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

Abstract

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.

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

“…NOP53 gene, located in 19q13.33, encodes a nucleolar protein involved in ribosome biogenesis. The germline variant p. Asp31His in NOP53 gene has recently been reported associated with NSFNMTC [ 69 ]. The patients had PTC and Hürthle cell carcinoma in one case, sometimes coexisting with MNG, including toxic MNG in two of the 11 affected members of the three families studied.…”

“…Tumor tissue showed a higher immunohistochemical expression of NOP53 compared to the adjacent normal thyroid tissue in all four cases studied. [ 69 ].…”

Lack of Mutations in POT1 Gene in Selected Families with Familial Non-Medullary Thyroid Cancer

“…This scenario would make it difficult to find a common link among the different affected families. Indeed, part of the families included in this study were included in a previous paper [32], where we suggest that non-syndromic FNMTC may be due to multiple mutations acting as risk alleles and modifier locus for FNMTC, in contrast with most hereditary cancers, in which only 2 or 3 high-penetrance causative genes have been described.…”

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

“…NOP53 participates in ribosome biogenesis and regulates the p53 activation in the case of ribosome biogenesis perturbation. The variant c.91G>C was also identified in three out of 44 families with FNMTC [ 127 ]. In the tumor samples, NOP53 expression was increased when compared to the adjacent normal tissue.…”

“…In the tumor samples, NOP53 expression was increased when compared to the adjacent normal tissue. Furthermore, NOP53 knockdown inhibited cell proliferation and colony formation in vitro [ 127 ]. Altogether, these findings suggested that this variant could have an oncogenic role in thyroid tumorigenesis [ 127 ].…”