Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk

Naomi Wilcox; Martine Dumont; Anna González-Neira; Sara Carvalho; Charles Joly Beauparlant; Marco Crotti; Craig Luccarini; Penny Soucy; Stéphane Dubois; Rocio Nuñez-Torres; Guillermo Pita; Eugene J. Gardner; Joe Dennis; M. Rosario Alonso; Nuria Álvarez; Caroline Baynes; Annie Claude Collin-Deschesnes; Sylvie Desjardins; Heiko Becher; Sabine Behrens; Manjeet K. Bolla; Jose E. Castelao; Jenny Chang-Claude; Sten Cornelissen; Thilo Dörk; Christoph Engel; Manuela Gago-Dominguez; Pascal Guénel; Andreas Hadjisavvas; Eric Hahnen; Mikael Hartman; Belén Herráez; Benita Kiat Tee Tan; Veronique Kiak Mien Tan; Su Ming Tan; Geok Hoon Lim; Ern Yu Tan; Peh Joo Ho; Alexis Jiaying Khng; Audrey Jung; Renske Keeman; Marion Kiechle; Jingmei Li; Maria A. Loizidou; Michael Lush; Kyriaki Michailidou; Mihalis I. Panayiotidis; Xueling Sim; Soo Hwang Teo; Jonathan P. Tyrer; Lizet E. van der Kolk; Cecilia Wahlström; Qin Wang; John R.B. Perry; Javier Benitez; Marjanka K. Schmidt; Rita K. Schmutzler; Paul D.P. Pharoah; Arnaud Droit; Alison M. Dunning; Anders Kvist; Peter Devilee; Douglas F. Easton; Jacques Simard

doi:10.1038/s41588-023-01466-z

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk

Naomi Wilcox, Martine Dumont, Anna González-Neira, Sara Carvalho, Charles Joly Beauparlant, Marco Crotti, Craig Luccarini, Penny Soucy, Stéphane Dubois, Rocio Nuñez-Torres, Guillermo Pita, Eugene J. Gardner, Joe Dennis, M. Rosario Alonso, Nuria Álvarez, Caroline Baynes, Annie Claude Collin-Deschesnes, Sylvie Desjardins, Heiko Becher, Sabine BehrensManjeet K. Bolla, Jose E. Castelao, Jenny Chang-Claude, Sten Cornelissen, Thilo Dörk, Christoph Engel, Manuela Gago-Dominguez, Pascal Guénel, Andreas Hadjisavvas, Eric Hahnen, Mikael Hartman, Belén Herráez, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Su Ming Tan, Geok Hoon Lim, Ern Yu Tan, Peh Joo Ho, Alexis Jiaying Khng, Audrey Jung, Renske Keeman, Marion Kiechle, Jingmei Li, Maria A. Loizidou, Michael Lush, Kyriaki Michailidou, Mihalis I. Panayiotidis, Xueling Sim, Soo Hwang Teo, Jonathan P. Tyrer, Lizet E. van der Kolk, Cecilia Wahlström, Qin Wang, John R.B. Perry, Javier Benitez, Marjanka K. Schmidt, Rita K. Schmutzler, Paul D.P. Pharoah, Arnaud Droit, Alison M. Dunning, Anders Kvist, Peter Devilee, Douglas F. Easton, Jacques Simard

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

15 Zitate (Scopus)

Abstract

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10⁻⁶): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10⁻⁴. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

Originalsprache	Englisch
Seiten (von - bis)	1435-1439
Seitenumfang	5
Fachzeitschrift	Nature Genetics
Jahrgang	55
Ausgabenummer	9
DOIs	https://doi.org/10.1038/s41588-023-01466-z
Publikationsstatus	Veröffentlicht - Sept. 2023
Extern publiziert	Ja

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Wilcox, N., Dumont, M., González-Neira, A., Carvalho, S., Joly Beauparlant, C., Crotti, M., Luccarini, C., Soucy, P., Dubois, S., Nuñez-Torres, R., Pita, G., Gardner, E. J., Dennis, J., Alonso, M. R., Álvarez, N., Baynes, C., Collin-Deschesnes, A. C., Desjardins, S., Becher, H., ... Simard, J. (2023). Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk. Nature Genetics, 55(9), 1435-1439. https://doi.org/10.1038/s41588-023-01466-z

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title = "Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk",

