The impact of coding germline variants on contralateral breast cancer risk and survival.

Morra, A; Mavaddat, N; Muranen, TA; Ahearn, TU; Allen, J; Andrulis, IL; Auvinen, P; Becher, H; Behrens, S; Blomqvist, C; Bojesen, SE; Bolla, MK; Brauch, H; Camp, NJ; Carvalho, S; Castelao, JE; Cessna, MH; Chang-Claude, J; Chenevix-Trench, G; NBCS Collaborators,; Czene, K; Decker, B; Dennis, J; Dörk, T; Dorling, L; Dunning, AM; Ekici, AB; Eriksson, M; Evans, DG; Fasching, PA; Figueroa, JD; Flyger, H; Gago-Dominguez, M; García-Closas, M; Geurts-Giele, WRR; Giles, GG; Guénel, P; Gündert, M; Hahnen, E; Hall, P; Hamann, U; Harrington, PA; He, W; Heikkilä, P; Hooning, MJ; Hoppe, R; Howell, A; Humphreys, K; kConFab Investigators,; Jakubowska, A; Jung, AY; Keeman, R; Kristensen, VN; Lubiński, J; Mannermaa, A; Manoochehri, M; Manoukian, S; Margolin, S; Mavroudis, D; Milne, RL; Mulligan, AM; Newman, WG; Park-Simon, T-W; Peterlongo, P; Pharoah, PDP; Rhenius, V; Saloustros, E; Sawyer, EJ; Schmutzler, RK; Shah, M; Spurdle, AB; Tomlinson, I; Truong, T; van Veen, EM; Vreeswijk, MPG; Wang, Q; Wendt, C; Yang, XR; Nevanlinna, H; Devilee, P; Easton, DF; Schmidt, MK

The impact of coding germline variants on contralateral breast cancer risk and survival.

Morra, A Mavaddat, N Muranen, TA Ahearn, TU Allen, J Andrulis, IL Auvinen, P Becher, H Behrens, S Blomqvist, C Bojesen, SE Bolla, MK Brauch, H Camp, NJ Carvalho, S Castelao, JE Cessna, MH Chang-Claude, J Chenevix-Trench, G NBCS Collaborators, Czene, K Decker, B Dennis, J Dörk, T Dorling, L Dunning, AM Ekici, AB Eriksson, M Evans, DG Fasching, PA Figueroa, JD Flyger, H Gago-Dominguez, M García-Closas, M Geurts-Giele, WRR Giles, GG Guénel, P Gündert, M Hahnen, E Hall, P Hamann, U Harrington, PA He, W Heikkilä, P Hooning, MJ Hoppe, R Howell, A Humphreys, K kConFab Investigators, Jakubowska, A Jung, AY Keeman, R Kristensen, VN Lubiński, J Mannermaa, A Manoochehri, M Manoukian, S Margolin, S Mavroudis, D Milne, RL Mulligan, AM Newman, WG Park-Simon, T-W Peterlongo, P Pharoah, PDP Rhenius, V Saloustros, E Sawyer, EJ Schmutzler, RK Shah, M Spurdle, AB Tomlinson, I Truong, T van Veen, EM Vreeswijk, MPG Wang, Q Wendt, C Yang, XR Nevanlinna, H Devilee, P Easton, DF Schmidt, MK

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Am J Hum Genet, 2023, 110, (3), pp. 475-486
Issue Date:: 2023-03-02

