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A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive subtype of mammary carcinoma. Here, we describe a case of an 81-year-old female diagnosed with ductal triple negative breast cancer with a germline pathogenic variant in BReast CAncer gene2 (BRCA2). Genetic testing also revealed the presence of four somatic mutations in the ephrin type-A receptor 3 (EphA3), TP53, BRCA1-associated protein (BAP1), and MYB genes. The BRCA2, TP53, and BAP1 gene mutations are highly predictive of a defective homologous recombination repair system and subsequent chromosomal instability in this patient. Coherently, the patient displayed a strong homologous recombination deficiency signature and high tumor mutational burden status, which are generally associated with increased probability of immune neoantigens formation and presentation, and with tumor immunogenicity. Analysis of immune checkpoint revealed high expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), programmed death 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), suggesting that the patient might likely benefit from immunotherapies. Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy.

SUBMITTER: Han Y

PROVIDER: S-EPMC10562433 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.

Han Yuyi Y Rovella Valentina V Smirnov Artem A Buonomo Oreste Claudio OC Mauriello Alessandro A Perretta Tommaso T Shi Yufang Y Woodmsith Jonathan J Bischof Julia J Melino Gerry G Candi Eleonora E Bernassola Francesca F

Cell death discovery 20231009 1

Triple-negative breast cancer (TNBC) is the most aggressive subtype of mammary carcinoma. Here, we describe a case of an 81-year-old female diagnosed with ductal triple negative breast cancer with a germline pathogenic variant in BReast CAncer gene2 (BRCA2). Genetic testing also revealed the presence of four somatic mutations in the ephrin type-A receptor 3 (EphA3), TP53, BRCA1-associated protein (BAP1), and MYB genes. The BRCA2, TP53, and BAP1 gene mutations are highly predictive of a defective ...[more]

PMID: 37813891

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Project description:Adoptive cell therapy with the use of tumor-infiltrating lymphocytes (TILs) is a very promising immunotherapeutic approach for the treatment of patients with colorectal cancer (CRC). However, within the tumor microenvironment, co‑inhibitory immune checkpoints can inactivate TILs. The aim of the present study was to examine the association between the TIL load, the mutation rate and the clinical outcome in the immune landscape of patients with CRC. RNA‑seq and whole exome seq data of 453 colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), along with the TIL load and clinicopathological information of each patient, were extracted from the TCGA GDC Data Portal and analyzed computationally. The expression of immune checkpoint molecules was compared between colon cancer and normal tissue. A total of 9 immune‑related gene signatures were investigated in CRC. Spearman's correlation analysis was performed to examine the correlation between the TIL load with the expression of each immune checkpoint molecule. Indoleamine 2,3‑dioxygenase 1 (IDO1) was found to be significantly overexpressed in CRC, whereas V‑domain Ig suppressor of T cell activation (VISTA) and lymphocyte activating 3 (LAG3) were markedly downregulated. A high expression of cytotoxic T‑lymphocyte‑associated protein 4 (CTLA‑4), IDO1, programmed cell death 1 (PD‑1) and T‑cell immunoreceptor with Ig and ITIM domains (TIGIT), tended to be associated with a better overall survival of the patients. In COAD, the TIL load positively correlated with the expression of adenosine A2A receptor (ADORA2A), CTLA‑4, hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activating 3 (LAG3), programmed death‑ligand PD‑L1, PD‑L2, TIGIT and VISTA, whereas in READ, such positive correlations were noted only between the TIL load and LAG3 or PD‑L2. The 'central memory T‑cell' and 'exhausted T‑cell' gene signatures were significantly lower among the READ tumors. The expression of PD‑1, PD‑L1, PD‑L2, CTLA‑4 and IDO1 was significantly higher among COAD patients with a high mutation rate (>34 mutations/Mb) compared to those with a lower rate. Somatic mutations in PD‑1, PD‑L1, CTLA‑4 and other checkpoint molecules did not seem to affect their expression levels. On the whole, the data of the present study highlight the association of immune checkpoint molecules with the TIL load, patient survival and a high mutation rate in CRC. The data corroborate that patients with colon cancer with higher PD1, PD‑L1/2, CTLA‑4 and IDO1 expression, and a high mutation rate, are the ones who will benefit more from the respective immune checkpoint inhibition therapies.

Project description: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.

Project description:BACKGROUND:MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues. METHODS:Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n =?5) and non-mutation carriers (n =?3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis. RESULTS:miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: >?2.0 and p <?0.05) and considered as potential biomarkers (area under the curve >?0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways. CONCLUSIONS:Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.

Project description:Background:This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients, who later participated in a clinical trial. BRCA1/2 germline mutation related hereditary cancers are candidates for new immune therapeutic interventions. However, contrary to what is expected of tumors with compromised DNA repair, a 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 BRCA1/2 related 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 data available from The Cancer Genome Atlas (TCGA) were performed using the R computing environment. To interpret the data, we have used published literature and web available resources such as Gene Ontology Tools, The Cancer immunome Atlas (TCIA) 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 that they express a range of phenotypes similar to sporadic cancers. Importantly, BRCA2 germline mutation related breast tumors have a different profile of genomic instability compared to those related to BRCA1. However, 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), but not other types of breast cancer, also express a high degree of HRD. Conclusion: : Tumor mutation burdon (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.

Dataset Information

A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.

Publications

A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.

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