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Comparative Study
. 2020 Mar 12;20(1):197.
doi: 10.1186/s12885-020-6605-1.

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

Ewa Przybytkowski  1 , Thomas Davis  1 , Abdelrahman Hosny  1 , Julia Eismann  2 , Ursula A Matulonis  2 , Gerburg M Wulf  3 , Sheida Nabavi  4
Affiliations
Comparative Study

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

Ewa Przybytkowski et al. BMC Cancer. .

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.

Keywords: BRCA1; BRCA2; BRCAness; Biomarkers; Breast cancer; Homologous recombination deficiency; Immunotherapy; Ovarian cancer; PARP; Platinum resistance; Tumor mutation burden.

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Conflict of interest statement

GMW reports grants from SU2C-AACR-DT0209, grants from Mary Kay Ash Foundation, grants from Ovarian Cancer Research Foundation, grants from Breast Cancer Alliance, grants from Breast Cancer Research Foundation, grants from NIH RO1 1R01CA226776–01, grants from Merck&Co, during the conduct of the study; In addition, Dr. Wulf has a patent Application 14/348810, Compositions and Methods for the Treatment of proliferative diseases pending, and a patent US 20090258352 A1, Pin1 as a marker for abnormal cell growth licensed to Cell Signaling; R&D Systems.

UAM reports personal fees from Astrazeneca, personal fees from Myriad Genetics, personal fees from Clovis, personal fees from Merck, personal fees from Eli Lilly, personal fees from Mersana, personal fees from Geneos, personal fees from Fuji Film, from 2X Oncology, personal fees from Cerulean, personal fees from Immunogen, personal fees from Novartis, outside the submitted work .

Figures

Fig. 1
Fig. 1
Biological processes enriched in breast and ovarian non-carriers from the clinical trial. The list of 813 genes was analyzed with Panther classification system (http://www.pantherdb.org). The table shows the top most significantly enriched biological process. The complete list of enriched processes is shown in Additional file 2: Table S2
Fig. 2
Fig. 2
The common genes upregulated in breast and ovarian non-carriers from the clinical trial are involved in immune functions. 60 genes overexpressed in breast non-carriers overlapped with those overexpressed in ovarian non-carriers. The list of 60 genes was analyzed with Panther classification system (http://www.pantherdb.org). The table shows the top most significantly enriched biological process. The complete list of processes is shown in Additional file 7: Table S7
Fig. 3
Fig. 3
Patterns of expression of 782 genes representing 28 immune cell types, in samples from the clinical trial. Heat-maps represent expression of 782 genes in breast (a) and ovarian (b) samples from our cohort. The 782 gene list is shown in Additional file 8: Table S8. Breast carriers (BC), breast non-carriers (BN), ovarian carriers (OC), ovarian non-carriers (ON). The numbers correspond to the patient number (Fig. 4a)
Fig. 4
Fig. 4
Subtypes of hereditary and sporadic breast and ovarian cancers in the clinical trial and in TCGA database. a) List of clinical trial samples. Subtyping of tumors from this cohort was obtained using TNBCtype tool (http://cbc.mc.vanderbilt.edu/tnbc) for breast cancers and CLOVAR scheme [14] for ovarian cancers. b) List of hereditary breast tumors from TCGA. Subtyping of these tumors was acquired from Lehmann at al [16]. c) Distribution of TNBC subtypes within TCGA breast cancers (sporadic TNBC and hereditary BRCA1 and BRCA2 related breast tumors). d) Distribution of HGSOC subtypes within TCGA ovarian cancers (sporadic HGSOC and hereditary BRCA1 and BRCA2 related ovarian tumors). The list of breast germline mutation carriers was established according the information acquired from CBioPortal (http://www.cbioportal.org) and iAtlas https://www.cri-iatlas.org/about/. The list of ovarian germline mutation carriers was established from CBioPortal (http://www.cbioportal.org) and it is shown in Additional file 9: Table S9. Immune Subtypes for our cohort were identified using tool available in iAtlas interactive platform and for TCGA samples were download from the site
Fig. 5
Fig. 5
Hereditary breast and ovarian cancers from the clinical trial and from TCGA database show high TMB and low overall immune activity relative to the sporadic tumors. Data obtained for our cohort (a, b), data acquired for TCGA breast (c-e) and ovarian (f-h) cancers. c and f) Somatic mutation count acquired from CBioPortal (http://www.cbioportal.org), d and g) Global immune gene expression representing averaged expression of genes from 28 meta-gene sets. Expression data was downloaded from FireBrowse data version 2016_01_28 (this link http://firebrowse.org/) e and h) Leukocyte fraction acquired from Cancer Research Institute iAtlas https://www.cri-iatlas.org/about/. The dotted lines indicate the average value for all the samples in each panel
Fig. 6
Fig. 6
Pattern of genomic instability vary widely within hereditary and sporadic breast and ovarian cancers and it is different in BRCA1 versus BRCA2 germline related tumors. Heat-maps represent genomic instability measures in breast (a) and ovarian (b) cancers from TCGA. The data was acquired from Cancer Research Institute iAtlas (https://www.cri-iatlas.org/about/)
Fig. 7
Fig. 7
High HR deficiency score characterize most of TNBC and predicts platinum sensitivity in HGSOC. a) Distribution of HR deficiency score across 33 TCGA cancer types, b) across the breast cancer subtypes and c) across the HGSOC subtypes. The data was acquired from Cancer Research Institute iAtlas (https://www.cri-iatlas.org/about/). d) HR deficiency score in HGSOC, which are resistant or sensitive to platinum-based therapy. The sensitivity/resistance criteria were established according to Integrated genomic analysis of ovarian carcinoma [27] and applied to TCGA data (Additional file 10: Table S10). The dotted lines indicate mean HR deficiency score for all HGSOC (top line) and all breast cancers (bottom line)
Fig. 8
Fig. 8
The immune response pattern in hereditary and sporadic breast and ovarian cancers from the clinical trial and from TCGA database. Expression of PD-L1 (CD274) in carriers and non-carriers from our cohort (a) in breast tumors from TCGA (b) and in HGSOC from TCGA (c). Heat-map showing relative contribution (percentage) of six universal intratumor immune states (C1-C6) within microenvironments of tumors from our cohort and from hereditary and sporadic breast and ovarian cancers form TCGA (d). PD-L1 for TCGA samples was downloaded from The Cancer Immunome Atlas (TCIA) (https://tcia.at/home). Immune Subtyping on the clinical trial samples was performed using the Immune Subtype Classifier available from The Cancer Research Institutes iAtlas (https://www.cri-iatlas.org/about/) and is also shown in Fig. 4a. Immune Subtypes for TCGA data were download from iAtlas
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