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

Anna Morra; Nasim Mavaddat; Taru A. Muranen; Thomas U. Ahearn; Jamie Allen; Irene L. Andrulis; Päivi Auvinen; Heiko Becher; Sabine Behrens; Carl Blomqvist; Stig E. Bojesen; Manjeet K. Bolla; Hiltrud Brauch; Nicola J. Camp; Sara Carvalho; Jose E. Castelao; Melissa H. Cessna; Jenny Chang-Claude; Georgia Chenevix-Trench; Kamila Czene; Brennan Decker; Joe Dennis; Thilo Dörk; Leila Dorling; Alison M. Dunning; Arif B. Ekici; Mikael Eriksson; D. Gareth Evans; Peter A. Fasching; Jonine D. Figueroa; Henrik Flyger; Manuela Gago-Dominguez; Montserrat García-Closas; Willemina R.R. Geurts-Giele; Graham G. Giles; Pascal Guénel; Melanie Gündert; Eric Hahnen; Per Hall; Ute Hamann; Patricia A. Harrington; Wei He; Päivi Heikkilä; Maartje J. Hooning; Reiner Hoppe; Anthony Howell; Keith Humphreys; Anna Jakubowska; Audrey Y. Jung; Renske Keeman; Vessela N. Kristensen; Jan Lubiński; Arto Mannermaa; Mehdi Manoochehri; Siranoush Manoukian; Sara Margolin; Dimitrios Mavroudis; Roger Milne; Anna Marie Mulligan; William G. Newman; Tjoung Won Park-Simon; Paolo Peterlongo; Paul D.P. Pharoah; Valerie Rhenius; Emmanouil Saloustros; Elinor J. Sawyer; Rita K. Schmutzler; Mitul Shah; Amanda B. Spurdle; Ian Tomlinson; Thérèse Truong; Elke M. van Veen; Maaike P.G. Vreeswijk; Qin Wang; Camilla Wendt; Xiaohong R. Yang; Heli Nevanlinna; Peter Devilee; Douglas F. Easton; Marjanka K. Schmidt; NBCS Collaborators; kConFab Investigators

doi:10.1016/j.ajhg.2023.02.003

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

Anna Morra, Nasim Mavaddat, Taru A. Muranen, Thomas U. Ahearn, Jamie Allen, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Sabine Behrens, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Nicola J. Camp, Sara Carvalho, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Kamila CzeneBrennan Decker, Joe Dennis, Thilo Dörk, Leila Dorling, Alison M. Dunning, Arif B. Ekici, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Willemina R.R. Geurts-Giele, Graham G. Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia A. Harrington, Wei He, Päivi Heikkilä, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, Anna Jakubowska, Audrey Y. Jung, Renske Keeman, Vessela N. Kristensen, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger Milne, Anna Marie Mulligan, William G. Newman, Tjoung Won Park-Simon, Paolo Peterlongo, Paul D.P. Pharoah, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Amanda B. Spurdle, Ian Tomlinson, Thérèse Truong, Elke M. van Veen, Maaike P.G. Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R. Yang, Heli Nevanlinna, Peter Devilee, Douglas F. Easton, Marjanka K. Schmidt, NBCS Collaborators, kConFab Investigators

Medicine Monash Health

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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.

Original language	English
Pages (from-to)	475-486
Number of pages	12
Journal	American Journal of Human Genetics
Volume	110
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2023.02.003
Publication status	Published - 2 Mar 2023

Keywords

breast cancer susceptibility genes
coding germline variants
contralateral breast cancer risk
survival

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2023.02.003Licence: CC BY-NC-ND

Cite this

Morra, A., Mavaddat, N., Muranen, T. A., Ahearn, T. U., Allen, J., Andrulis, I. L., Auvinen, P., Becher, H., Behrens, S., Blomqvist, C., Bojesen, S. E., Bolla, M. K., Brauch, H., Camp, N. J., Carvalho, S., Castelao, J. E., Cessna, M. H., Chang-Claude, J., Chenevix-Trench, G., ... kConFab Investigators (2023). The impact of coding germline variants on contralateral breast cancer risk and survival. American Journal of Human Genetics, 110(3), 475-486. https://doi.org/10.1016/j.ajhg.2023.02.003

