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Title: Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility
Authors: Toledo, Rodrigo A.
Hatakana, Roxanne
Lourenco, Delmar M.
Lindsey, Susan C. [UNIFESP]
Camacho, Cleber P. [UNIFESP]
Almeida, Marcio
Lima, Jose V.
Sekiya, Tomoko
Garralda, Elena
Naslavsky, Michel S.
Yamamoto, Guilherme L.
Lazar, Monize
Meirelles, Osorio
Sobreira, Tiago J. P.
Lebrao, Maria Lucia
Duarte, Yeda A. O.
Blangero, John
Zatz, Mayana
Cerutti, Janete M. [UNIFESP]
Maciel, Rui M. B. [UNIFESP]
Toledo, Sergio P. A. [UNIFESP]
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Brazilian Natl Lab Biosci
Hosp Univ Sanchinarro
AT&T Genom Comp Ctr
Santa Casa Hosp
Keywords: multiple endocrine neoplasias
RET oncogene
medullary thyroid carcinoma
Issue Date: 1-Feb-2015
Publisher: Bioscientifica Ltd
Citation: Endocrine-related Cancer. Bristol: Bioscientifica Ltd, v. 22, n. 1, p. 65-76, 2015.
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.
ISSN: 1351-0088
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