A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.
Autor: | Rodrigue A; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada., Margaillan G; CHU de Québec-Université Laval Research Center, Genomics Center, Québec City, QC, Canada., Torres Gomes T; Instituto Nacional de Câncer, Centro de Pesquisa, Programa de Pesquisa Clínica, Rio de Janeiro, Brazil.; Instituto Federal do Rio de Janeiro, Laboratório de Genética Molecular, Maracanã, Rio de Janeiro, Brazil., Coulombe Y; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada., Montalban G; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada.; CHU de Québec-Université Laval Research Center, Genomics Center, Québec City, QC, Canada., da Costa E Silva Carvalho S; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Instituto Nacional de Câncer, Centro de Pesquisa, Programa de Pesquisa Clínica, Rio de Janeiro, Brazil.; Department of Genetics at Ribeirão Preto Medical School, University of São Paulo; Center for Cell-Based Therapy (CEPID/FAPESP); National Institute of Science and Technology in Stem Cell and Cell Therapy (INCTC/CNPq), Ribeirão Preto, SP, Brazil., Milano L; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada., Ducy M; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada.; CHU de Québec-Université Laval Research Center, Genomics Center, Québec City, QC, Canada., De-Gregoriis G; Instituto Nacional de Câncer, Centro de Pesquisa, Programa de Pesquisa Clínica, Rio de Janeiro, Brazil.; Instituto Federal do Rio de Janeiro, Laboratório de Genética Molecular, Maracanã, Rio de Janeiro, Brazil., Dellaire G; Department of Pathology, Dalhousie University, Halifax, NS, Canada., Araújo da Silva W Jr; Department of Genetics at Ribeirão Preto Medical School, University of São Paulo; Center for Cell-Based Therapy (CEPID/FAPESP); National Institute of Science and Technology in Stem Cell and Cell Therapy (INCTC/CNPq), Ribeirão Preto, SP, Brazil., Monteiro AN; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA., Carvalho MA; Instituto Nacional de Câncer, Centro de Pesquisa, Programa de Pesquisa Clínica, Rio de Janeiro, Brazil.; Instituto Federal do Rio de Janeiro, Laboratório de Genética Molecular, Maracanã, Rio de Janeiro, Brazil., Simard J; CHU de Québec-Université Laval Research Center, Genomics Center, Québec City, QC, Canada., Masson JY; CHU de Québec-Université Laval, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada. |
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Jazyk: | angličtina |
Zdroj: | Nucleic acids research [Nucleic Acids Res] 2019 Nov 18; Vol. 47 (20), pp. 10662-10677. |
DOI: | 10.1093/nar/gkz780 |
Abstrakt: | 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. (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.) |
Databáze: | MEDLINE |
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