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

Amélie Rodrigue; Guillaume Margaillan; Thiago Torres Gomes; Yan Coulombe; Gemma Montalban; Simone Da Costa E.Silva Carvalho; Larissa Milano; Mandy Ducy; Giuliana De-Gregoriis; Graham Dellaire; Wilson Araújo Da Silva; Alvaro N. Monteiro; Marcelo A. Carvalho; Jacques Simard; Jean Yves Masson

doi:10.1093/nar/gkz780

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

Amélie Rodrigue, Guillaume Margaillan, Thiago Torres Gomes, Yan Coulombe, Gemma Montalban, Simone Da Costa E.Silva Carvalho, Larissa Milano, Mandy Ducy, Giuliana De-Gregoriis, Graham Dellaire, Wilson Araújo Da Silva, Alvaro N. Monteiro, Marcelo A. Carvalho, Jacques Simard, Jean Yves Masson

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38 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	10662-10677
Número de páginas	16
Publicación	Nucleic Acids Research
Volumen	47
N.º	20
DOI	https://doi.org/10.1093/nar/gkz780
Estado	Published - nov. 18 2019

Nota bibliográfica

Funding Information:
Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de L’Économie, et de l’Innovation du Québec through Génome Québec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Fundac¸ão de Amparo à Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Fundac¸ão do Câncer/Programa de On-cobiologia (to M.A.C.); Conselho Nacional de Desen-volvimento Científico e Tecnológico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Fundac¸ão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Ministère de l’Économie, de la Science et de l’Innovation du Québec through the PSR-SIIRI-949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT-156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research. Conflict of interest statement. None declared.

Funding Information:
Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de L'? conomie, et de l'Innovation du Qu?bec through G?nome Qu?bec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Funda??o do C?ncer/Programa de Oncobiologia (to M.A.C.); Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Minist?re de l'? conomie, de la Science et de l'Innovation du Qu?bec through the PSR-SIIRI- 949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT- 156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research.

Publisher Copyright:
© The Author(s) 2019.

ASJC Scopus Subject Areas

Genetics

ODS de las Naciones Unidas

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Rodrigue, A., Margaillan, G., Gomes, T. T., Coulombe, Y., Montalban, G., Carvalho, S. D. C. E. S., Milano, L., Ducy, M., De-Gregoriis, G., Dellaire, G., Da Silva, W. A., Monteiro, A. N., Carvalho, M. A., Simard, J., & Masson, J. Y. (2019). A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor. Nucleic Acids Research, 47(20), 10662-10677. https://doi.org/10.1093/nar/gkz780

Rodrigue, A, Margaillan, G, Gomes, TT, Coulombe, Y, Montalban, G, Carvalho, SDCES, Milano, L, Ducy, M, De-Gregoriis, G, Dellaire, G, Da Silva, WA, Monteiro, AN, Carvalho, MA, Simard, J & Masson, JY 2019, 'A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor', Nucleic Acids Research, vol. 47, n.º 20, pp. 10662-10677. https://doi.org/10.1093/nar/gkz780

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

abstract = "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.",

author = "Am{\'e}lie Rodrigue and Guillaume Margaillan and Gomes, {Thiago Torres} and Yan Coulombe and Gemma Montalban and Carvalho, {Simone Da Costa E.Silva} and Larissa Milano and Mandy Ducy and Giuliana De-Gregoriis and Graham Dellaire and {Da Silva}, {Wilson Ara{\'u}jo} and Monteiro, {Alvaro N.} and Carvalho, {Marcelo A.} and Jacques Simard and Masson, {Jean Yves}",

note = "Funding Information: Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Minist{\`e}re de L{\textquoteright}{\'E}conomie, et de l{\textquoteright}Innovation du Qu{\'e}bec through G{\'e}nome Qu{\'e}bec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Fundac¸{\~a}o de Amparo {\`a} Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Fundac¸{\~a}o do C{\^a}ncer/Programa de On-cobiologia (to M.A.C.); Conselho Nacional de Desen-volvimento Cient{\'i}fico e Tecnol{\'o}gico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Fundac¸{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Minist{\`e}re de l{\textquoteright}{\'E}conomie, de la Science et de l{\textquoteright}Innovation du Qu{\'e}bec through the PSR-SIIRI-949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT-156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research. Conflict of interest statement. None declared. Funding Information: Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de L'? conomie, et de l'Innovation du Qu?bec through G?nome Qu?bec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Funda??o do C?ncer/Programa de Oncobiologia (to M.A.C.); Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Minist?re de l'? conomie, de la Science et de l'Innovation du Qu?bec through the PSR-SIIRI- 949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT- 156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research. Publisher Copyright: {\textcopyright} The Author(s) 2019.",

year = "2019",

month = nov,

day = "18",

doi = "10.1093/nar/gkz780",

language = "English",

volume = "47",

pages = "10662--10677",

journal = "Nucleic Acids Research",

issn = "0305-1048",

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TY - JOUR

T1 - A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor

AU - Rodrigue, Amélie

AU - Margaillan, Guillaume

AU - Gomes, Thiago Torres

AU - Coulombe, Yan

AU - Montalban, Gemma

AU - Carvalho, Simone Da Costa E.Silva

AU - Milano, Larissa

AU - Ducy, Mandy

AU - De-Gregoriis, Giuliana

AU - Dellaire, Graham

AU - Da Silva, Wilson Araújo

AU - Monteiro, Alvaro N.

AU - Carvalho, Marcelo A.

AU - Simard, Jacques

AU - Masson, Jean Yves

N1 - Funding Information: Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de L’Économie, et de l’Innovation du Québec through Génome Québec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Fundac¸ão de Amparo à Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Fundac¸ão do Câncer/Programa de On-cobiologia (to M.A.C.); Conselho Nacional de Desen-volvimento Científico e Tecnológico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Fundac¸ão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Ministère de l’Économie, de la Science et de l’Innovation du Québec through the PSR-SIIRI-949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT-156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research. Conflict of interest statement. None declared. Funding Information: Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de L'? conomie, et de l'Innovation du Qu?bec through G?nome Qu?bec, as well as the Quebec Breast Cancer Foundation (to J.-Y.M. and J.S.); Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro/FAPERJ (to M.A.C.); Funda??o do C?ncer/Programa de Oncobiologia (to M.A.C.); Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico/CNPq (to M.A.C.) (S.C.S.C Project 141974/2015-0); Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP) [W.A.S.-J. grant 2013/08135-2]; Minist?re de l'? conomie, de la Science et de l'Innovation du Qu?bec through the PSR-SIIRI- 949 program (to J.-Y.M./J.S.); CIHR [Project grant PJT- 156017 to G.D.; Foundation grant to J.-Y.M.]. G.D. is a senior scientist of the Beatrice Hunter Cancer Research Institute. J.S. holds a Canada Research Chair in Oncogenetics and J.-Y.M. is a FRQS Chair in genome stability. Funding for open access charge: Canadian Institutes of Health Research. Publisher Copyright: © The Author(s) 2019.

PY - 2019/11/18

Y1 - 2019/11/18

N2 - 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.

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

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