Cells that carry BRCA1/2 germline mutations have a high degree of genomic instability due to dysfunctional HR repair mechanisms and consequently a high TMB. High TMB has been associated with immunogenicity and response to immune checkpoint inhibitors such PD–1/PD-L1 antibodies in melanoma and lung cancer . We found that breast and ovarian cancers from the clinical trial #NCT01623349, which carry BRCA1/2 germline mutation, as well as germline mutation carriers from TCGA database had a high TMB as reported previously [40,41] but did not score high on overall immune activity and PD-L1 expression relative to non-carriers. These data are consistent with recently published larger cohorts  who also reported no increase in PD-L1 expression or TILs in BRCA1-like tumors. However, it has to be kept in mind that the TMB in breast and ovarian cancers, even that from BRCA1 germline mutation carriers, is an order of magnitude lower compared to hypermutated cancers such as melanoma and lung cancer (The Cancer Immunome Atlas (TCIA) https://tcia.at/home). A lack of a positive correlation between TMB and immune infiltration in various types of tumors was recently described by others . There are at least two possible caveats for the evaluation of TMB from genomic data. For one, the sequencing data is prone to inconsistencies due to various ways of processing NGS data and diverse criteria for relevant mutations . Secondly, DNA sequencing data for highly immune infiltrated tumors can be affected by the immune cell “contamination”, reducing the readings for genomic instability.
The breast and ovarian cancers from BRCA1/2 germline mutation carriers show a unique responsiveness to PARP-inhibition and it was suggested that they express distinctive phenotype, which they share with some sporadic breast and ovarian cancers . Hence, the idea of “BRCAness”. We have addressed the extent of “BRCAness” phenotype in hereditary and sporadic TNBC and HGSOC from TCGA database. According to our results, “BRCAness” is not a unique phenotype of BRCA1/2 mutation carriers, but rather an attribute of majority of HGSOC and of a few subtypes of sporadic TNBC, which also happened to be the most frequent subtypes found within hereditary BRCA1 germline mutation carriers (BL1 and M). BRCA2 germline mutation related breast cancers on the other hand, do not express any “BRCAness” features except high genomic instability, and express the range of PAM50 phenotypes, similar to all sporadic breast cancers . Consequently, the subtyping criteria developed for sporadic tumors can be applied for identifying “BRCAness” in sporadic and germline mutation associated tumors.
While BRCA1/2 related hereditary tumors may not have a unique phenotype, the breast cancers that carry BRCA1/2 deficiency have a unique genotype characterized by distinctive mutation profile [22,23]. Distinct copy number signature (“BRCA1-like”) is also shared between cancers related to germline mutation in BRCA1 gene and sporadic cancers whose BRCA1 protein was inactivated through other mechanisms [47,48]. Remarkably, the “BRCA1-like” subgroup distinguished with the copy number criteria had down regulated expression of proteins related to immune functions and was associated mostly with BL1 and M subtypes of Lehmann .
The global immune activity varies widely between breast and ovarian cancer subtypes and the immune microenvironments are heterogenous. Especially interesting finding is that two subtypes of TNBC (BL1 and M), which score high on “BRCAness” and are the most prevalent in hereditary BRCA1 germline mutation carriers have fundamentally different immune profiles, predominantly C2 and C1, respectively. The data suggest that the diversity of immune responses in the microenvironments of hereditary and sporadic TNBC and HGSOC may be associated with their particular phenotypes. In this respect, the subtyping of breast and ovarian tumors according to criteria developed for sporadic tumors may also be useful for testing various immune interventions. In our clinical trial samples, the majority of non-carriers expressed at diagnosis the C3 inflammatory immune profile, defined by elevated Th17 and Th1 genes, while majority of carriers expressed C1 wound healing profile. Further studies, with bigger cohorts, are needed to confirm this finding and to explore its significance.
In iAtlas, germline mutation carriers had the highest degree of HR deficiency of all breast and ovarian cancers. However, the surprising finding was that all ovarian cancers and almost all TNBC (with exception of LAR subtype), but not ER+ or HER2+ breast cancers, had a high degree of HR deficiency as well. This could explain the sensitivity of those tumors (TNBC and HGSOC) to DNA damaging chemotherapy and PARP inhibition. Indeed, we have shown that the platinum sensitive HGSOC from TCGA had significantly higher HR deficiency compared to resistant tumors. Similar results were obtained by Telli et al. Their study included both TNBC and ovarian cancers and used combined HR deficiency score, defined in a similar way as the HR score provided in iAtlas . They suggested a clinical application of the score to identify TNBC (not deficient in BRCA1/2), which likely respond to platinum. If we apply their criteria for response, (HRD score 42), only two subtypes (BL1 and M) of sporadic TNBC and most of the subtypes of HGSOC will qualified as possibly sensitive to the therapy. Interestingly, the ovarian cancers from TCGA database, sensitive to platinum had HRD score above 42 (46.5) and resistant tumors had the score below 42 (36.4). Thus, our results validated the HR deficiency score as candidate biomarker for resistance to platinum.
BRCA1/2 germline related breast and ovarian cancers have the highest HR deficiency score of 33 tumor types analyzed in iAtlas and rather low mutational burden relative to hypermutated tumors (Cancer Research Institute iAtlas https://www.cri-iatlas.org/about/). We have found that they also show a low aneuploidy score relative to sporadic tumors. The low CNV load was also evident, but only in BRCA2 related breast and ovarian cancers. Genomic instability is the outcome of few processes going on simultaneously: DNA damage, DNA repair and immunoediting that is the clearance of cells with unrepaired damage by the immune system . In BRCA1/2 germline mutation related tumors relatively low TMB (compared to hypermutated tumors) may be explained by effective immunoediting, rather than by effective DNA repair. It is tempting to speculate that immunoediting can compensate for the lack of adequate repair. If so, the immunoediting will have particular impact on hereditary tumors or sporadic tumors with BRCA1/2 dysfunction . In support of this, low aneuploidy in BRCA1/2 germline related breast and ovarian cancers may also suggest more active immunosurveillence against cancer associated hyperploidy [52–54]. Active immunoediting in tumors from BRCA1/2 germline mutation carries may be consistent with a positive response to immune therapies in TNBC tumors despite the fact that they have relatively low TMB .
Looking from immune-centric point of view on patients with BRCA1/2 germline mutations, one wonders how BRCA1/2 deficiency influences the systemic immunity independent of its role in breast and ovarian tumorigenesis? Indeed, B-cell differentiation and maturation requires DDR  and BRCA1 protein have a direct role in B cells lymphomagenesis  suggesting the possible alterations in the systemic immunity of germline mutation carriers. In keeping with this, BRCA1/2 germline mutation carriers have higher risk of developing certain leukemias and lymphomas [58,59].
The possibility of systemic immunity playing a role in tumorigenesis in the carriers of BRCA1/2 germline mutations was already suggested by others. It has been shown that DNA damage in cells that carry BRCA1/2 germline mutation was often overestimated and can hardly account for tumorigenesis . Therefore, it was proposed that other factors, such as local inflammation and/or viral infections may put stress on immune system, which is already compromised by the germline mutation and promote the tumor formation in specific tissues such as breast and ovaries .
Cancer immunosuiveillence has been studied extensively for the last decade leading to the successful immune therapies . Even though the immunotherapies are aimed at tumor microenvironment, systemic immunity is required for the process of tumor rejection after the therapy . Thus, better understanding of the effects of cancer promoting hereditary mutations on the function of the systemic immunity may be very important. It can help to develop better immunotherapeutic strategies and new approaches for preventing and/or delaying the hereditary cancer, giving hope to many affected families.