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

Ewa Przybytkowski,Julia Eismann,Thomas Davis,Ursula A Matulonis,Abdelrahman Hosny,Sheida Nabavi,Gerburg M Wulf

doi:10.1186/s12885-020-6605-1

Abstract

BackgroundBRCA1/2 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.MethodsMining 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.ResultsWe 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.ConclusionsTMB 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 registrationPhase 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.

Highlights

BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions
Breast and ovarian cancers in BRCA1/2 germline mutation carriers show relatively low overall immune activity at diagnosis, compared to very immune active non-carriers In our clinical trial samples, we observed a striking difference in the gene expression profiles between germline mutation carriers and non-carriers
Considering that elevated tumor mutation burden (TMB) in hereditary breast and ovarian cancers was not associated with high immune activity in the tumor microenvironment, we looked at other measures of instability that potentially could influence immune response in breast and ovarian cancers

Summary

Introduction

BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. 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. Immunosurveillance should be relevant to BRCA1/2 germline mutation carriers, whose tumors have dysfunctional homologous recombination (HR), the main pathway for DNA double strand break repair [3]. The HR deficiency of hereditary breast and ovarian cancers makes them vulnerable to the inhibition of alternative pathways of DNA repair with inhibitors of Poly (ADP-Ribose) Polymerase (PARP) [4]. There are interests in expanding the use of PARP inhibitors to sporadic breast and ovarian cancers, some of which express phenotypes similar to hereditary tumors. The “BRCAness” phenotype is still poorly defined [7]

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