LOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive revie

Author(s)

Maciel, Rui M. B. ^[1] ; Maia, Ana Luiza ^[2]

Affiliation

^[1] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Escola Paulista Med, Sao Paulo, SP - Brazil

^[2] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Fac Med, Thyroid Unit, Porto Alegre, RS - Brazil

• Document type: Review article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 186, n. 1, p. R15-R30, JAN 1 2022.
• Web of Science Citations: 0

Abstract

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation. (AU)

• FAPESP's process: 13/01476-9 - Screening of variants of unkown significance (VUS) in the RET proto-oncogene in patients with multiple endocrine neoplasia type 2 and healthy individual controls
• Grantee: Sergio Pereira de Almeida Toledo
• Support Opportunities: Regular Research Grants
• 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: 06/60402-1 - Medular carcinoma of the thyroid: revisiting the clinical, molecular biological, biochemical and biological aspects following findings of molecular genetics
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Research Projects - Thematic Grants