@article{87351ac82493437a835a85f942afbf1d,

title = "The impact of coding germline variants on contralateral breast cancer risk and survival",

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.",

keywords = "breast cancer susceptibility genes, coding germline variants, contralateral breast cancer risk, survival",

author = "Anna Morra and Nasim Mavaddat and Muranen, {Taru A.} and Ahearn, {Thomas U.} and Jamie Allen and Andrulis, {Irene L.} and P{\"a}ivi Auvinen and Heiko Becher and Sabine Behrens and Carl Blomqvist and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Hiltrud Brauch and Camp, {Nicola J.} and Sara Carvalho and Castelao, {Jose E.} and Cessna, {Melissa H.} and Jenny Chang-Claude and Georgia Chenevix-Trench and Sahlberg, {Kristine K.} and B{\o}rresen-Dale, {Anne Lise} and Gram, {Inger Torhild} and Olsen, {Karina Standahl} and Olav Engebr{\aa}ten and Bj{\o}rn Naume and J{\"u}rgen Geisler and OSBREAC and {Grenaker Aln{\ae}s}, {Grethe I.} and Kamila Czene and Brennan Decker and Joe Dennis and Thilo D{\"o}rk and Leila Dorling and Dunning, {Alison M.} and Ekici, {Arif B.} and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Figueroa, {Jonine D.} and Henrik Flyger and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Geurts-Giele, {Willemina R.R.} and Giles, {Graham G.} and Pascal Gu{\'e}nel and Melanie G{\"u}ndert and Eric Hahnen and Per Hall and Ute Hamann and Harrington, {Patricia A.} and Wei He and P{\"a}ivi Heikkil{\"a} and Hooning, {Maartje J.} and Reiner Hoppe and Anthony Howell and Keith Humphreys and David Amor and Lesley Andrews and Yoland Antill and Rosemary Balleine and Jonathan Beesley and Ian Bennett and Michael Bogwitz and Leon Botes and Meagan Brennan and Melissa Brown and Michael Buckley and Jo Burke and Phyllis Butow and Liz Caldon and Ian Campbell and Michelle Cao and Anannya Chakrabarti and Deepa Chauhan and Manisha Chauhan and Alice Christian and Paul Cohen and Alison Colley and Ashley Crook and James Cui and Eliza Courtney and Margaret Cummings and Dawson, {Sarah Jane} and Anna DeFazio and Martin Delatycki and Rebecca Dickson and Joanne Dixon and Ted Edkins and Stacey Edwards and Gelareh Farshid and Andrew Fellows and Georgina Fenton and Michael Field and James Flanagan and Peter Fong and Laura Forrest and Stephen Fox and Juliet French and Michael Friedlander and Clara Gaff and Mike Gattas and Peter George and Sian Greening and Marion Harris and Stewart Hart and Nick Hayward and John Hopper and Cass Hoskins and Clare Hunt and Paul James and Mark Jenkins and Alexa Kidd and Judy Kirk and Jessica Koehler and James Kollias and Sunil Lakhani and Mitchell Lawrence and Jason Lee and Shuai Li and Geoff Lindeman and Lara Lipton and Liz Lobb and Sherene Loi and Graham Mann and Deborah Marsh and McLachlan, {Sue Anne} and Bettina Meiser and Sophie Nightingale and Shona O'Connell and Sarah O'Sullivan and Ortega, {David Gallego} and Nick Pachter and Pang, {Jia Min} and Gargi Pathak and Briony Patterson and Amy Pearn and Kelly Phillips and Ellen Pieper and Susan Ramus and Edwina Rickard and Bridget Robinson and Mona Saleh and Anita Skandarajah and Elizabeth Salisbury and Christobel Saunders and Jodi Saunus and Rodney Scott and Clare Scott and Adrienne Sexton and Andrew Shelling and Peter Simpson and Melissa Southey and Spurdle, {Amanda B.} and Jessica Taylor and Renea Taylor and Heather Thorne and Alison Trainer and Kathy Tucker and Jane Visvader and Logan Walker and Rachael Williams and Ingrid Winship and Young, {Mary Ann} and Milita Zaheed and Anna Jakubowska and Jung, {Audrey Y.} and Renske Keeman and Kristensen, {Vessela N.} and Jan Lubi{\'n}ski and Arto Mannermaa and Mehdi Manoochehri and Siranoush Manoukian and Sara Margolin and Dimitrios Mavroudis and Roger Milne and Mulligan, {Anna Marie} and Newman, {William G.} and Park-Simon, {Tjoung Won} and Paolo Peterlongo and Pharoah, {Paul D.P.} and Valerie Rhenius and Emmanouil Saloustros and Sawyer, {Elinor J.} and Schmutzler, {Rita K.} and Mitul Shah and Spurdle, {Amanda B.} and Ian Tomlinson and Th{\'e}r{\`e}se Truong and {van Veen}, {Elke M.} and Vreeswijk, {Maaike P.G.} and Qin Wang and Camilla Wendt and Yang, {Xiaohong R.} and Heli Nevanlinna and Peter Devilee and Easton, {Douglas F.} and Schmidt, {Marjanka K.} and {NBCS Collaborators} and {kConFab Investigators}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = mar,