abstract = "Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.",

author = "Naomi Wilcox and Martine Dumont and Anna Gonz{\'a}lez-Neira and Sara Carvalho and {Joly Beauparlant}, Charles and Marco Crotti and Craig Luccarini and Penny Soucy and St{\'e}phane Dubois and Rocio Nu{\~n}ez-Torres and Guillermo Pita and Gardner, {Eugene J.} and Joe Dennis and Alonso, {M. Rosario} and Nuria {\'A}lvarez and Caroline Baynes and Collin-Deschesnes, {Annie Claude} and Sylvie Desjardins and Heiko Becher and Sabine Behrens and Bolla, {Manjeet K.} and Castelao, {Jose E.} and Jenny Chang-Claude and Sten Cornelissen and Thilo D{\"o}rk and Christoph Engel and Manuela Gago-Dominguez and Pascal Gu{\'e}nel and Andreas Hadjisavvas and Eric Hahnen and Mikael Hartman and Bel{\'e}n Herr{\'a}ez and Tan, {Benita Kiat Tee} and Tan, {Veronique Kiak Mien} and Tan, {Su Ming} and Lim, {Geok Hoon} and Tan, {Ern Yu} and Ho, {Peh Joo} and Khng, {Alexis Jiaying} and Audrey Jung and Renske Keeman and Marion Kiechle and Jingmei Li and Loizidou, {Maria A.} and Michael Lush and Kyriaki Michailidou and Panayiotidis, {Mihalis I.} and Xueling Sim and Teo, {Soo Hwang} and Tyrer, {Jonathan P.} and {van der Kolk}, {Lizet E.} and Cecilia Wahlstr{\"o}m and Qin Wang and Perry, {John R.B.} and Javier Benitez and Schmidt, {Marjanka K.} and Schmutzler, {Rita K.} and Pharoah, {Paul D.P.} and Arnaud Droit and Dunning, {Alison M.} and Anders Kvist and Peter Devilee and Easton, {Douglas F.} and Jacques Simard",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

doi = "10.1038/s41588-023-01466-z",

language = "English",

volume = "55",

pages = "1435--1439",

journal = "Nature Genetics",

issn = "1061-4036",

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Wilcox, N, Dumont, M, González-Neira, A, Carvalho, S, Joly Beauparlant, C, Crotti, M, Luccarini, C, Soucy, P, Dubois, S, Nuñez-Torres, R, Pita, G, Gardner, EJ, Dennis, J, Alonso, MR, Álvarez, N, Baynes, C, Collin-Deschesnes, AC, Desjardins, S, Becher, H, Behrens, S, Bolla, MK, Castelao, JE, Chang-Claude, J, Cornelissen, S, Dörk, T, Engel, C, Gago-Dominguez, M, Guénel, P, Hadjisavvas, A, Hahnen, E, Hartman, M, Herráez, B, Tan, BKT, Tan, VKM, Tan, SM, Lim, GH, Tan, EY, Ho, PJ, Khng, AJ, Jung, A, Keeman, R, Kiechle, M, Li, J, Loizidou, MA, Lush, M, Michailidou, K, Panayiotidis, MI, Sim, X, Teo, SH, Tyrer, JP, van der Kolk, LE, Wahlström, C, Wang, Q, Perry, JRB, Benitez, J, Schmidt, MK, Schmutzler, RK, Pharoah, PDP, Droit, A, Dunning, AM, Kvist, A, Devilee, P, Easton, DF & Simard, J 2023, 'Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk', Nature Genetics, Jg. 55, Nr. 9, S. 1435-1439. https://doi.org/10.1038/s41588-023-01466-z

TY - JOUR

T1 - Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk

AU - Wilcox, Naomi

AU - Dumont, Martine

AU - González-Neira, Anna

AU - Carvalho, Sara

AU - Joly Beauparlant, Charles

AU - Crotti, Marco

AU - Luccarini, Craig

AU - Soucy, Penny

AU - Dubois, Stéphane

AU - Nuñez-Torres, Rocio

AU - Pita, Guillermo

AU - Gardner, Eugene J.

AU - Dennis, Joe

AU - Alonso, M. Rosario

AU - Álvarez, Nuria

AU - Baynes, Caroline

AU - Collin-Deschesnes, Annie Claude

AU - Desjardins, Sylvie

AU - Becher, Heiko

AU - Behrens, Sabine

AU - Bolla, Manjeet K.

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Cornelissen, Sten

AU - Dörk, Thilo

AU - Engel, Christoph

AU - Gago-Dominguez, Manuela

AU - Guénel, Pascal

AU - Hadjisavvas, Andreas

AU - Hahnen, Eric

AU - Hartman, Mikael

AU - Herráez, Belén

AU - Tan, Benita Kiat Tee

AU - Tan, Veronique Kiak Mien

AU - Tan, Su Ming

AU - Lim, Geok Hoon

AU - Tan, Ern Yu

AU - Ho, Peh Joo

AU - Khng, Alexis Jiaying

AU - Jung, Audrey

AU - Keeman, Renske

AU - Kiechle, Marion

AU - Li, Jingmei

AU - Loizidou, Maria A.

AU - Lush, Michael

AU - Michailidou, Kyriaki

AU - Panayiotidis, Mihalis I.

AU - Sim, Xueling

AU - Teo, Soo Hwang

AU - Tyrer, Jonathan P.

AU - van der Kolk, Lizet E.

AU - Wahlström, Cecilia

AU - Wang, Qin

AU - Perry, John R.B.

AU - Benitez, Javier

AU - Schmidt, Marjanka K.

AU - Schmutzler, Rita K.

AU - Pharoah, Paul D.P.

AU - Droit, Arnaud

AU - Dunning, Alison M.

AU - Kvist, Anders

AU - Devilee, Peter

AU - Easton, Douglas F.

AU - Simard, Jacques

PY - 2023/9

Y1 - 2023/9

N2 - Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

AB - Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

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DO - 10.1038/s41588-023-01466-z

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SN - 1061-4036

VL - 55

SP - 1435

EP - 1439

JO - Nature Genetics

JF - Nature Genetics

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ER -

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk

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