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Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer

1
Faculty of Medicine, Sao Paulo State University, UNESP, Botucatu SP 18618-687, Brazil
2
International Research Center, A.C. Camargo Cancer Center, São Paulo SP 01508-010, Brazil
3
Department of Surgery and Orthopedics, Experimental Research Unity, Faculty of Medicine, São Paulo State University, UNESP, Botucatu SP 18618-687, Brazil
4
Department of Veterinary Surgery and Anesthesiology, São Paulo State University, UNESP, Botucatu SP 18618-681, Brazil
5
Department of Genetics and Evolutionary Biology, University of São Paulo, USP, São Paulo SP 05508-090, Brazil
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Department of Clinical Genetics, Vejle University Hospital, 7100 Vejle, Denmark
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Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, UnB, Brasília DF 70910-900, Brazil
8
Krembil Research Institute, UHN, University of Toronto, Toronto, ON M5G 2C4, Canada
9
Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovakia
10
Cancer Genetics Unit, Centro de Oncologia, Hospital Sirio Libanês, São Paulo SP 01308-050, Brazil
11
Department of Clinical Genetics, Vejle University Hospital, Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(5), 1289; https://doi.org/10.3390/cancers12051289
Received: 25 March 2020 / Revised: 7 May 2020 / Accepted: 12 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue Genetic Markers and Cancer Risk)
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. View Full-Text
Keywords: exome sequencing; MUS81; breast cancer; thyroid cancer; functional analysis; familial cancer exome sequencing; MUS81; breast cancer; thyroid cancer; functional analysis; familial cancer
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MDPI and ACS Style

Pinheiro, M.; Lupinacci, F.C.S.; Santiago, K.M.; Drigo, S.A.; Marchi, F.A.; Fonseca-Alves, C.E.; Andrade, S.C.d.S.; Aagaard, M.M.; Basso, T.R.; dos Reis, M.B.; Villacis, R.A.R.; Roffé, M.; Hajj, G.N.M.; Jurisica, I.; Kowalski, L.P.; Achatz, M.I.; Rogatto, S.R. Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer. Cancers 2020, 12, 1289. https://doi.org/10.3390/cancers12051289

AMA Style

Pinheiro M, Lupinacci FCS, Santiago KM, Drigo SA, Marchi FA, Fonseca-Alves CE, Andrade SCdS, Aagaard MM, Basso TR, dos Reis MB, Villacis RAR, Roffé M, Hajj GNM, Jurisica I, Kowalski LP, Achatz MI, Rogatto SR. Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer. Cancers. 2020; 12(5):1289. https://doi.org/10.3390/cancers12051289

Chicago/Turabian Style

Pinheiro, Maisa; Lupinacci, Fernanda C.S.; Santiago, Karina M.; Drigo, Sandra A.; Marchi, Fabio A.; Fonseca-Alves, Carlos E.; Andrade, Sonia C.d.S.; Aagaard, Mads M.; Basso, Tatiane R.; dos Reis, Mariana B.; Villacis, Rolando A.R.; Roffé, Martin; Hajj, Glaucia N.M.; Jurisica, Igor; Kowalski, Luiz P.; Achatz, Maria I.; Rogatto, Silvia R. 2020. "Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer" Cancers 12, no. 5: 1289. https://doi.org/10.3390/cancers12051289

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