. 2025 Apr 1;117(4):728-736.

doi: 10.1093/jnci/djae306.

Childhood, adolescent, and young adulthood cancer risk in BRCA1 or BRCA2 pathogenic variant carriers

Shuai Li^{1

2

3}, Laura Madanat-Harjuoja^{4

5}, Goska Leslie³, Daniel R Barnes³, Manjeet K Bolla³, Joe Dennis³, Michael T Parsons⁶, Paraskevi Apostolou⁷, Norbert Arnold^{8

9}, Kristin Bosse¹⁰; EMBRACE Collaborators; Jackie Cook¹¹, Christoph Engel^{12

13}, D Gareth Evans^{14

15}, Florentia Fostira⁷, Megan N Frone¹⁶, Andrea Gehrig¹⁷, Mark H Greene¹⁶, Karl Hackmann¹⁸, Eric Hahnen^{19

20}, Nadia Harbeck²¹, Jan Hauke^{19

20

22}, Julia Hentschel²³, Judit Horvath²⁴, Louise Izatt²⁵, Marion Kiechle²⁶, Irene Konstantopoulou⁷, Fiona Lalloo²⁷, Joanne Ngeow^{28

29}, Dieter Niederacher³⁰, Julia Ritter³¹, Marta Santamariña^{32

33

34}, Rita K Schmutzler^{19

20

22}, Claire Searle³⁵, Christian Sutter³⁶, Marc Tischkowitz^{37

38}, Vishakha Tripathi²⁵, Ana Vega^{32

33

34}, Hannah Wallaschek³⁹, Shan Wang-Gohrke⁴⁰, Barbara Wappenschmidt^{19

20}, Bernhard H F Weber^{41

42}, Drakoulis Yannoukakos⁷, Emily Zhao³, Douglas F Easton^{3

43}, Antonis C Antoniou³, Georgia Chenevix-Trench⁴⁴, Timothy R Rebbeck^{45

46}, Lisa R Diller^{47

48}

Collaborators, Affiliations

Collaborators

Affiliations

¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
⁴ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki 00029, Finland.
⁵ Finnish Cancer Registry, Helsinki 00130, Finland.
⁶ Public Health Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁷ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens 15310, Greece.
⁸ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, Kiel 24105, Germany.
⁹ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, Kiel 24118, Germany.
¹⁰ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72074, Germany.
¹¹ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, United Kingdom.
¹² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany.
¹³ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany.
¹⁴ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.
¹⁵ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850-9772, United States.
¹⁷ Department of Human Genetics, University Würzburg, Würzburg 97074, Germany.
¹⁸ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden, Dresden, TU 01307, Germany.
¹⁹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
²⁰ Center for Integrated Oncology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
²¹ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich 81377, Germany.
²² Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
²³ Institute of Human Genetics, University Hospital Leipzig, Leipzig 04103, Germany.
²⁴ Institute of Human Genetics, University of Münster, Münster 48149, Germany.
²⁵ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
²⁶ Department of Gynaecology and Obstetrics, University Hospital Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich 80333, Germany.
²⁷ Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom.
²⁸ Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore.
²⁹ Cancer Genetics Service, National Cancer Centre, 169610, Singapore.
³⁰ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.
³¹ Institute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin 13353, Germany.
³² Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
³³ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela 15706, Spain.
³⁴ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela 15706, Spain.
³⁵ Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, United Kingdom.
³⁶ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg 69120, Germany.
³⁷ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
³⁸ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC H4A 3J1, Canada.
³⁹ Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.
⁴⁰ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany.
⁴¹ Institute of Human Genetics, University Regensburg, Regensburg 93053, Germany.
⁴² Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg 93053, Germany.
⁴³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
⁴⁴ Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁴⁵ Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States.
⁴⁶ Dana-Farber Cancer Institute, Boston, MA 02115, United States.
⁴⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, United States.
⁴⁸ Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States.

PMID: 39585318
PMCID: PMC11972678 (available on 2025-11-25)
DOI: 10.1093/jnci/djae306

Childhood, adolescent, and young adulthood cancer risk in BRCA1 or BRCA2 pathogenic variant carriers

Shuai Li et al. J Natl Cancer Inst. 2025.

. 2025 Apr 1;117(4):728-736.

doi: 10.1093/jnci/djae306.

