Pathology of tumors associated with pathogenic germline variants in nine breast cancer susceptibility genes

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Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contribution 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: Case-control; BRIDGES study
Setting: Multicenter, international
Participants: 42,680 cases and 46,387 controls, women aged 18-79 years, sampled
independently of family history, from 38 studies.
Exposures: Protein truncating variants (PTVs) and likely pathogenic missense variants
(MSVs) in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.
Main Outcomes and Measures: BC ‘intrinsic-like’ subtypes as defined by ER, PR, HER2
status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying PTVs and pathogenic MSVs in the nine BC susceptibility genes.
Results: Mean ages at interview (controls) and diagnosis (cases) were 55.1 and 55.8 years respectively. 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)+HER2─highgrade subtype (OR=4.99, 95%CI:3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but 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+HER2+, and HR─HER2+subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes a decline in OR was observed with increasing age. Together the nine genes contributed to 27.3% of all triple-negative tumors in women age 40 years.
Conclusions and Relevance: Variants in the nine 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 aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.
Original languageEnglish
JournalJAMA oncology
Publication statusAccepted/In press - 19 Oct 2021


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