TY - JOUR

T1 - Pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes

AU - Mavaddat, Nasim

AU - Dorling, Leila

AU - Carvalho, Sara

AU - Allen, Jamie

AU - González-Neira, Anna

AU - Keeman, Renske

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Wang, Qin

AU - Ahearn, Thomas U.

AU - Andrulis, Irene L.

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Briceno, Ignacio

AU - Brüning, Thomas

AU - Camp, Nicola J.

AU - Campbell, Archie

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chenevix-Trench, Georgia

AU - Christiansen, Hans

AU - Czene, Kamila

AU - Dörk, Thilo

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine D.

AU - Flyger, Henrik

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - Geisler, Jürgen

AU - Giles, Graham G.

AU - Guénel, Pascal

AU - Hadjisavvas, Andreas

AU - Hahnen, Eric

AU - Hall, Per

AU - Hamann, Ute

AU - Hartikainen, Jaana M.

AU - Hartman, Mikael

AU - Hoppe, Reiner

AU - Howell, Anthony

AU - Jakubowska, Anna

AU - Jung, Audrey

AU - Khusnutdinova, Elza K.

AU - Breast Cancer Association Consortium

N1 - Publisher Copyright: © 2022 American Medical Association

PY - 2022

Y1 - 2022

N2 - 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 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.

AB - 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 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.

UR - http://www.scopus.com/inward/record.url?scp=85124213071&partnerID=8YFLogxK

U2 - 10.1001/jamaoncol.2021.6744

DO - 10.1001/jamaoncol.2021.6744

M3 - Journal article

C2 - 35084436

AN - SCOPUS:85124213071

VL - 8

JO - JAMA Oncology

JF - JAMA Oncology

SN - 2374-2437

IS - 3

M1 - e216744

ER -