Author(s):
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
Date: 2020
Persistent ID: http://hdl.handle.net/11449/200526
Origin: Oasisbr
Subject(s): Breast cancer; Exome sequencing; Familial cancer; Functional analysis; MUS81; Thyroid cancer
Description
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Syddansk Universitet
Fundação 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)
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.
Faculty of Medicine Sao Paulo State University UNESP
International Research Center A.C. Camargo Cancer Center
Department of Surgery and Orthopedics Experimental Research Unity Faculty of Medicine São Paulo State University UNESP
Department of Veterinary Surgery and Anesthesiology São Paulo State University UNESP
Department of Genetics and Evolutionary Biology University of São Paulo USP
Department of Clinical Genetics Vejle University Hospital
Department of Genetics and Morphology Institute of Biological Sciences University of Brasília UnB, DF
Krembil Research Institute UHN University of Toronto
Institute of Neuroimmunology Slovak Academy of Sciences
Cancer Genetics Unit Centro de Oncologia Hospital Sirio Libanês
Department of Clinical Genetics Vejle University Hospital Institute of Regional Health Research University of Southern Denmark
Faculty of Medicine Sao Paulo State University UNESP
Department of Surgery and Orthopedics Experimental Research Unity Faculty of Medicine São Paulo State University UNESP
Department of Veterinary Surgery and Anesthesiology São Paulo State University UNESP
FAPESP: 2012/12714-5
FAPESP: 2013/0186-7
FAPESP: 2014/03983-8
CNPq: 481132/2012-0
CAPES: PDSE 8195/14-5
