An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

Abstract

Background: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD. Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. Trial registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

“…However, our functional analysis revealed a series of novel details. In ovarian cancers, we find an enhanced immune signature in somatic BRCA1 and germline BRCA2 carriers in agreement with previous reports [ 61 ], in which, however, differentiation between mutation types has not been explored. The most profound differences in ovarian cancers were observed between the transcriptomes of germline and somatic BRCA2 mutated cases.…”

“…Finally, we observed considerable differences in the deregulation of transcriptome for the same mutation when comparing breast and ovarian cancers. Consistent with previous reports BRCA mutations in breast cancer were mostly associated with regulation of cell cycle, DNA damage, and cell proliferation in breast cancer [71], and with immune system-related processes in ovarian cancer [61], which may be an indicator of differential role of BRCA1 and BRCA2 in the pathogenesis of these diseases. Previous studies have already suggested mechanisms of how DNA damage may trigger immune response [72,73]; however, the question of why its intensity is higher in ovarian rather than in breast cancer remains open.…”

Transcriptome Analysis of Ovarian and Uterine Clear Cell Malignancies

“…To compare the transcriptome profile of PD-L1 positive versus negative ovarian CCCs with metastatic HGS and primary HGSOCs, we collected publicly available raw RNA seq data from Mitra et al. study (GSE137237) ( 20 ). The top 2,000 statistically significantly differentially expressed genes (corrected p < 0.05) for various group comparisons were analyzed, including ovarian PD-L1+ versus PD-L1− CCC, HGS metastatic versus matched HGS primary tumors, and HGS primary tumor versus normal fallopian tubes ( Supplementary Dataset 2, ST2A-C ).…”

“…The Illumina TruSeq RNA Access library preparation kit was used for gene expression profiling of the 11 ovarian and five uterine tumors, as described previously (18,19). Publicly available raw RNA-seq data using TruSeq RNA Access library prep kit from 10 BRCA-mutated high grade serous ovarian cancers (HGSOC) (GSE141142) was collected and directly compared with our ovarian CCC RNA-seq data (20). The same methods of library preparation (i.e., TruSeq RNA Access of Illumina) were used in both studies allowing for direct comparison of transcriptome between the two different histologic subtypes.…”

Liquid Biopsies to Evaluate Immunogenicity of Gynecological/Breast Tumors: On the Way to Blood-Based Biomarkers for Immunotherapies

“…In this context, it was shown that BRCA1 mutant TNBCs had a higher tissue TMB, more TILs, and a higher expression of PD-L1 and CTLA-4 as compared to wild-type TNBCs [91]. However, in hereditary BRCA1/2 mutant BC and OC patients, TMB was not associated with the magnitude of immune response [92]. The promising effect of ICI in mismatch repair-deficient BCs might be due to the combinational regimen with PARP inhibitors [27], which were shown to induce PD-L1 expression [28, 93].…”