Identification of NID1 as a novel candidate susceptibility gene for familial non-medullary thyroid carcinoma using whole-exome sequencing

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Barbalho de Mello, Luis Eduardo ; Ribeiro Carneiro, Thaise Nayane ; Araujo, Aline Neves ; Alves, Camila Xavier ; Favoretto Galante, Pedro Alexandre ; Buzatto, Vanessa Candiotti ; de Almeida, Maria das Gracas ; Vermeulen-Serpa, Karina Marques ; de Lima Vale, Sancha Helena ; de Pinto Paiva, Fernando Jose ; Brandao-Neto, Jose ; Cerutti, Janete Maria

• Document type: Journal article
• Source: ENDOCRINE CONNECTIONS; v. 11, n. 1, p. 16-pg., 2022-01-01.

Abstract

The genetics underlying non-syndromic familial non-medullary thyroid carcinoma (FNMTC) is still poorly understood. To identify susceptibility genes for FNMTC, we performed whole-exome sequencing (WES) in a Brazilian family affected by papillary thyroid carcinoma (PTC) in three consecutive generations. WES was performed in four affected and two unaffected family members. Manual inspection in over 100 previously reported susceptibility genes for FNMTC showed that no variants in known genes co-segregated with disease phenotype in this family. Novel candidate genes were investigated using PhenoDB and filtered using Genome Aggregation (gnomAD) and Online Archive of Brazilian Mutations (ABraOM) population databases. The missense variant p.Ile657Met in the NID1 gene was the only variant that co-segregated with the disease, while absent in unaffected family members and controls. The allele frequency for this variant was In silico analysis predicted the variant to be deleterious or likely damaging to the protein function. Somatic mutations in NID1 gene were found in nearly 500 cases of different cancer subtypes in the intOGen platform. Immunohistochemistry analysis showed NID1 expression in PTC cells, while it was absent in normal thyroid tissue. Our findings were corroborated using data from the TCGA cohort. Moreover, higher expression of NID1 was associated with higher likelihood of relapse after treatment and N1b disease in PTCs from the TCGA cohort. Although replication studies are needed to better understand the role of this variant in the FNMTC susceptibility, the NID1 variant (c.1971T>G) identified in this study fulfills several criteria that suggest it as a new FNMTC predisposing gene. (AU)

• FAPESP's process: 18/15579-8 - Retroelements: a driving force generating genetic novelties in the human and mouse genome
• Grantee: Pedro Alexandre Favoretto Galante
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/23497-1 - Genetic profile identified in thyroid tumors affect tumor cell metabolism?
• Grantee: Janete Maria Cerutti
• Support Opportunities: Regular Research Grants