Variants in microRNA genes in familial papillary thyroid carcinoma

// Jerneja Tomsic 1, 7 , Rebecca Fultz 1 , Sandya Liyanarachchi 1 , Luke K. Genutis 1 , Yanqiang Wang 1 , Wei Li 1 , Stefano Volinia 2 , Krystian Jazdzewski 3, 4 , Huiling He 1 , Paul E Wakely Jr. 5 , Leigha Senter 6 , Albert de la Chapelle 1 1 Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 2 Deptartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 3 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland 4 Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland 5 Department of Pathology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA 6 Department of Internal Medicine, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 7 Division of Biomarkers Early Detection Prevention, City of Hope, Duarte, CA, USA Correspondence to: Albert de la Chapelle, email: albert.delachapelle@osumc.edu Keywords: genetics, predisposition, miRNA, thyroid, variants Received: July 15, 2016 Accepted: December 16, 2016 Published: December 23, 2016 ABSTRACT Papillary Thyroid Carcinoma (PTC) displays one of the highest familiality scores of all cancers as measured by case-control studies, yet only a handful of genes have been implicated until now. Variants in microRNAs have been associated with the risk of several cancers including PTC but the magnitude of this involvement is unclear. This study was designed to test to what extent genomic variants in microRNAs contribute to PTC risk. We used SOLiD technology to sequence 321 genomic regions encoding 427 miRNAs in one affected individual from each of 80 PTC families. After excluding variants with frequency ≥ 1% in 1000 Genomes Phase 1 ( n = 1092) we detected 1978 variants. After further functional filtering steps 25 variants in pre-miRs remained. Co-segregation was observed for six out of 16 tested miRNA variants with PTC in the families, namely let-7e, miR-181b, miR-135a, miR-15b, miR-320, and miR-484. Expression of miR-135a and miR-181b was tested in normal thyroid and tumor tissue from patients that carry the variants and a decrease in expression was observed. In vitro assays were applied to measure the effect of the variants on microRNAs’ maturation. Four out of six variants were tested. Only the let-7e and miR-181b variants showed an effect on processing leading to lower levels of mature miRNA. These two variants were not detected in 1170 sporadic PTC cases nor in 1404 controls. Taken together, our data show that high penetrance germline sequence variants of miRNAs potentially predispose to a fraction of all PTC but are not common.