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

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Toledo, Rodrigo A. ^[1] ; Hatakana, Roxanne ^[1] ; Lourenco, Jr., Delmar M. ^[1] ; Lindsey, Susan C. ^[2] ; Camacho, Cleber P. ^[2] ; Almeida, Marcio ^[3] ; Lima, Jr., Jose V. ^[4] ; Sekiya, Tomoko ^[1] ; Garralda, Elena ^[5] ; Naslavsky, Michel S. ^[6] ; Yamamoto, Guilherme L. ^[6] ; Lazar, Monize ^[6] ; Meirelles, Osorio ^[7] ; Sobreira, Tiago J. P. ^[8] ; Lebrao, Maria Lucia ^[9] ; Duarte, Yeda A. O. ^[10] ; Blangero, John ^[3] ; Zatz, Mayana ^[6] ; Cerutti, Janete M. ^[11] ; Maciel, Rui M. B. ^[2] ; Toledo, Sergio P. A. ^{[1, 2]}

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^[1] Univ Sao Paulo, Sch Med, Hosp Clin, Endocrine Genet Unit, Lab Invest Med, LIM 25, BR-05403010 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Med, Div Endocrinol, Lab Mol & Translat Endocrinol, Sao Paulo - Brazil

^[3] AT&T Genom Comp Ctr, Texas Biomed Res Inst, Dept Genet, San Antonio, TX - USA

^[4] Santa Casa Hosp, Div Endocrinol, Sao Paulo - Brazil

^[5] Hosp Univ Sanchinarro, Ctr Integral Oncol Clara Campal, Madrid - Spain

^[6] Univ Sao Paulo, Human Genome Res Ctr, BR-05403010 Sao Paulo - Brazil

^[7] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 - USA

^[8] Brazilian Natl Lab Biosci, Sao Paulo - Brazil

^[9] Univ Sao Paulo, Sch Publ Hlth, BR-05403010 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Sch Nursing, BR-05403010 Sao Paulo - Brazil

^[11] Univ Fed Sao Paulo, Dept Morphol & Genet, Div Genet, Genet Bases Thyroid Tumors Lab, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Endocrine-Related Cancer; v. 22, n. 1, p. 65-76, FEB 2015.
• Citações Web of Science: 26

Resumo

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. (AU)

• Processo FAPESP: 10/51547-1 - Carcinoma medular de tiroide hereditario: percepcao e atitude de pacientes, familiares e profissionais de saude sobre questoes bioeticas.
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/01476-9 - Rastreamento de variantes de significado desconhecido (VUS) no proto-oncogene RET em pacientes com neoplasia endócrina múltipla tipo 2 e indivíduos saudáveis da população brasileira
• Beneficiário: Sergio Pereira de Almeida Toledo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/60402-1 - Carcinoma medular da tiróide: revisitação à clínica, à biologia molecular, à bioquímica e à biologia do desenvolvimento depois dos achados da genética molecular
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Temático