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Field	Value	Language
dc.contributor.author	Morra, A
dc.contributor.author	Mavaddat, N
dc.contributor.author	Muranen, TA
dc.contributor.author	Ahearn, TU
dc.contributor.author	Allen, J
dc.contributor.author	Andrulis, IL
dc.contributor.author	Auvinen, P
dc.contributor.author	Becher, H
dc.contributor.author	Behrens, S
dc.contributor.author	Blomqvist, C
dc.contributor.author	Bojesen, SE
dc.contributor.author	Bolla, MK
dc.contributor.author	Brauch, H
dc.contributor.author	Camp, NJ
dc.contributor.author	Carvalho, S
dc.contributor.author	Castelao, JE
dc.contributor.author	Cessna, MH
dc.contributor.author	Chang-Claude, J
dc.contributor.author	Chenevix-Trench, G
dc.contributor.author	NBCS Collaborators,
dc.contributor.author	Czene, K
dc.contributor.author	Decker, B
dc.contributor.author	Dennis, J
dc.contributor.author	Dörk, T
dc.contributor.author	Dorling, L
dc.contributor.author	Dunning, AM
dc.contributor.author	Ekici, AB
dc.contributor.author	Eriksson, M
dc.contributor.author	Evans, DG
dc.contributor.author	Fasching, PA
dc.contributor.author	Figueroa, JD
dc.contributor.author	Flyger, H
dc.contributor.author	Gago-Dominguez, M
dc.contributor.author	García-Closas, M
dc.contributor.author	Geurts-Giele, WRR
dc.contributor.author	Giles, GG
dc.contributor.author	Guénel, P
dc.contributor.author	Gündert, M
dc.contributor.author	Hahnen, E
dc.contributor.author	Hall, P
dc.contributor.author	Hamann, U
dc.contributor.author	Harrington, PA
dc.contributor.author	He, W
dc.contributor.author	Heikkilä, P
dc.contributor.author	Hooning, MJ
dc.contributor.author	Hoppe, R
dc.contributor.author	Howell, A
dc.contributor.author	Humphreys, K
dc.contributor.author	kConFab Investigators,
dc.contributor.author	Jakubowska, A
dc.contributor.author	Jung, AY
dc.contributor.author	Keeman, R
dc.contributor.author	Kristensen, VN
dc.contributor.author	Lubiński, J
dc.contributor.author	Mannermaa, A
dc.contributor.author	Manoochehri, M
dc.contributor.author	Manoukian, S
dc.contributor.author	Margolin, S
dc.contributor.author	Mavroudis, D
dc.contributor.author	Milne, RL
dc.contributor.author	Mulligan, AM
dc.contributor.author	Newman, WG
dc.contributor.author	Park-Simon, T-W
dc.contributor.author	Peterlongo, P
dc.contributor.author	Pharoah, PDP
dc.contributor.author	Rhenius, V
dc.contributor.author	Saloustros, E
dc.contributor.author	Sawyer, EJ
dc.contributor.author	Schmutzler, RK
dc.contributor.author	Shah, M
dc.contributor.author	Spurdle, AB
dc.contributor.author	Tomlinson, I
dc.contributor.author	Truong, T
dc.contributor.author	van Veen, EM
dc.contributor.author	Vreeswijk, MPG
dc.contributor.author	Wang, Q
dc.contributor.author	Wendt, C
dc.contributor.author	Yang, XR
dc.contributor.author	Nevanlinna, H
dc.contributor.author	Devilee, P
dc.contributor.author	Easton, DF
dc.contributor.author	Schmidt, MK
dc.date.accessioned	2025-01-15T11:48:35Z
dc.date.available	2023-02-01
dc.date.available	2025-01-15T11:48:35Z
dc.date.issued	2023-03-02
dc.identifier.citation	Am J Hum Genet, 2023, 110, (3), pp. 475-486
dc.identifier.issn	0002-9297
dc.identifier.issn	1537-6605
dc.identifier.uri	http://hdl.handle.net/10453/183650
dc.description.abstract	Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Am J Hum Genet
dc.relation.isbasedon	10.1016/j.ajhg.2023.02.003
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Genetics & Heredity
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	42 Health sciences
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Genes, BRCA2
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Germ Cells
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Germ Cells
dc.subject.mesh	Humans
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Genes, BRCA2
dc.subject.mesh	Female
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Genes, BRCA2
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Germ Cells
dc.subject.mesh	Genetic Predisposition to Disease
dc.title	The impact of coding germline variants on contralateral breast cancer risk and survival.
dc.type	Journal Article
utslib.citation.volume	110
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-01-15T11:48:33Z
pubs.issue	3
pubs.publication-status	Published
pubs.volume	110
utslib.citation.issue	3

Abstract:

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

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