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A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor

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Rodrigue, Amelie [1, 2, 3] ; Margaillan, Guillaume [4] ; Gomes, Thiago Torres [5, 6] ; Coulombe, Yan [1, 2, 3] ; Montalban, Gemma [1, 2, 3, 4] ; Carvalho, Simone da Costa e Silva [7, 1, 5, 8, 9] ; Milano, Larissa [1, 2, 3] ; Ducy, Mandy [1, 2, 3, 4] ; De-Gregoriis, Giuliana [5, 6] ; Dellaire, Graham [10] ; da Silva Jr, Wilson Araujo ; Monteiro, Alvaro N. [11] ; Carvalho, Marcelo A. [5, 6] ; Simard, Jacques [4] ; Masson, Jean-Yves [1, 2, 3]
Número total de Autores: 15
Afiliação do(s) autor(es):
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[1] Univ Laval, CHU Quebec, Oncol Div, 9 McMahon, Quebec City, PQ G1R 3S3 - Canada
[2] Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ G1V 0A6 - Canada
[3] Laval Univ, Canc Res Ctr, Quebec City, PQ G1V 0A6 - Canada
[4] Univ Laval, Res Ctr, Genom Ctr, CHU Quebec, Quebec City, PQ - Canada
[5] Inst Nacl Canc, Ctr Pesquisa, Programa Pesquisa Clin, Rio De Janeiro - Brazil
[6] Inst Fed Rio de Janeiro, Lab Genet Mol, Maracana, RJ - Brazil
[7] Univ Sao Paulo, Dept Genet, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil
[8] FAPESP, Ctr Cell Based Therapy CEPID, Ribeirao Preto, SP - Brazil
[9] CNPq, Natl Inst Sci & Technol Stem Cell & Cell Therapy, Ribeirao Preto, SP - Brazil
[10] Dalhousie Univ, Dept Pathol, Halifax, NS - Canada
[11] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL - USA
Número total de Afiliações: 11
Tipo de documento: Artigo Científico
Fonte: Nucleic Acids Research; v. 47, n. 20, p. 10662-10677, NOV 18 2019.
Citações Web of Science: 1

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. (AU)

Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
Beneficiário:Dimas Tadeu Covas
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs