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
PY - 2022/3/1
Y1 - 2022/3/1
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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Breast Neoplasms/genetics
KW - Case-Control Studies
KW - Female
KW - Genes, BRCA2
KW - Genetic Predisposition to Disease
KW - Germ Cells
KW - Germ-Line Mutation
KW - Humans
KW - Middle Aged
KW - Young Adult
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
SN - 2374-2437
VL - 8
SP - e216744
JO - JAMA Oncology
JF - JAMA Oncology
IS - 3
ER -