Paper
Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity
Published May 31, 2024 · Kathleen E. Houlahan, Aziz Khan, Noah F. Greenwald
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Abstract
Tumors with the same diagnosis can have different molecular profiles and response to treatment. It remains unclear when and why these differences arise. Somatic genomic aberrations occur within the context of a highly variable germline genome. Interrogating 5870 breast cancer lesions, we demonstrated that germline-derived epitopes in recurrently amplified genes influence somatic evolution by mediating immunoediting. Individuals with a high germline-epitope burden in human epidermal growth factor receptor 2 (HER2/ERBB2) are less likely to develop HER2-positive breast cancer compared with other subtypes. The same holds true for recurrent amplicons defining three aggressive estrogen receptor (ER)–positive subgroups. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an “immune cold” phenotype. These data show that the germline genome plays a role in dictating somatic evolution. Editor’s summary Cancers such as HER2-positive breast cancer are typically characterized by their location and marker proteins that influence how they behave and what treatments they respond to. However, not all cancers or tumors that nominally fall into a single category behave the same way. Some of these differences are caused by genetically encoded attributes affecting the tumor’s interactions with the immune system, as shown by Houlahan et al. (see the Perspective by Waddell and Addala). The authors demonstrated that a patient’s germline variants in an oncogene of interest, such as HER2, as well as their human leukocyte antigens responsible for the presentation of antigens to T cells, help to determine which tumors might survive and which ones will likely be destroyed by the patient’s immune system. —Yevgeniya Nusinovich INTRODUCTION Cancer is defined by a set of abnormal biological capacities, termed the “hallmarks of cancer,” which can be acquired by hijacking various cellular processes. As a result, tumors with the same clinical characteristics can vary dramatically across individuals, and these distinct molecular vulnerabilities can have important prognostic and therapeutic implications. Oncogenic alterations are acquired within the context of an individual’s inherited DNA—known as the germline genome—which differ across individuals at millions of polymorphic sites. It remains poorly understood how inherited variants impact the evolution of a tumor. The most compelling example is that deleterious germline variants in BRCA1 and, to a lesser extent, BRCA2, are preferentially associated with the development of triple negative breast cancer and estrogen receptor (ER)–positive (ER+) breast cancer, respectively, implying that germline variants modulate specific subtypes of disease. The mechanistic basis for this preference is incompletely characterized. Various lines of evidence suggest that avoidance of the adaptive immune system determines which somatic mutations persist within a tumor. It remains less clear how germline differences influence immunoediting. Generally, germline variants have not been considered a source of immunogenic epitopes because cytotoxic response should be dampened by central and peripheral tolerance. However, nonmutated immunogenic epitopes have been identified in genes such as ERBB2 in breast and ovarian cancer and H4 histone in prostate cancer, among others, suggesting that germline variants may play a role in immunosurveillance. RATIONALE We sought to investigate whether germline variants sculpt somatic evolution by mediating immunoediting. Specifically, we hypothesized that the burden of germline-derived epitopes in recurrently amplified driver genes may select against somatic gene amplification. This is because amplification of a gene with a high burden of germline-derived epitopes would increase epitope availability, likelihood of epitope presentation, and immune-mediated cell death. Thus, somatic amplification of the gene would come at a fitness cost in cells with a high burden of germline-derived epitopes. Instead, a tumor may favor an alternative oncogenic pathway with lower fitness costs. RESULTS We leveraged paired tumor and normal sequencing data from 4918 primary and 611 metastatic breast cancer patients, as well as somatic genomic profiles from 341 patients with ductal carcinoma in situ (DCIS), and evaluated the relationship between germline-derived epitope burden (GEB) and subtype commitment, defined by the acquisition of focal oncogenic amplifications. As proof of concept, we identified two immunogenic peptides derived from the germline sequence of human epidermal growth factor receptor 2 (HER2; peptides GP2 and E75) and hypothesized that the ability to present either peptide would be negatively associated with developing HER2+ breast cancer. We discovered that individuals who possess MHC class I alleles that can bind and present GP2 or E75 are less likely to develop HER2+ breast cancer than other breast cancer subtypes. In addition to GP2 and E75, we found that individuals with a high GEB in ERBB2, encoding HER2, are less likely to develop HER2+ breast cancer. The same negative association was observed for three recurrent amplicons observed in distinct ER+ breast cancers, which are characterized by high risk of relapse. Negative associations were robust to the definition of subtype, binding affinity threshold, and the algorithm to predict binding affinity. Tumors that overcame immune-mediated negative selection were more aggressive and exhibited microenvironments depleted of lymphocytes. In DCIS, before immune escape, high GEB was negatively associated with invasive breast cancer recurrence, suggesting that GEB is protective in the preinvasive setting. CONCLUSION These data indicate that supposedly “benign” germline variants with little to no functional genic effect may, in aggregate, sculpt breast cancer subtypes and disease aggression through immunoediting. These data also indicate that immunoediting pressures differ during the course of a patient’s disease, potentially informing the timing of therapeutic interventions. Exploiting germline-mediated immunoediting may inform the development of biomarkers that predict risk of invasive breast cancer recurrence and further refine risk stratification within invasive breast cancer subtypes. Germline-mediated immunoediting sculpts cancer subtypes and metastatic proclivity. During tumorigenesis, lesions with high GEB in cancer genes are less likely to acquire somatic amplification of that gene. In preinvasive breast tumors, high GEB is protective against invasive breast cancer (IBC) recurrence. However, established tumors that acquire somatic amplification are forced to develop an immune suppressive and evasive phenotype and are more aggressive [Figure created using Biorender.com].
Germline variants in breast cancer genes can influence tumor evolution and aggressiveness by influencing immune responses, potentially guiding therapeutic interventions and predicting recurrence risk.
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