day = "2",

doi = "10.1016/j.ajhg.2023.02.003",

language = "English",

volume = "110",

pages = "475--486",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

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, 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, Jakubowska, A, Jung, AY, Keeman, R, Kristensen, VN, Lubiński, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Mavroudis, D, Milne, R, Mulligan, AM, Newman, WG, Park-Simon, TW, 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, NBCS Collaborators & kConFab Investigators 2023, 'The impact of coding germline variants on contralateral breast cancer risk and survival', American Journal of Human Genetics, vol. 110, no. 3, pp. 475-486. https://doi.org/10.1016/j.ajhg.2023.02.003

TY - JOUR

T1 - The impact of coding germline variants on contralateral breast cancer risk and survival

AU - Morra, Anna

AU - Mavaddat, Nasim

AU - Muranen, Taru A.

AU - Ahearn, Thomas U.

AU - Allen, Jamie

AU - Andrulis, Irene L.

AU - Auvinen, Päivi

AU - Becher, Heiko

AU - Behrens, Sabine

AU - Blomqvist, Carl

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brauch, Hiltrud

AU - Camp, Nicola J.

AU - Carvalho, Sara

AU - Castelao, Jose E.

AU - Cessna, Melissa H.

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Sahlberg, Kristine K.

AU - Børresen-Dale, Anne Lise

AU - Gram, Inger Torhild

AU - Olsen, Karina Standahl

AU - Engebråten, Olav

AU - Naume, Bjørn

AU - Geisler, Jürgen

AU - OSBREAC, null

AU - Grenaker Alnæs, Grethe I.

AU - Czene, Kamila

AU - Decker, Brennan

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dorling, Leila

AU - Dunning, Alison M.

AU - Ekici, Arif B.

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine D.

AU - Flyger, Henrik

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Geurts-Giele, Willemina R.R.

AU - Giles, Graham G.

AU - Guénel, Pascal

AU - Gündert, Melanie

AU - Hahnen, Eric

AU - Hall, Per

AU - Hamann, Ute

AU - Harrington, Patricia A.

AU - He, Wei

AU - Heikkilä, Päivi

AU - Hooning, Maartje J.

