Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

By V. Abkevich, K. Timms, Bryan T. J. Hennessy, John D. Potter, M. Carey, L. Meyer, K. Smith-McCune, R. Broaddus, K. Lu, Jian Chen and 10 more. British Journal of Cancer, 2012

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Background:Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH).Methods:Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines.Results:Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects.Conclusion:The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/96a3a0fb395ffc6e6c6c22d1524e5ae27637ba52

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Citations in the corpus

Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “This phenomenon has been observed in BRCA1/2-mutated cell lines with BRCA1/2 reversion mutations, which restore BRCA1/2 and HR function; these lines are still interpreted as HR deficient by the aforementioned assays (54).”
Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer (2016, background): “The combined cisplatin cohort was not used in the development of theHRD score,HRD threshold, or any of the individual components of the HRD score (LOH, TAI, LST), butwere the first two cohorts inwhich TAIwas tested.”
Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. (2017, background): “drug transporters expressed in the liver (MATE1) and kidneys (OCT2, MATE1, and MATE2K).(38) Similarly, in vitro studies have shown that rucaparib inhibits MATE1 and MATE2-K”
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. (2015, background): “Homologous recombination (HR) deficiency is thought to lead to a specific copy number profile, resulting in allelic imbalance (Abkevich et al., 2012; Birkbak et al., 2012; Popova et al., 2012).”
Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas (2018, neutral): “Computation of homologous recombination deficiency (HRD) scores—We calculated HRD scores following previous published 3 components of HRD/genome scarring scores: HRD-LOH (Abkevich et al., 2012), LST (Popova et al.”
Landscape of somatic mutations in 560 breast cancer whole genome sequences (2016, neutral): “Of the 560 breast cancers, 90 had germline (60) or somatic (14) inactivating mutations in BRCA1 (35) or BRCA2 (39) or showed methylation of the BRCA1 promoter (16).”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, methodology): “Resulting allele-specific data generated by ASCAT were used in the calculation of the homologous recombination deficiency (HRD) index score using implementations made in R 49,50 .”