Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes

Mavaddat, Nasim and Dorling, Leila and Carvalho, Sara and Allen, Jamie and Gonzalez-Neira, Anna and Keeman, Renske and Bolla, Manjeet K. and Dennis, Joe and Wang, Qin and Ahearn, Thomas U. and Andrulis, Irene L. and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Blomqvist, Carl and Bogdanova, Natalia and Bojesen, Stig E. and Briceno, Ignacio and Bruning, Thomas and Camp, Nicola J. and Campbell, Archie and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Chenevix-Trench, Georgia and Christiansen, Hans and Czene, Kamila and Dork, Thilo and Eriksson, Mikael and Evans, D. Gareth and Fasching, Peter A. and Figueroa, Jonine D. and Flyger, Henrik and Gabrielson, Marike and Gago-Dominguez, Manuela and Geisler, Jurgen and Giles, Graham G. and Guenel, Pascal and Hadjisavvas, Andreas and Hahnen, Eric and Hall, Per and Hamann, Ute and Hartikainen, Jaana M. and Hartman, Mikael and Hoppe, Reiner and Howell, Anthony and Jakubowska, Anna and Jung, Audrey and Khusnutdinova, Elza K. and Kristensen, Vessela N. and Li, Jingmei and Lim, Swee Ho and Lindblom, Annika and Loizidou, Maria A. and Lophatananon, Artitaya and Lubinski, Jan and Madsen, Michael J. and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Mavroudis, Dimitrios and Milne, Roger L. and Mohd Taib, Nur Aishah and Morra, Anna and Muir, Kenneth and Obi, Nadia and Osorio, Ana and Park-Simon, Tjoung-Won and Peterlongo, Paolo and Radice, Paolo and Saloustros, Emmanouil and Sawyer, Elinor J. and Schmutzler, Rita K. and Shah, Mitul and Sim, Xueling and Southey, Melissa C. and Thorne, Heather and Tomlinson, Ian and Torres, Diana and Truong, Therese and Yip, Cheng Har and Spurdle, Amanda B. and Vreeswijk, Maaike P. G. and Dunning, Alison M. and Garcia-Closas, Montserrat and Pharoah, Paul D. P. and Kvist, Anders and Muranen, Taru A. and Nevanlinna, Heli and Teo, Soo Hwang and Devilee, Peter and Schmidt, Marjanka K. and Easton, Douglas F. and Consortium, Breast Canc Assoc (2022) Pathology of tumors associated with Pathogenic Germline Variants in 9 breast cancer susceptibility genes. Jama Oncology, 8 (3). DOI

Full text not available from this repository.


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 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991and 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.

Item Type: Article
Funders: Wellcome Trust [Grant No: 216767/Z/19/Z]
Uncontrolled Keywords: Rare germline genetic variants; Breast cancer; Risk prediction; Gene panel testing
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Medicine > Surgery Department
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 06 Sep 2023 03:56
Last Modified: 06 Sep 2023 03:56

Actions (login required)

View Item View Item