MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS

Detalhes bibliográficos
Autor(a) principal: Khaled Puñales, Marcia
Data de Publicação: 2022
Outros Autores: Gross, Jorge Luiz, Maia, Ana Luiza
Tipo de documento: Artigo
Idioma: por
Título da fonte: Clinical and Biomedical Research
Texto Completo: https://seer.ufrgs.br/index.php/hcpa/article/view/126198
Resumo: Hereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or others. Three phenotypic subtypes have been reported. MEN 2A(1), MEN 2A(2) and MEN 2A(3). Germline mutations in the RET proto-oncogene cause MEN 2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN 2 syndromes. The purpose of this study was to identify RET proto-oncogene mutations and analyze a possible relationship between genotype-phenotype in Brazilian kindred with MTC. A total of 57 patients with histopathological and immunohistochemistry diagnosis of MTC were included. This sample was formed from index cases and affected members of 16 familieswith hereditary MTC and 10 individuals with sporadic tumors. DNA was extracted from leukocytes of the affected individuals and relatives. Exons 10, 11, 13, 14, 15 and 16 were amplificated by PCR, using specific primers. The presence of mutation was determined by SSCP, enzymatic restriction analysis and/or automatic sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN 2A, 3 MEN 2A associated with CLA, 3 MEN 2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 in 6 families with MEN 2A, only one kindred had the mutation at codon 618. The 3 kindred with MEN 2A+CLA, both cases of FMTC and the only family classified as other hereditary forms of the MTC presented the mutation in codon 634. A mutation at codon M918T was identified in the 3 individuals with MEN 2B. The genetic screening was able to identified 23 assymtomatic carriers and determine the hereditary MCT pattern in 3 individuals with apparently sporadic tumors. In conclusion, genetic testing can identify affected and assymtomatic individuals with hereditary disease, allowing early diagnosis and treatment. 
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spelling MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSISIMPLICAÇÕES CLÍNICAS DO DIAGNÓSTICO MOLECULAR NO MANEJO DO CARCINOMA MEDULAR DE TIREÓIDE HEREDITÁRIOCMTproto-oncogene RETNEM 2ANEM 2BCMTFMTCproto-oncogene RETMEN 2AMEN 2BFMTCHereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or others. Three phenotypic subtypes have been reported. MEN 2A(1), MEN 2A(2) and MEN 2A(3). Germline mutations in the RET proto-oncogene cause MEN 2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN 2 syndromes. The purpose of this study was to identify RET proto-oncogene mutations and analyze a possible relationship between genotype-phenotype in Brazilian kindred with MTC. A total of 57 patients with histopathological and immunohistochemistry diagnosis of MTC were included. This sample was formed from index cases and affected members of 16 familieswith hereditary MTC and 10 individuals with sporadic tumors. DNA was extracted from leukocytes of the affected individuals and relatives. Exons 10, 11, 13, 14, 15 and 16 were amplificated by PCR, using specific primers. The presence of mutation was determined by SSCP, enzymatic restriction analysis and/or automatic sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN 2A, 3 MEN 2A associated with CLA, 3 MEN 2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 in 6 families with MEN 2A, only one kindred had the mutation at codon 618. The 3 kindred with MEN 2A+CLA, both cases of FMTC and the only family classified as other hereditary forms of the MTC presented the mutation in codon 634. A mutation at codon M918T was identified in the 3 individuals with MEN 2B. The genetic screening was able to identified 23 assymtomatic carriers and determine the hereditary MCT pattern in 3 individuals with apparently sporadic tumors. In conclusion, genetic testing can identify affected and assymtomatic individuals with hereditary disease, allowing early diagnosis and treatment. O carcinoma medular de tireóide (CMT) hereditário pode apresentar-se como componente das síndromes de Neoplasia Endócrina Múltipla (NEM 2A e 2B) ou Carcinoma Medular de Tireóide Familiar (CMTF). Diferentes mutações no RET foram identificadas como responsáveis pelo CMT e estudos recentes sugerem uma correlação entre o genótipo-fenótipo, podendo existir uma grande variabilidade de síndromes clínicas associadas às diferentes mutações. O presente estudo realizou a análise molecular do RET em indivíduos com CMT e avaliou a correlação entre fenótipo-genótipo nos afetados e seus familiares. Foram incluídos 57indivíduos com diagnóstico histopatológico/imunohistoquímico de CMT (10 esporádicos e 47 hereditários, provenientes de 16 famílias). O DNA genômico foi extraído de leucócitos periféricos e os exons 10, 11, 13, 14, 15 e/ou 16 do RET amplificados por PCR com primers específicos. A presença de mutações foi determinada por SSCP, restrição enzimática e/ou sequenciamento. Das famílias com CMT hereditário, 7 apresentavam NEM 2A, 3 NEM 2A associada à Líquen Amilóide Cutânea (CLA), 3 NEM 2B, 2 CMTF e 1 outras formas hereditárias. Em 6 famílias com NEM 2A, nas 3 com NEM 2A+CLA e nas 2 com CMTF a mutação estavapresente códon 634. Enquanto que a outra família com NEM 2A apresentava a mutação no códon 618. Nos indivíduos com NEM 2B foi detectada uma mutação de novo no códon M918T. Na família classificada como outros, a mutação também localizava-se no códon 634. O diagnóstico molecular identificou mutações em todos indivíduos com doença hereditária, em 23 indivíduos carreadores sem evidência