Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer
Autor(a) principal: | |
---|---|
Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3390/cancers12051289 http://hdl.handle.net/11449/200526 |
Resumo: | Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability. |
id |
UNSP_4e6daef15ca6c8548ed4823439ad5760 |
---|---|
oai_identifier_str |
oai:repositorio.unesp.br:11449/200526 |
network_acronym_str |
UNSP |
network_name_str |
Repositório Institucional da UNESP |
repository_id_str |
2946 |
spelling |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancerBreast cancerExome sequencingFamilial cancerFunctional analysisMUS81Thyroid cancerMultiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.Syddansk UniversitetFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Faculty of Medicine Sao Paulo State University UNESPInternational Research Center A.C. Camargo Cancer CenterDepartment of Surgery and Orthopedics Experimental Research Unity Faculty of Medicine São Paulo State University UNESPDepartment of Veterinary Surgery and Anesthesiology São Paulo State University UNESPDepartment of Genetics and Evolutionary Biology University of São Paulo USPDepartment of Clinical Genetics Vejle University HospitalDepartment of Genetics and Morphology Institute of Biological Sciences University of Brasília UnB, DFKrembil Research Institute UHN University of TorontoInstitute of Neuroimmunology Slovak Academy of SciencesCancer Genetics Unit Centro de Oncologia Hospital Sirio LibanêsDepartment of Clinical Genetics Vejle University Hospital Institute of Regional Health Research University of Southern DenmarkFaculty of Medicine Sao Paulo State University UNESPDepartment of Surgery and Orthopedics Experimental Research Unity Faculty of Medicine São Paulo State University UNESPDepartment of Veterinary Surgery and Anesthesiology São Paulo State University UNESPFAPESP: 2012/12714-5FAPESP: 2013/0186-7FAPESP: 2014/03983-8CNPq: 481132/2012-0CAPES: PDSE 8195/14-5Universidade Estadual Paulista (Unesp)A.C. Camargo Cancer CenterUniversidade de São Paulo (USP)Vejle University HospitalUnBUniversity of TorontoSlovak Academy of SciencesHospital Sirio LibanêsUniversity of Southern DenmarkPinheiro, Maisa [UNESP]Lupinacci, Fernanda Cristina SullaSantiago, Karina MirandaDrigo, Sandra Aparecida [UNESP]Marchi, Fabio AlbuquerqueFonseca-Alves, Carlos Eduardo [UNESP]Andrade, Sonia Cristina da SilvaAagaard, Mads MalikBasso, Tatiane RamosReis, Mariana Bisarro DosVillacis, Rolando André RiosRoffé, MartinHajj, Glaucia Noeli MarosoJurisica, IgorKowalski, Luiz PauloAchatz, Maria IsabelRogatto, Silvia Regina2020-12-12T02:08:56Z2020-12-12T02:08:56Z2020-05-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/cancers12051289Cancers, v. 12, n. 5, 2020.2072-6694http://hdl.handle.net/11449/20052610.3390/cancers120512892-s2.0-85085524745Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengCancersinfo:eu-repo/semantics/openAccess2024-08-14T14:19:55Zoai:repositorio.unesp.br:11449/200526Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-14T14:19:55Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
title |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
spellingShingle |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer Pinheiro, Maisa [UNESP] Breast cancer Exome sequencing Familial cancer Functional analysis MUS81 Thyroid cancer |
title_short |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
title_full |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
title_fullStr |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
title_full_unstemmed |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
title_sort |
Germline mutation in mus81 resulting in impaired protein stability is associated with familial breast and thyroid cancer |
author |
Pinheiro, Maisa [UNESP] |
author_facet |
Pinheiro, Maisa [UNESP] Lupinacci, Fernanda Cristina Sulla Santiago, Karina Miranda Drigo, Sandra Aparecida [UNESP] Marchi, Fabio Albuquerque Fonseca-Alves, Carlos Eduardo [UNESP] Andrade, Sonia Cristina da Silva Aagaard, Mads Malik Basso, Tatiane Ramos Reis, Mariana Bisarro Dos Villacis, Rolando André Rios Roffé, Martin Hajj, Glaucia Noeli Maroso Jurisica, Igor Kowalski, Luiz Paulo Achatz, Maria Isabel Rogatto, Silvia Regina |
author_role |
author |
author2 |
Lupinacci, Fernanda Cristina Sulla Santiago, Karina Miranda Drigo, Sandra Aparecida [UNESP] Marchi, Fabio Albuquerque Fonseca-Alves, Carlos Eduardo [UNESP] Andrade, Sonia Cristina da Silva Aagaard, Mads Malik Basso, Tatiane Ramos Reis, Mariana Bisarro Dos Villacis, Rolando André Rios Roffé, Martin Hajj, Glaucia Noeli Maroso Jurisica, Igor Kowalski, Luiz Paulo Achatz, Maria Isabel Rogatto, Silvia Regina |
author2_role |
author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) A.C. Camargo Cancer Center Universidade de São Paulo (USP) Vejle University Hospital UnB University of Toronto Slovak Academy of Sciences Hospital Sirio Libanês University of Southern Denmark |
dc.contributor.author.fl_str_mv |
Pinheiro, Maisa [UNESP] Lupinacci, Fernanda Cristina Sulla Santiago, Karina Miranda Drigo, Sandra Aparecida [UNESP] Marchi, Fabio Albuquerque Fonseca-Alves, Carlos Eduardo [UNESP] Andrade, Sonia Cristina da Silva Aagaard, Mads Malik Basso, Tatiane Ramos Reis, Mariana Bisarro Dos Villacis, Rolando André Rios Roffé, Martin Hajj, Glaucia Noeli Maroso Jurisica, Igor Kowalski, Luiz Paulo Achatz, Maria Isabel Rogatto, Silvia Regina |
dc.subject.por.fl_str_mv |
Breast cancer Exome sequencing Familial cancer Functional analysis MUS81 Thyroid cancer |
topic |
Breast cancer Exome sequencing Familial cancer Functional analysis MUS81 Thyroid cancer |
description |
Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-12T02:08:56Z 2020-12-12T02:08:56Z 2020-05-01 |
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.uri.fl_str_mv |
http://dx.doi.org/10.3390/cancers12051289 Cancers, v. 12, n. 5, 2020. 2072-6694 http://hdl.handle.net/11449/200526 10.3390/cancers12051289 2-s2.0-85085524745 |
url |
http://dx.doi.org/10.3390/cancers12051289 http://hdl.handle.net/11449/200526 |
identifier_str_mv |
Cancers, v. 12, n. 5, 2020. 2072-6694 10.3390/cancers12051289 2-s2.0-85085524745 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cancers |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808128216129339392 |