Cited by 327PARP inhibition in cancer therapyBRCA gene mutations in cancerCancer Genomics and Diagnostics

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Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers

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Watkins, Johnathan A, Irshad, Sheeba, Grigoriadis, Anita, Tutt, Andrew NJ·2014·Breast Cancer Research

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Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies have been found to be particularly effective in tumors that harbor deleterious germline or somatic mutations in the BRCA1 or BRCA2 genes, the products of which contribute to the conservative homologous recombination repair of DNA double-strand breaks. Nonetheless, several setbacks in clinical trial settings have highlighted some of the issues surrounding the investigation of PARP inhibitors, especially the identification of patients who stand to benefit from such drugs. One potential approach to finding this patient subpopulation is to examine the tumor DNA for evidence of a homologous recombination defect. However, although the genomes of many breast and ovarian cancers are replete with aberrations, the presence of numerous factors able to shape the genomic landscape means that only some of the observed DNA abnormalities are the outcome of a cancer cell's inability to faithfully repair DNA double-strand breaks. Consequently, recently developed methods for comprehensively capturing the diverse ways in which homologous recombination deficiencies may arise beyond BRCA1/2 mutation have used DNA microarray and sequencing data to account for potentially confounding features in the genome. Scores capturing telomeric allelic imbalance, loss of heterozygosity (LOH) and large scale transition score, as well as the total number of coding mutations are measures that summarize the total burden of certain forms of genomic abnormality. By contrast, other studies have comprehensively catalogued different types of mutational pattern and their relative contributions to a given tumor sample. Although at least one study to explore the use of the LOH scar in a prospective clinical trial of a PARP inhibitor in ovarian cancer is under way, limitations that result in a relatively low positive predictive value for these biomarkers remain. Tumors whose genome has undergone one or more events that restore high-fidelity homologous recombination are likely to be misclassified as double-strand break repair-deficient and thereby sensitive to PARP inhibitors and DNA damaging chemotherapies as a result of prior repair deficiency and its genomic scarring. Therefore, we propose that integration of a genomic scar-based biomarker with a marker of resistance in a high genomic scarring burden context may improve the performance of any companion diagnostic for PARP inhibitors.

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Self-citation

Authors: Watkins, J. A., Irshad, S., Grigoriadis, A., & Tutt, A. N.
Affiliations: Guy's Hospital (GB)
Corresponding author: Grigoriadis, Anita
ORCID: Watkins, Johnathan A
Irshad, Sheeba
Grigoriadis, Anita
Tutt, Andrew NJ
Venue: Breast Cancer Research
Publisher: Springer Science and Business Media LLC
Published: 2014-06-03
Volume: 16
Issue: 3
Pages: 211-211
ISSN: 1465-5411 (ISSN-L)
1465-542X
DOI: 10.1186/bcr3670
PMC: PMC4053155
OpenAlex: W2100419317
Cited by: 327
References: 58
Citations by year: 2026: 14 · 2025: 14 · 2024: 21 · 2023: 31 · 2022: 54 · 2021: 42 · 2020: 25 · 2019: 25 · 2018: 23 · 2017: 27 · 2016: 35 · 2015: 15 · 2014: 1
FWCI: 2.95
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
www.springer.com/tdm (unspecified)
Locations: Breast Cancer Research (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Research Portal (King's College London) (publishedVersion, other-oa)
Funders: National Institute for Health and Care Research
King's College London
Topics: Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: homologous recombination deficiency, PARP inhibitors, BRCA1, BRCA2, loss of heterozygosity, telomeric allelic imbalance, mutational signatures, drug response biomarkers, breast cancer, ovarian cancer, DNA double-strand break repair, platinum-based chemotherapy, companion diagnostics, predictive biomarkers
MeSH terms: Poly(ADP-ribose) Polymerase Inhibitors, Breast Neoplasms, Chromosome Aberrations, Female, Humans, Ovarian Neoplasms, Biomarkers, Tumor, BRCA1 Protein, BRCA2 Protein, DNA Breaks, Double-Stranded, Homologous Recombination, Recombinational DNA Repair

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Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers

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