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Open AccessArticle

NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer

Department of Endocrinology and Nutrition, ICMDM, Hospital Clinic, 08036 Barcelona, Spain
Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Faculty of Medicine, University of Barcelona, 08007 Barcelona, Spain
Department of Endocrinology and Nutrition, Hospital de Elda, 03600 Elda, Alicante, Spain
Department of Endocrinology and Nutrition, Hospital General Universitario de Alicante, 03010 Alicante, Spain
Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA 9430, USA
Department of Biochemistry and Molecular Genetics, CDB, Hospital Clínic, 08036 Barcelona, Spain
Author to whom correspondence should be addressed.
Genes 2019, 10(11), 899;
Received: 4 September 2019 / Revised: 11 October 2019 / Accepted: 4 November 2019 / Published: 7 November 2019
(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)
Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3–9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier. View Full-Text
Keywords: thyroid cancer; genetic abnormalities; molecular testing; NOP53; oncogenic mutations thyroid cancer; genetic abnormalities; molecular testing; NOP53; oncogenic mutations
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Orois, A.; Gara, S.K.; Mora, M.; Halperin, I.; Martínez, S.; Alfayate, R.; Kebebew, E.; Oriola, J. NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer. Genes 2019, 10, 899.

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