AU - Hoppe, Reiner

AU - Howell, Anthony

AU - Humphreys, Keith

AU - Amor, David

AU - Andrews, Lesley

AU - Antill, Yoland

AU - Balleine, Rosemary

AU - Beesley, Jonathan

AU - Bennett, Ian

AU - Bogwitz, Michael

AU - Botes, Leon

AU - Brennan, Meagan

AU - Brown, Melissa

AU - Buckley, Michael

AU - Burke, Jo

AU - Butow, Phyllis

AU - Caldon, Liz

AU - Campbell, Ian

AU - Cao, Michelle

AU - Chakrabarti, Anannya

AU - Chauhan, Deepa

AU - Chauhan, Manisha

AU - Christian, Alice

AU - Cohen, Paul

AU - Colley, Alison

AU - Crook, Ashley

AU - Cui, James

AU - Courtney, Eliza

AU - Cummings, Margaret

AU - Dawson, Sarah Jane

AU - DeFazio, Anna

AU - Delatycki, Martin

AU - Dickson, Rebecca

AU - Dixon, Joanne

AU - Edkins, Ted

AU - Edwards, Stacey

AU - Farshid, Gelareh

AU - Fellows, Andrew

AU - Fenton, Georgina

AU - Field, Michael

AU - Flanagan, James

AU - Fong, Peter

AU - Forrest, Laura

AU - Fox, Stephen

AU - French, Juliet

AU - Friedlander, Michael

AU - Gaff, Clara

AU - Gattas, Mike

AU - George, Peter

AU - Greening, Sian

AU - Harris, Marion

AU - Hart, Stewart

AU - Hayward, Nick

AU - Hopper, John

AU - Hoskins, Cass

AU - Hunt, Clare

AU - James, Paul

AU - Jenkins, Mark

AU - Kidd, Alexa

AU - Kirk, Judy

AU - Koehler, Jessica

AU - Kollias, James

AU - Lakhani, Sunil

AU - Lawrence, Mitchell

AU - Lee, Jason

AU - Li, Shuai

AU - Lindeman, Geoff

AU - Lipton, Lara

AU - Lobb, Liz

AU - Loi, Sherene

AU - Mann, Graham

AU - Marsh, Deborah

AU - McLachlan, Sue Anne

AU - Meiser, Bettina

AU - Nightingale, Sophie

AU - O'Connell, Shona

AU - O'Sullivan, Sarah

AU - Ortega, David Gallego

AU - Pachter, Nick

AU - Pang, Jia Min

AU - Pathak, Gargi

AU - Patterson, Briony

AU - Pearn, Amy

AU - Phillips, Kelly

AU - Pieper, Ellen

AU - Ramus, Susan

AU - Rickard, Edwina

AU - Robinson, Bridget

AU - Saleh, Mona

AU - Skandarajah, Anita

AU - Salisbury, Elizabeth

AU - Saunders, Christobel

AU - Saunus, Jodi

AU - Scott, Rodney

AU - Scott, Clare

AU - Sexton, Adrienne

AU - Shelling, Andrew

AU - Simpson, Peter

AU - Southey, Melissa

AU - Spurdle, Amanda B.

AU - Taylor, Jessica

AU - Taylor, Renea

AU - Thorne, Heather

AU - Trainer, Alison

AU - Tucker, Kathy

AU - Visvader, Jane

AU - Walker, Logan

AU - Williams, Rachael

AU - Winship, Ingrid

AU - Young, Mary Ann

AU - Zaheed, Milita

AU - Jakubowska, Anna

AU - Jung, Audrey Y.

AU - Keeman, Renske

AU - Kristensen, Vessela N.

AU - Lubiński, Jan

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Mavroudis, Dimitrios

AU - Milne, Roger

AU - Mulligan, Anna Marie

AU - Newman, William G.

AU - Park-Simon, Tjoung Won

AU - Peterlongo, Paolo

AU - Pharoah, Paul D.P.

AU - Rhenius, Valerie

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K.

AU - Shah, Mitul

AU - Spurdle, Amanda B.

AU - Tomlinson, Ian

AU - Truong, Thérèse

AU - van Veen, Elke M.

AU - Vreeswijk, Maaike P.G.

AU - Wang, Qin

AU - Wendt, Camilla

AU - Yang, Xiaohong R.

AU - Nevanlinna, Heli

AU - Devilee, Peter

AU - Easton, Douglas F.

AU - Schmidt, Marjanka K.

AU - NBCS Collaborators

AU - kConFab Investigators

PY - 2023/3/2

Y1 - 2023/3/2

N2 - 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.

AB - 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.

KW - breast cancer susceptibility genes

KW - coding germline variants

KW - contralateral breast cancer risk

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85149226266&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2023.02.003

DO - 10.1016/j.ajhg.2023.02.003

M3 - Article

AN - SCOPUS:85149226266

SN - 0002-9297

VL - 110

SP - 475

EP - 486

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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