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

Author(s):Show less -

Pinheiro, Maisa ^{[1, 2]} ; Sulla Lupinacci, Fernanda Cristina ^[1] ; Santiago, Karina Miranda ^[1] ; Drigo, Sandra Aparecida ^[3] ; Marchi, Fabio Albuquerque ^[1] ; Fonseca-Alves, Carlos Eduardo ^[4] ; da Silva Andrade, Sonia Cristina ^[5] ; Aagaard, Mads Malik ^[6] ; Basso, Tatiane Ramos ^[1] ; dos Reis, Mariana Bisarro ^[1] ; Rios Villacis, Rolando Andre ^[7] ; Roffe, Martin ^[1] ; Maroso Hajj, Glaucia Noeli ^[1] ; Jurisica, Igor ^{[8, 9]} ; Kowalski, Luiz Paulo ^[1] ; Achatz, Maria Isabel ^[10] ; Rogatto, Silvia Regina ^[11]

Affiliation:Show less -

^[1] AC Camargo Canc Ctr, Int Res Ctr, BR-01508010 Sao Paulo, SP - Brazil

^[2] Sao Paulo State Univ, UNESP, Fac Med, BR-18618687 Botucatu, SP - Brazil

^[3] Sao Paulo State Univ, UNESP, Dept Surg & Orthoped, Expt Res Unity, Fac Med, BR-18618687 Botucatu, SP - Brazil

^[4] Sao Paulo State Univ, UNESP, Dept Vet Surg & Anesthesiol, BR-18618681 Botucatu, SP - Brazil

^[5] Univ Sao Paulo, USP, Dept Genet & Evolutionary Biol, BR-05508090 Sao Paulo, SP - Brazil

^[6] Vejle Univ Hosp, Dept Clin Genet, DK-7100 Vejle - Denmark

^[7] Univ Brasilia, UnB, Inst Biol Sci, Dept Genet & Morphol, BR-70910900 Brasilia, DF - Brazil

^[8] Univ Toronto, UHN, Krembil Res Inst, Toronto, ON M5G 2C4 - Canada

^[9] Slovak Acad Sci, Inst Neuroimmunol, Bratislava 84510 - Slovakia

^[10] Hosp Sirio Libanes, Ctr Oncol, Canc Genet Unit, BR-01308050 Sao Paulo, SP - Brazil

^[11] Univ Southern Denmark, Dept Clin Genet, Vejle Univ Hosp, Inst Reg Hlth Res, DK-5000 Odense - Denmark

• Document type: Journal article
• Source: CANCERS; v. 12, n. 5 MAY 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 14/03983-8 - Predisposition gene identification in thyroid and breast carcinomas syndrome by exome sequencing
• Grantee: Maísa Pinheiro
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/12714-5 - Predisposition gene identification in thyroid and breast carcinomas syndrome by exoma sequencing
• Grantee: Maísa Pinheiro
• Support type: Scholarships in Brazil - Master