Authors

Collaborators

Affiliations

¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
⁴ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki 00029, Finland.
⁵ Finnish Cancer Registry, Helsinki 00130, Finland.
⁶ Public Health Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁷ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens 15310, Greece.
⁸ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, Kiel 24105, Germany.
⁹ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, Kiel 24118, Germany.
¹⁰ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72074, Germany.
¹¹ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, United Kingdom.
¹² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany.
¹³ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany.
¹⁴ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.
¹⁵ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850-9772, United States.
¹⁷ Department of Human Genetics, University Würzburg, Würzburg 97074, Germany.
¹⁸ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden, Dresden, TU 01307, Germany.
¹⁹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
²⁰ Center for Integrated Oncology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.
²¹ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich 81377, Germany.
²² Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
²³ Institute of Human Genetics, University Hospital Leipzig, Leipzig 04103, Germany.
²⁴ Institute of Human Genetics, University of Münster, Münster 48149, Germany.
²⁵ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
²⁶ Department of Gynaecology and Obstetrics, University Hospital Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich 80333, Germany.
²⁷ Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom.
²⁸ Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore.
²⁹ Cancer Genetics Service, National Cancer Centre, 169610, Singapore.
³⁰ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.
³¹ Institute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin 13353, Germany.
³² Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
³³ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela 15706, Spain.
³⁴ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela 15706, Spain.
³⁵ Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, United Kingdom.
³⁶ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg 69120, Germany.
³⁷ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
³⁸ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC H4A 3J1, Canada.
³⁹ Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.
⁴⁰ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany.
⁴¹ Institute of Human Genetics, University Regensburg, Regensburg 93053, Germany.
⁴² Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg 93053, Germany.
⁴³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
⁴⁴ Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁴⁵ Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States.
⁴⁶ Dana-Farber Cancer Institute, Boston, MA 02115, United States.
⁴⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, United States.
⁴⁸ Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States.

PMID: 39585318
PMCID: PMC11972678 (available on 2025-11-25)
DOI: 10.1093/jnci/djae306

Abstract

Background: Whether carriers of BRCA1 or BRCA2 pathogenic variants have increased risks of childhood, adolescent, and young adult cancers is controversial. We aimed to evaluate this risk and to inform clinical care of young BRCA1 and BRCA2 pathogenic variant carriers and genetic testing for childhood, adolescent, and young adult cancer patients.

Methods: Using data from 47 117 individuals from 3086 BRCA1 or BRCA2 families, we conducted pedigree analysis to estimate relative risks (RRs) for cancers diagnosed before age 30 years.

Results: Our data included 274 cancers diagnosed before age 30 years: 139 breast cancers, 10 ovarian cancers, and 125 nonbreast nonovarian cancers. Associations for breast cancer in young adulthood (aged 20-29 years) were found with relative risks of 11.4 (95% confidence interval [CI] = 5.5 to 23.7) and 5.2 (95% CI = 1.6 to 17.7) for BRCA1 and BRCA2 pathogenic variant carriers, respectively. No association was found for any other investigated childhood, adolescent, and young adult cancer or for all nonbreast nonovarian cancers combined; the relative risks were 0.4 (95% CI = 0.1 to 1.4) and 1.4 (95% CI = 0.7 to 3.0) in BRCA1 and BRCA2 pathogenic variant carriers, respectively.

Conclusion: We found no evidence that BRCA1 and BRCA2 pathogenic variant carriers have an increased childhood, adolescent, and young adult cancer risk aside from breast cancer in women aged between 20 and 30 years. Our results, along with a critical evaluation of previous germline sequencing studies, suggest that the childhood and adolescent cancer risk conferred by BRCA1 and BRCA2 pathogenic variant would be low (ie, RR < 2) if it existed. Our findings do not support pathogenic variant testing for offspring of BRCA1 and BRCA2 pathogenic variant carriers at ages younger than 18 years or for conducting BRCA1 and BRCA2 pathogenic variant testing for childhood and adolescent cancer patients.

© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

D.G.E. receives consultancy honorarium from Everything Genetic Ltd that is not related to this work. N.H. receives honoraria for lectures and/or consulting that is not related to this work, from Amgen, AstraZeneca, Daiichi-Sankyo, EPG Communication, Gilead, Lilly, MEDSCAPE, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Springer, Viatris, and Zuelligpharma. M.K. has the following that is not related to this work: remunerations from Springer Press, Biermann Press, Celgene, Astra Zeneca, Myriad Genetics, TEVA, Eli Lilly, GSK, GSK, Seagen, and AllergoSan, FOMF; consultant/advisory roles in Myriad Genetics, Bavarian KVB, DKMS Life, BLAEK, TEVA, Exeltis, and BESINS; equity owners of Therawis Diagnostic GmbH and AIM GmbH; funding from Sphingotec, Deutsche Krebshilfe, DFG, Senator Roesner Foundation, Dr Pommer-Jung Foundation, Waltraut Bergmann Foundation, Bavarian State Ministry of Economy, BMBF, and Innovation Fond GBA. J.NYY. receives research funding from AstraZeneca that is not related to this work. The other authors have no conflict of interest to declare.

Comment in

BRCA1/2 germline sequencing in children and adolescents with cancer: it is the context that matters.
Goudie C. Goudie C. J Natl Cancer Inst. 2025 Apr 1;117(4):580-582. doi: 10.1093/jnci/djae339. J Natl Cancer Inst. 2025. PMID: 39847476 No abstract available.

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Childhood, adolescent, and young adulthood cancer risk in BRCA1 or BRCA2 pathogenic variant carriers

Collaborators

Affiliations

Childhood, adolescent, and young adulthood cancer risk in BRCA1 or BRCA2 pathogenic variant carriers

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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