A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor
| Autor: | Simone da Costa e Silva Carvalho, Mandy Ducy, Jean-Yves Masson, Giuliana De-Gregoriis, Amélie Rodrigue, Thiago T. Gomes, Gemma Montalban, Marcelo A. Carvalho, Guillaume Margaillan, Larissa Milano, Wilson A. Silva, Yan Coulombe, Graham Dellaire, Alvaro N.A. Monteiro, Jacques Simard |
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| Rok vydání: | 2019 |
| Předmět: |
Genetics
0303 health sciences Mutation DNA damage PALB2 MUTAÇÃO GENÉTICA Biology Genome Integrity Repair and Replication medicine.disease_cause medicine.disease Germline 3. Good health 03 medical and health sciences 0302 clinical medicine Fanconi anemia 030220 oncology & carcinogenesis PARP inhibitor medicine Missense mutation Homologous recombination 030304 developmental biology |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Nucleic Acids Research |
| Popis: | While biallelic mutations in the PALB2 tumor suppressor cause Fanconi anemia subtype FA-N, monoallelic mutations predispose to breast and familial pancreatic cancer. Although hundreds of missense variants in PALB2 have been identified in patients to date, only a few have clear functional and clinical relevance. Herein, we investigate the effects of 44 PALB2 variants of uncertain significance found in breast cancer patients and provide detailed analysis by systematic functional assays. Our comprehensive functional analysis reveals two hotspots for potentially deleterious variations within PALB2, one at each terminus. PALB2 N-terminus variants p.P8L [c.23C>T], p.Y28C [c.83A>G], and p.R37H [c.110G>A] compromised PALB2-mediated homologous recombination. At the C-terminus, PALB2 variants p.L947F [c.2841G>T], p.L947S [c.2840T>C], and most strikingly p.T1030I [c.3089C>T] and p.W1140G [c.3418T>C], stood out with pronounced PARP inhibitor sensitivity and cytoplasmic accumulation in addition to marked defects in recruitment to DNA damage sites, interaction with BRCA2 and homologous recombination. Altogether, our findings show that a combination of functional assays is necessary to assess the impact of germline missense variants on PALB2 function, in order to guide proper classification of their deleteriousness. |
| Databáze: | OpenAIRE |
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