Abstract GS03-11: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity
Authors: Houlahan Kathleen , Khan Aziz , Greenwald Noah , West Robert , Angelo Michael , Curtis Christina 
Published: May 2024

Abstract
Background: Somatic genomic aberrations are acquired within the context of germline genomes which differ across individuals at millions of polymorphic sites. However, the role of germline variation in somatic evolution remains poorly understood. The most compelling example is is that deleterious germline variants in BRCA1 and, to a lesser extent, BRCA2 are preferentially associated with the development of triple-negative breast cancer (BC). The variable frequency of BC subtypes across ancestral populations further suggests a role for germline contributions. On the other hand, various lines of evidence indicate that avoidance of the adaptive immune system is a strong determinant of which somatic mutations persist within a tumor. Whether and how germline differences influence immunoediting has not been studied. Building on these observations, we sought to investigate whether germline variation mediates somatic evolution through immunoediting. Specifically, we hypothesize inherited variation in oncogenes would be subject to varied immunoediting pressures during malignant transformation and progression. A high burden of germline-derived epitopes in recurrently amplified oncogenes is predicted to select against amplification of the cognate gene during malignant transformation because this would increase epitope availability, the likelihood of epitope presentation, and immune-mediated cell death. Instead, immune pressures may select for amplification of an alternate driver gene with a lower germline-mediated epitope burden. We evaluated this hypothesis in a collection of 3,855 BC, spanning ductal carcinoma in situ (DCIS) to invasive BC, and metastatic lesions. Methods: We analyzed paired tumor and normal sequencing data from 1,087 primary and 702 metastatic breast cancer patients as well as somatic genomic profiles from 341 patients with DCIS using a novel algorithm to estimate germline-derived epitope burden (GEB) based on an individual’s genotype and class 1 HLA alleles. The relationship between GEB and subtype commitment, defined by the acquisition of focal oncogenic amplifications in five prognostic subgroups of BC: HER2+ disease and four high-risk of relapse ER+/HER2 integrative subgroups/clusters (ICs) which we previously described (IC1: 17q23, IC2: 11q13, IC6: 8p12, and IC9: 8q24) was evaluated. Specifically, we evaluated the association between the GEB per gene and whether an individual developed the corresponding subtype via logistic regression, correcting for the first six genetic principal components and somatic mutation burden. Outcome associations were evaluated via Cox Proportional Hazards Models. Results: Interrogating 3,855 breast cancer lesions, we demonstrate that germline-derived epitopes in recurrently amplified genes influence somatic evolution by mediating immunoediting. Individuals with a high GEB in ERBB2/HER2 are significantly less likely to develop HER2-positive breast cancer compared to other subtypes. The same holds true for recurrent amplicons that define four aggressive, high-risk of relapse, ER-positive integrative subgroups. Thus, GEB selects against cognate oncogene amplification. Tumors that overcome such immune-mediated negative selection are more aggressive and exhibited microenvironments depleted of lymphocytes, consistent with “immune cold” tumors. Conclusions: We demonstrate that inherited variation sculpts breast cancer subtypes, aggressivity, and immune landscapes by mediating anti-tumor immune responses. The implications of these findings are severalfold. First, GEB is prognostic, complementing other molecular measurements. Second, immunoediting pressures differ across the disease course, with implications for the timing of therapeutic interventions. Third, these data illuminate a broad source of currently under-appreciated immunogenic antigens.
Citation Format: Kathleen Houlahan, Aziz Khan, Noah Greenwald, Robert West, Michael Angelo, Christina Curtis. Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-11.