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A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

A. Srivastava, B. Miao, D. Skopelitou, V. Kumar, A. Kumar, N. Paramasivam, E. Bonora, K. Hemminki, A. Försti, OR. Bandapalli,

. 2020 ; 12 (6) : . [pub] 20200601

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20019107

Grantová podpora
856620 Horizon 2020

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.

Citace poskytuje Crossref.org

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$a A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer / $c A. Srivastava, B. Miao, D. Skopelitou, V. Kumar, A. Kumar, N. Paramasivam, E. Bonora, K. Hemminki, A. Försti, OR. Bandapalli,
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$a 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.
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$a Skopelitou, Diamanto $u Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
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$a Kumar, Varun $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, 69120 Heidelberg, Germany.
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$a Kumar, Abhishek $u Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India.
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$a Paramasivam, Nagarajan $u Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
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