期刊
NUCLEIC ACIDS RESEARCH
卷 47, 期 20, 页码 10662-10677出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz780
关键词
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资金
- Government of Canada through Genome Canada
- Canadian Institutes of Health Research
- Ministere de L'Economie, et de l'Innovation du Quebec through Genome Quebec
- Quebec Breast Cancer Foundation
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro/FAPERJ
- Fundacao do Cancer/Programa de Oncobiologia
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/CNPq [141974/2015-0]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/08135-2]
- Ministere de l'Economie, de la Science et de l'Innovation du Quebec [PSR-SIIRI-949]
- CIHR [PJT-156017]
- Canada Research Chair in Oncogenetics
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.
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