ArticleGenome biology2019
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents.
Article in Genome biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 120 citations in OpenAlex.
- Resistance to neoadjuvant talazoparib in triple-negative breast cancer by BRN2-induced ATR/STAT3 pathways or SHLD2 subclone expansion.Proceedings of the National Academy of Sciences of the United States of America · 2026Trial
- Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial.JCO precision oncology · 2023Trial
- Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2026Article
- PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers.International journal of molecular sciences · 2026Review
- Topographical archetypes of somatic mutagenesis in cancer.bioRxiv : the preprint server for biology · 2026Article
- Role of clonal lineage analysis via next-generation sequencing in identifying the origin of multiple cancers and guiding treatment options.Japanese journal of clinical oncology · 2026Article
- Whole genome sequencing approach to assess homologous recombination deficiency in a pan-cancer cohort.Communications medicine · 2026Article
- Osteosarcoma 3D patient derived cultures to test genome-informed personalized treatment options: a feasibility study.Frontiers in medicine · 2026Article
- Differential sensitivity of MCPH1- and BRCA2-deficient cancer cells to PARP-1 inhibition.PloS one · 2026Article
- Complex Relationships Between Homologous Recombination Deficiency (HRD) Score and Mutational Status of Homologous Recombination Repair (HRR) Genes in Prostate Carcinomas.International journal of molecular sciences · 2025Article
- Safe delivery of a highly toxic anthracycline derivative through liposomal nanoformulation achieves complete cancer regression.Molecular cancer · 2025Article
- Tissue specificity and chromosomal alterations shape divergent immune programs in HRD tumors.bioRxiv : the preprint server for biology · 2025Article
- Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies.Genome medicine · 2025Article
- Article
- Predictive biomarkers for the efficacy of PARP inhibitors in ovarian cancer: an updated systematic review.BJC reports · 2025Article
- Homologous recombination deficiency (HRD) testing landscape: clinical applications and technical validation for routine diagnostics.Biomarker research · 2025Review
- A review on trends in development and translation of omics signatures in cancer.Computational and structural biotechnology journal · 2024Review
- Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells.International journal of molecular sciences · 2024Article
- Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.Cancer research and treatment · 2024Review
- Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.NPJ precision oncology · 2024Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHomologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.
resultsUsing whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.
conclusionOur results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.