Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/37805 http://dx.doi.org/10.1210/jc.2013-2993 |
Resumo: | Context: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers.Objective: the aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis.Design: Fifteen p.G533C carriers with MTC were chosen for the initial screening. the subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. the results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). the identified CNVs were validated by quantitative PCR in an extended cohort (n = 32).Results: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. the validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057).Conclusion: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness. |
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Araujo, Aline Neves [UNIFESP]Moraes, Lais [UNIFESP]Franca, Maria Inez C. [UNIFESP]Hakonarson, HakonLi, JinPellegrino, RenataMaciel, Rui Monteiro de Barros [UNIFESP]Cerutti, Janete Maria [UNIFESP]Universidade Federal de São Paulo (UNIFESP)Univ Penn2016-01-24T14:37:20Z2016-01-24T14:37:20Z2014-06-01Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 99, n. 6, p. E1104-E1112, 2014.0021-972Xhttp://repositorio.unifesp.br/handle/11600/37805http://dx.doi.org/10.1210/jc.2013-299310.1210/jc.2013-2993WOS:000342340500024Context: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers.Objective: the aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis.Design: Fifteen p.G533C carriers with MTC were chosen for the initial screening. the subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. the results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). the identified CNVs were validated by quantitative PCR in an extended cohort (n = 32).Results: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. the validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057).Conclusion: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, Genet Bases Thyroid Tumor Lab, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Div Endocrinol, Lab Mol & Translat Endocrinol, BR-04039032 São Paulo, BrazilUniv Penn, Childrens Hosp Philadelphia, Ctr Appl Genom, Res Inst, Philadelphia, PA 19104 USAUniv Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, Genet Bases Thyroid Tumor Lab, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Div Endocrinol, Lab Mol & Translat Endocrinol, BR-04039032 São Paulo, BrazilFAPESP: 10/51547-1FAPESP: 11/10787FAPESP: 12/02902-9Web of ScienceE1104-E1112engEndocrine SocJournal of Clinical Endocrinology & MetabolismGenome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP11600/378052023-02-15 11:05:00.363metadata only accessoai:repositorio.unifesp.br:11600/37805Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-02-15T14:05Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
title |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
spellingShingle |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis Araujo, Aline Neves [UNIFESP] |
title_short |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
title_full |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
title_fullStr |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
title_full_unstemmed |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
title_sort |
Genome-Wide Copy Number Analysis in a Family With p.G533C RET Mutation and Medullary Thyroid Carcinoma Identified Regions Potentially Associated With a Higher Predisposition to Lymph Node Metastasis |
author |
Araujo, Aline Neves [UNIFESP] |
author_facet |
Araujo, Aline Neves [UNIFESP] Moraes, Lais [UNIFESP] Franca, Maria Inez C. [UNIFESP] Hakonarson, Hakon Li, Jin Pellegrino, Renata Maciel, Rui Monteiro de Barros [UNIFESP] Cerutti, Janete Maria [UNIFESP] |
author_role |
author |
author2 |
Moraes, Lais [UNIFESP] Franca, Maria Inez C. [UNIFESP] Hakonarson, Hakon Li, Jin Pellegrino, Renata Maciel, Rui Monteiro de Barros [UNIFESP] Cerutti, Janete Maria [UNIFESP] |
author2_role |
author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Univ Penn |
dc.contributor.author.fl_str_mv |
Araujo, Aline Neves [UNIFESP] Moraes, Lais [UNIFESP] Franca, Maria Inez C. [UNIFESP] Hakonarson, Hakon Li, Jin Pellegrino, Renata Maciel, Rui Monteiro de Barros [UNIFESP] Cerutti, Janete Maria [UNIFESP] |
description |
Context: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers.Objective: the aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis.Design: Fifteen p.G533C carriers with MTC were chosen for the initial screening. the subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. the results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). the identified CNVs were validated by quantitative PCR in an extended cohort (n = 32).Results: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. the validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057).Conclusion: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness. |
publishDate |
2014 |
dc.date.issued.fl_str_mv |
2014-06-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:37:20Z |
dc.date.available.fl_str_mv |
2016-01-24T14:37:20Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 99, n. 6, p. E1104-E1112, 2014. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/37805 http://dx.doi.org/10.1210/jc.2013-2993 |
dc.identifier.issn.none.fl_str_mv |
0021-972X |
dc.identifier.doi.none.fl_str_mv |
10.1210/jc.2013-2993 |
dc.identifier.wos.none.fl_str_mv |
WOS:000342340500024 |
identifier_str_mv |
Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 99, n. 6, p. E1104-E1112, 2014. 0021-972X 10.1210/jc.2013-2993 WOS:000342340500024 |
url |
http://repositorio.unifesp.br/handle/11600/37805 http://dx.doi.org/10.1210/jc.2013-2993 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
Journal of Clinical Endocrinology & Metabolism |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
E1104-E1112 |
dc.publisher.none.fl_str_mv |
Endocrine Soc |
publisher.none.fl_str_mv |
Endocrine Soc |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UNIFESP instname:Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
instname_str |
Universidade Federal de São Paulo (UNIFESP) |
instacron_str |
UNIFESP |
institution |
UNIFESP |
reponame_str |
Repositório Institucional da UNIFESP |
collection |
Repositório Institucional da UNIFESP |
repository.name.fl_str_mv |
Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP) |
repository.mail.fl_str_mv |
|
_version_ |
1802764197066440704 |