenesis of PTC. Further evidence supporting this argument came from the study showing a genetic association between PTC and a single nucleotide polymorphism (SNP, rs2910164) in the precursor of miR-146a. Individuals heterozygous for the SNP had an increased risk of acquiring PTC (OR-1.62, 95% CI 1.3-2.0, P=0.000007). It was further demonstrated that the processing of the microRNA was affected by the SNP. Heterozygosity as a genetic risk rather than either homozygosity is a rare phenomenon and should be critically evaluated. It was later shown that the phenomenon is caused by the existence of additional mature microRNAs generated from the passenger strand of the miR-146a precursor. In the case of miR-146a the presence of the SNP generates two isoforms (marked *): miR-146a*G from the allele carrying G, and miR-146a*C from the C allele, each with its distinct set of target genes. Thus, GG and CC homozygotes each produce two mature molecules (miR-146a from the leading strand, and miR-146a*G or *C, respectively, from the passenger strand) while GC heterozygotes differ from both homozygotes by producing three mature miRs (miR-146a and both miR-146a*G and miR-146a*C). The microarray data showed that widely different transcriptomes occurred in the PTC tumors from heterozygous and homozygous patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology