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JOURNAL ARTICLE

Identification of rare variants predisposing to thyroid cancer

Yanqiang Wang, Sandya Liyanarachchi, Katherine E Miller, Taina T Nieminen, Daniel F Comiskey, Wei Li, Pamela Brock, David E Symer, Keiko Akagi, Katherine E DeLap, Huiling He, Daniel C Koboldt, Albert de la Chapelle
Thyroid: Official Journal of the American Thyroid Association 2019 April 8
30957677

BACKGROUND: Familial non-medullary thyroid cancer (FNMTC) accounts for a relatively small proportion of thyroid cancer cases, but it displays strong genetic predisposition. So far, only a few of NMTC susceptible genes and low-penetrance variants contributing to NMTC have been described. In this study, we aim to identify rare germline variants that may predispose individuals to non-medullary thyroid carcinoma (NMTC) by sequencing a cohort of 17 NMTC families.

METHODS: We performed whole genome sequencing (WGS) and genome-wide linkage analysis in 17 NMTC families. MendelScan and BasePlayer were applied to screen germline variants followed by customized filtering. The remaining candidate variants were subsequently validated by Sanger sequencing. A panel of 277 known cancer predisposition genes were also screened in these families.

RESULTS: We report a total of 41 rare coding candidate variants in 40 genes identified by WGS, including 24 missense, 5 frameshift, 5 splice change and 7 nonsense variants. Sanger sequencing confirmed all 41 rare variants and proved their cosegregation with NMTC in the extended pedigrees. In silico functional analysis of the candidate genes using Ingenuity Pathway Analysis showed that cancer was the top category of "Diseases and Disorders". Additionally, a targeted search displayed 6 variants in known cancer predisposition genes, including 1 frameshift variant and 5 missense variants.

CONCLUSIONS: Our data identify rare germline variants that may play important roles in NMTC predisposition. We propose that in future research including functional characterization, these variants and genes be considered primary candidates for thyroid cancer predisposition.

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