Epigenomic landscape of homologous recombination deficient (HRD) triple-negative breast cancer (TNBC)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE255554 | GEO | 2024/09/26
REPOSITORIES: GEO
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Project description:Epigenomic landscape of homologous recombination deficient (HRD) triple-negative breast cancer (TNBC)
| PRJNA1075433 | ENA
Project description:We developed a gene expression-based classifier for homologous recombination deficiency (HRD) in breast cancer patients using WES and RNA-seq data obtained from 94 TNBC samples from a Malaysian hospital-based cohort (MyBrCa). This classifier was able to predict for high levels of a mutational signature associated with HRD in an additional MyBrCa TNBC validation cohort (this EGA study) as well as in TNBCs from TCGA. We also validated the classifier on a NanoString platform with both fresh frozen and FFPE tissue.
| EGAS00001006518 | EGA
Project description:Homologous recombination deficiency (HRD) has emerged as a key vulnerability in selected cancer types and is associated with response to platinum and PARPi-based treatment strategies. However, additional biomarkers and targeted therapy options are needed to broaden the range of patients that could benefit from this therapeutic niche. Here, we show that the SARC-HRD signature, composed of ten genes of the homologous recombination repair pathway, stratifies a cohort of sarcoma patients, and associates with genomic biomarkers of HRD, with disease progression and with the CINSARC prognostic signature. Equivalently to CINSARC, high levels of SARC-HRD are associated with poor metastasis-free survival, underscoring the potential of SARC-HRD to predict disease outcome. By pharmacotyping patient-derived cell models, we identified promising drug targets within the DNA damage response for sarcoma with HRD traits. Inhibition of ATR, CHK1 and WEE1 elicited synthetic lethality in sarcoma cells with HRD, which concomitantly showed an upregulation of ATR signaling. Combinatorial drug testing further revealed synergistic drug combinations between ATRi, WEE1i, PARP1/2i and chemotherapeutic agents with potential clinical impact. Mechanistically, targeting ATR signaling at multiple levels induced a replication defect and apoptotic cell death. Taken together, our results demonstrate the therapeutic benefit of targeting DDR mechanisms in sarcoma with HRDness traits and their potential clinical utility for treating a broader spectrum of tumor types.
2026-06-04 | GSE299349 | GEO
Project description:The aggressive triple negative breast cancers (TNBCs), which lack estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), comprise a high-risk subset of human breast cancers which remain poorly characterized and lack effective treatments. While meta-analyses have recently suggested the complexity of these tumors, no robust phenotypes have been defined. We identified four distinct subtypes through gene expression analyses of 198 TNBCs (84 Discovery, 114 Validation). We then classified 221 publically available TNBCs profiled on the same mRNA expression array. All three sets supported stratification of tumors by cell cycle (Subtype 1 Luminal – FOXA1, LUM), DNA repair (Subtype 2, Mesenchymal – ADIPOQ, MES), downregulated immunological (Subtype 3, Basal-Like – SOX10/8, BL), and upregulated immunological (Subtype 4, Basal Immune – STAT1, BI) signaling pathways. Additional classified data sets demonstrate significantly lower risk of relapse and death with BI tumors, and highest risk with BL tumors, even after correction with known risk factors. DNA copy number profiling of our primary study set produced optimal differentiation of the LUM subtype from the remaining tumors, and drove expression of FGFR2 and CDK1 in BL and BI subtypes. Subtype-specific targets include MUC1 in LUM tumors, CTLA4 in BI tumors, and a potential dependence of MES tumors on NTRK2, DDR2, PDGFRA, TEK, and ADRB2, which, upon validation, could enable targeted treatment with tyrosine-kinase inhibitors and beta-blockers. These findings further define TNBCs and provide the rationale for studies targeting agents against these tumor subtypes, thereby enabling a higher potential for preventive efficacy in patients with TNBC.
2015-12-25 | GSE76339 | GEO
Project description:Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. However，in colorectal cancer (CRC), the role of HRD alterations is mostly unknown. This study aims to explore the the Efficacy and Safety of Fluzoparib combined with Irinotecan in the Second-line treatment of HRD alterations metastatic colorectal cancer.
| 8652 | ecrin-mdr-crc
Project description:Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Most TNBCs are initially sensitive to DNA damaging chemotherapy, a substantial fraction acquire resistance to treatments and progress to advanced stages associated with poor prognosis. We identify the spliceosome U2 small nuclear ribonucleoprotein (snRNP) complex as a modulator of chemotherapy efficacy in TNBC. Transient treatment with U2snRNP inhibitors induced a persistent DNA damage in TNBC cells and patient-derived organoids (PDOs), regardless of their homologous recombination proficiency. Transcriptome analyses revealed that U2snRNP inhibition causes a pervasive deregulation of genes involved in the DNA damage response (DDR), which relied on their genomic structure characterized by a high number of small exons. Importantly, a pulse of splicing inhibition was sufficient to elicit long-lasting repression of DDR proteins and to enhance the cytotoxic effect of platinum-based drugs and poly ADP-ribose polymerase inhibitors (PARPi) in multiple TNBC models. These findings identify the U2snRNP as an actionable target that can be exploited to enhance chemotherapy efficacy in TNBCs.
2025-07-04 | GSE271749 | GEO
Project description:The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis via a dynamic bidirectional tumor–stroma dialog. Here, we show that homologous recombination-defective (HRD) neoplastic epithelium reprograms its TME in a genotype-specific manner to promote cancer aggressiveness. Autochthonous mouse models, co-culture systems, and human PDAC specimens revealed that tumoral ATM serine/threonine kinase status impacts cancer-associated fibroblast fate towards αSMA+ myofibroblastic (myCAF) differentiation, while P53 operates mostly tumor cell intrinsic. Vice versa, myCAFs foster cancer aggressiveness and specific chemoresistance patterns. Secretomics, proteomics, and in vitro approaches uncovered a greater TGF-β1 release in ATM-deficient cells associated with an enhanced reactive oxygen species/actomyosin-mediated mechanism. Pharmacological interference with TGF-β signaling reverts myofibroblast differentiation, chemoresistance, and tumor promotion in various ATM-deficient PDAC models. Overall, our findings demonstrate specific TME reprogramming by HRD PDACs towards a cancer-promoting fate, and their eligibility for combinatorial therapies targeting intrinsic vulnerabilities and extrinsic tumor–stroma oncogenic crosstalks.
2026-04-27 | PXD042750 | Pride
Project description:Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to PARP inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T-cell receptor profiles, along with validatory multimodal datasets from > 100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTreg) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC-II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
2024-07-08 | GSE222556 | GEO
Project description:Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to PARP inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T-cell receptor profiles, along with validatory multimodal datasets from > 100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTreg) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC-II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
2024-07-08 | GSE222555 | GEO
Project description:Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to PARP inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T-cell receptor profiles, along with validatory multimodal datasets from > 100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTreg) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC-II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
2024-07-08 | GSE269793 | GEO