Pathology of Tumors Associated with Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Nasim Mavaddat*, Leila Dorling, Sara Carvalho, Jamie Allen, Anna González-Neira, Renske Keeman, Manjeet K. Bolla, Joe Dennis, Qin Wang, Thomas U. Ahearn, Irene L. Andrulis, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Ignacio Briceno, Thomas BrüningNicola J. Camp, Archie Campbell, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Hans Christiansen, Kamila Czene, Thilo Dörk, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Jürgen Geisler, Graham G. Giles, Pascal Guénel, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Jaana M. Hartikainen, Mikael Hartman, Reiner Hoppe, Anthony Howell, Anna Jakubowska, Audrey Jung, Elza K. Khusnutdinova, Vessela N. Kristensen, Jingmei Li, Swee Ho Lim, Annika Lindblom, Maria A. Loizidou, Artitaya Lophatananon, Jan Lubiński, Michael J. Madsen, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Nur Aishah Mohd Taib, Anna Morra, Kenneth Muir, Nadia Obi, Ana Osorio, Tjoung Won Park-Simon, Paolo Peterlongo, Paolo Radice, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Xueling Sim, Melissa C. Southey, Heather Thorne, Ian Tomlinson, Diana Torres, Thérèse Truong, Cheng Har Yip, Amanda B. Spurdle, Maaike P.G. Vreeswijk, Alison M. Dunning, Montserrat García-Closas, Paul D.P. Pharoah, Anders Kvist, Taru A. Muranen, Heli Nevanlinna, Soo Hwang Teo, Peter Devilee, Marjanka K. Schmidt, Douglas F. Easton

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)


Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. Objective: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. Design, Setting, and Participants: The multicenter, international case-control analysis of the BRIDGES study included 42680 patients and 46387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. Exposures: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. Main Outcomes and Measures: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. Results: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2-high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+and HR-ERBB2+subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. Conclusions and Relevance: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

Original languageEnglish
JournalJAMA oncology
Issue number3
Publication statusPublished - 2022


Dive into the research topics of 'Pathology of Tumors Associated with Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes'. Together they form a unique fingerprint.

Cite this