Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases 69120 Heidelberg Germany

Department of Medicine 1 and Clinical Chemistry University Hospital of Heidelberg 69120 Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Hopp Children's Cancer Center 69120 Heidelberg Germany

Institute of Bioinformatics International Technology Park Bangalore 560066 India

Manipal Academy of Higher Education Manipal 576104 Karnataka India

Medical Faculty Heidelberg University 69120 Heidelberg Germany

Unit of Medical Genetics Department of Medical and Surgical Sciences S Orsola Malpighi Hospital University of Bologna 40138 Bologna Italy

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Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer

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