clínica da neoplasia e em 3 indivíduos com CMT aparentemente esporádico, destacando a importância do rastreamento genético como método diagnóstico.HCPA/FAMED/UFRGS2022-09-23info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionPeer-reviewed ArticleAvaliado por Paresapplication/pdfhttps://seer.ufrgs.br/index.php/hcpa/article/view/126198Clinical & Biomedical Research; Vol. 23 No. 1 - 2 (2003): Revista HCPAClinical and Biomedical Research; v. 23 n. 1 - 2 (2003): Revista HCPA2357-9730reponame:Clinical and Biomedical Researchinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSporhttps://seer.ufrgs.br/index.php/hcpa/article/view/126198/85682Copyright (c) 2022 Marcia Khaled Puñales, Jorge Luiz Gross, Ana Luiza Maiahttp://creativecommons.org/licenses/by/4.0info:eu-repo/semantics/openAccess Khaled Puñales, MarciaGross, Jorge Luiz Maia, Ana Luiza 2022-09-27T20:38:15Zoai:seer.ufrgs.br:article/126198Revistahttps://www.seer.ufrgs.br/index.php/hcpaPUBhttps://seer.ufrgs.br/index.php/hcpa/oai||cbr@hcpa.edu.br2357-97302357-9730opendoar:2022-09-27T20:38:15Clinical and Biomedical Research - Universidade Federal do Rio Grande do Sul (UFRGS)false
dc.title.none.fl_str_mv MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
IMPLICAÇÕES CLÍNICAS DO DIAGNÓSTICO MOLECULAR NO MANEJO DO CARCINOMA MEDULAR DE TIREÓIDE HEREDITÁRIO
title MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
spellingShingle MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
Khaled Puñales, Marcia
CMT
proto-oncogene RET
NEM 2A
NEM 2B
CMTF
MTC
proto-oncogene RET
MEN 2A
MEN 2B
FMTC
title_short MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
title_full MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
title_fullStr MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
title_full_unstemmed MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
title_sort MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS
author Khaled Puñales, Marcia
author_facet Khaled Puñales, Marcia
Gross, Jorge Luiz
Maia, Ana Luiza
author_role author
author2 Gross, Jorge Luiz
Maia, Ana Luiza
author2_role author
author
dc.contributor.author.fl_str_mv Khaled Puñales, Marcia
Gross, Jorge Luiz
Maia, Ana Luiza
dc.subject.por.fl_str_mv CMT
proto-oncogene RET
NEM 2A
NEM 2B
CMTF
MTC
proto-oncogene RET
MEN 2A
MEN 2B
FMTC
topic CMT
proto-oncogene RET
NEM 2A
NEM 2B
CMTF
MTC
proto-oncogene RET
MEN 2A
MEN 2B
FMTC
description Hereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or others. Three phenotypic subtypes have been reported. MEN 2A(1), MEN 2A(2) and MEN 2A(3). Germline mutations in the RET proto-oncogene cause MEN 2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN 2 syndromes. The purpose of this study was to identify RET proto-oncogene mutations and analyze a possible relationship between genotype-phenotype in Brazilian kindred with MTC. A total of 57 patients with histopathological and immunohistochemistry diagnosis of MTC were included. This sample was formed from index cases and affected members of 16 familieswith hereditary MTC and 10 individuals with sporadic tumors. DNA was extracted from leukocytes of the affected individuals and relatives. Exons 10, 11, 13, 14, 15 and 16 were amplificated by PCR, using specific primers. The presence of mutation was determined by SSCP, enzymatic restriction analysis and/or automatic sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN 2A, 3 MEN 2A associated with CLA, 3 MEN 2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 in 6 families with MEN 2A, only one kindred had the mutation at codon 618. The 3 kindred with MEN 2A+CLA, both cases of FMTC and the only family classified as other hereditary forms of the MTC presented the mutation in codon 634. A mutation at codon M918T was identified in the 3 individuals with MEN 2B. The genetic screening was able to identified 23 assymtomatic carriers and determine the hereditary MCT pattern in 3 individuals with apparently sporadic tumors. In conclusion, genetic testing can identify affected and assymtomatic individuals with hereditary disease, allowing early diagnosis and treatment. 
publishDate 2022
dc.date.none.fl_str_mv 2022-09-23
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Peer-reviewed Article
Avaliado por Pares
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://seer.ufrgs.br/index.php/hcpa/article/view/126198
url https://seer.ufrgs.br/index.php/hcpa/article/view/126198
dc.language.iso.fl_str_mv por
language por
dc.relation.none.fl_str_mv https://seer.ufrgs.br/index.php/hcpa/article/view/126198/85682
dc.rights.driver.fl_str_mv Copyright (c) 2022 Marcia Khaled Puñales, Jorge Luiz Gross, Ana Luiza Maia
http://creativecommons.org/licenses/by/4.0
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Copyright (c) 2022 Marcia Khaled Puñales, Jorge Luiz Gross, Ana Luiza Maia
http://creativecommons.org/licenses/by/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv HCPA/FAMED/UFRGS
publisher.none.fl_str_mv HCPA/FAMED/UFRGS
dc.source.none.fl_str_mv Clinical & Biomedical Research; Vol. 23 No. 1 - 2 (2003): Revista HCPA
Clinical and Biomedical Research; v. 23 n. 1 - 2 (2003): Revista HCPA
2357-9730
reponame:Clinical and Biomedical Research
instname:Universidade Federal do Rio Grande do Sul (UFRGS)
instacron:UFRGS
instname_str Universidade Federal do Rio Grande do Sul (UFRGS)
instacron_str UFRGS
institution UFRGS
reponame_str Clinical and Biomedical Research
collection Clinical and Biomedical Research
repository.name.fl_str_mv Clinical and Biomedical Research - Universidade Federal do Rio Grande do Sul (UFRGS)
repository.mail.fl_str_mv ||cbr@hcpa.edu.br
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