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Endocr Relat Cancer. 2015 Feb;22(1):65-76. doi: 10.1530/ERC-14-0491. Epub 2014 Nov 25.

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility.

Author information

1
Endocrine Genetics Unit (Laboratório de Investigação Médica/LIM-25) of Hospital das ClínicasUniversity of São Paulo School of Medicine, São Paulo, São Paulo 05403-010, BrazilNursing SchoolSchool of Public HealthHuman Genome Research CenterUniversity of São Paulo, São Paulo, São Paulo, BrazilDivision of GeneticsGenetic Bases of Thyroid Tumors Laboratory, Department of Morphology and GeneticsDivision of EndocrinologyLaboratory of Molecular and Translational Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, São Paulo, BrazilBrazilian National Laboratory of BiosciencesCampinas, São Paulo, BrazilCentro Integral Oncológico Clara CampalHospital Universitário Sanchinarro, Madrid, SpainDepartment of GeneticsTexas Biomedical Research Institute, AT&T Genomic Computing Center, San Antonio, Texas, USAEndocrinology DivisionSanta Casa Hospital, São Paulo, São Paulo, BrazilLaboratory of Epidemiology and Population SciencesNational Institute on Aging, Bethesda, Maryland, USA toledorodrigo@usp.br toledorodrigo79@gmail.com.
2
Endocrine Genetics Unit (Laboratório de Investigação Médica/LIM-25) of Hospital das ClínicasUniversity of São Paulo School of Medicine, São Paulo, São Paulo 05403-010, BrazilNursing SchoolSchool of Public HealthHuman Genome Research CenterUniversity of São Paulo, São Paulo, São Paulo, BrazilDivision of GeneticsGenetic Bases of Thyroid Tumors Laboratory, Department of Morphology and GeneticsDivision of EndocrinologyLaboratory of Molecular and Translational Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, São Paulo, BrazilBrazilian National Laboratory of BiosciencesCampinas, São Paulo, BrazilCentro Integral Oncológico Clara CampalHospital Universitário Sanchinarro, Madrid, SpainDepartment of GeneticsTexas Biomedical Research Institute, AT&T Genomic Computing Center, San Antonio, Texas, USAEndocrinology DivisionSanta Casa Hospital, São Paulo, São Paulo, BrazilLaboratory of Epidemiology and Population SciencesNational Institute on Aging, Bethesda, Maryland, USA.
3
Endocrine Genetics Unit (Laboratório de Investigação Médica/LIM-25) of Hospital das ClínicasUniversity of São Paulo School of Medicine, São Paulo, São Paulo 05403-010, BrazilNursing SchoolSchool of Public HealthHuman Genome Research CenterUniversity of São Paulo, São Paulo, São Paulo, BrazilDivision of GeneticsGenetic Bases of Thyroid Tumors Laboratory, Department of Morphology and GeneticsDivision of EndocrinologyLaboratory of Molecular and Translational Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, São Paulo, BrazilBrazilian National Laboratory of BiosciencesCampinas, São Paulo, BrazilCentro Integral Oncológico Clara CampalHospital Universitário Sanchinarro, Madrid, SpainDepartment of GeneticsTexas Biomedical Research Institute, AT&T Genomic Computing Center, San Antonio, Texas, USAEndocrinology DivisionSanta Casa Hospital, São Paulo, São Paulo, BrazilLaboratory of Epidemiology and Population SciencesNational Institute on Aging, Bethesda, Maryland, USA Endocrine Genetics Unit (Laboratório de Investigação Médica/LIM-25) of Hospital das ClínicasUniversity of São Paulo School of Medicine, São Paulo, São Paulo 05403-010, BrazilNursing SchoolSchool of Public HealthHuman Genome Research CenterUniversity of São Paulo, São Paulo, São Paulo, BrazilDivision of GeneticsGenetic Bases of Thyroid Tumors Laboratory, Department of Morphology and GeneticsDivision of EndocrinologyLaboratory of Molecular and Translational Endocrinology, Department of Medicine, Federal University of São Paulo, São Paulo, São Paulo, BrazilBrazilian National Laboratory of BiosciencesCampinas, São Paulo, BrazilCentro Integral Oncológico Clara CampalHospital Universitário Sanchinarro, Madrid, SpainDepartment of GeneticsTexas Biomedical Research Institute, AT&T Genomic Computing Center, San Antonio, Texas, USAEndocrinology DivisionSanta Casa Hospital, São Paulo, São Paulo, BrazilLaboratory of Epidemiology and Population SciencesNat

Abstract

Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.

KEYWORDS:

MEN2; RET oncogene; genetics; medullary thyroid carcinoma; multiple endocrine neoplasias

PMID:
25425582
PMCID:
PMC4289937
DOI:
10.1530/ERC-14-0491
[Indexed for MEDLINE]
Free PMC Article

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