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Genome-wide mutational consequences of nucleotide excision repair-deficiency through XPC deletion in a human adult stem cell culture

ABSTRACT: Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are selectively sensitive to cisplatin treatment. While NER-deficiency has been linked to mutational Signature 5, not all NER-deficient tumors are characterized by a high Signature 5 contribution, illustrating the importance to further characterize the mutational consequences of NER-deficiency. Here, we analyzed the mutational profile of a human adult stem cell (organoid) culture that is deficient in NER through XPC deletion by CRISPR-Cas9 gene-editing, and subsequent whole-genome sequencing analysis of a clonally derived organoid. We found that XPC deletion results in an increase in base substitution load and specifically induces Signature 8 mutations, a mutational signature with previously unknown etiology. Presence of Signature 8 may, therefore, serve as a novel biomarker for NER-deficient tumors and could improve personalized treatment strategies.

PROVIDER: EGAS00001002681 | EGA |

REPOSITORIES: EGA

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Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Project description:Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

2024-02-23 | GSE256301 | GEO

Project description:Mutational profile of mismatch repair deficiency

| PRJNA587789 | ENA

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Project description:Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

| EGAS00001004405 | EGA

Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with Constitutional Mismatch Repair Deficiency

Project description:Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variantsÃ‚Â in one of the mismatch repair (MMR) genes, is a childhood cancer predisposition syndrome that often results in the development of multiple tumors early in life. A better understanding of mutational processes driving subsequent CMMRD tumors could advance optimal treatment. Therefore, we performed a genomic characterization of 41 tumors from 17 individuals with CMMRD. Mutational patterns in these tumors were found to be influenced by multiple factors, including the affected MMR genes, tumor types and somatic polymerase proofreading mutations. Temozolomide treatment left prominent mutational signatures in two second primary hematologic malignancies. Furthermore, a novel indel signature was found in 54% of the tumors, characterized by one base pair cytosine insertions in cytosine homopolymers. In conclusion, the analysis of sequential tumors in individuals with CMMRD reveals diverse mutational patterns influenced by the underlying mutated MMR gene, tumor type and treatment history.

| EGAS00001007660 | EGA

The molecular landscape of homologous recombination deficient, end-stage, high grade serous ovarian cancer

Project description:High grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency, and while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multi-omics approach to interrogating mechanisms of resistance, using multiple autopsy samples collected from 15 women with HR-deficient HGSC.

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Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>

2020-06-29 | MTBLS1764 | MetaboLights

Characterization of gastric tumor organoids with specific oncogenic pathway activations

Project description:Gastric cancer ranks the fifth most common malignancy and the third leading cause of cancer related death worldwide. Classical chemotherapy is still the standard treatment in advanced stages, with only two targeted therapies currently in clinical use. Several targeted trials have failed, likely due to missing relevant biomarkers that predict response. Patient derived cancer organoids (PDOs) constitute a three dimensional cell culture system showing self renewal, self organization and regularly unlimited proliferation while faithfully recapitulating many aspects of the tumor they are derived from. Nevertheless, the complex individual mutational landscape hampers the use of PDOs for basic and translational research. We therefore characterized three murine tumor organoid models with defined mutational patterns altering specific oncogenic pathways: a RAS activated (KrasG12D, Tp53R172H), a WNT activated (Apcfl/fl, Tp53R172H) and a diffuse (Cdh1fl/fl, Apcfl/fl) tumor model. The models were analyzed phenotypically, a proteome signature was established and a drug screen performed. The models were morphologically diverse, were characterized by individual protein expression signatures and showed differential drug sensitivities. The developed organoid models allow functional assays as well as pathway specific drug interference testing in a genetically defined setting.

2022-08-22 | PXD022015 | Pride

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku. B cells were stimulated to undergo class switch recombination in vitro. Chromatin from B cells was harvested 72 hours post-stimulation and used for RPA ChIP to study the extent of resection of DNA DSBs.

2012-09-30 | E-GEOD-35698 | biostudies-arrayexpress

Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti–PD-1 Immunotherapy in Endometrial Carcinoma

Project description:Responses to immune checkpoint blockade (ICB) are variable among mismatch repair-deficient (MMRd) cancers. We completed a phase 2 clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared to epigenetic MMRd; however, within each category of MMRd, mutation burden was not associated with ICB response. Notably, JAK1 mutations did not confer resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of anti-tumor immunity against mutational and epigenetic MMRd cancers. Whereas effector CD8+ T cell responses correlated with regression of mutational MMRd tumors, highly active CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and extrinsic factors that influence ICB response.

2022-10-07 | GSE212217 | GEO

DNA Repair Profiling of HGSC Organoids

Project description:<p>In this study, 34 ovarian tumor organoids generated from 23 patients underwent paired DNA damage repair defect functional analyses and whole exome sequencing analysis to compare genetic mutational status to DNA repair functional capacity. 22 of the patients had high grade serous cancer and 1 of the patients had low grade serous cancer. A normal control, fresh parent tumor, and cells from the organoid culture generated from the parent tumor underwent whole exome sequencing analysis and the data from the sequencing analysis is provided here.</p>

| phs001685 | dbGaP

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