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. 2015 May 1:3:9.
doi: 10.1186/s40364-015-0033-4. eCollection 2015.

Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs

Andrea M Marquard #  1 , Aron C Eklund #  1 , Tejal Joshi  1 , Marcin Krzystanek  1 , Francesco Favero  1 , Zhigang C Wang  2   3 , Andrea L Richardson  4 , Daniel P Silver  2   5 , Zoltan Szallasi  1   6 , Nicolai J Birkbak  1
Affiliations

Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs

Andrea M Marquard et al. Biomark Res. .

Abstract

Background: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.

Results: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy.

Conclusions: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.

Keywords: Cancer; Genomic scars; Homologous recombination deficiency.

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Figures

Figure 1
Figure 1
Overview of the type of genomic scars measured by each HR signature. Dark and light grey are used to indicate paternal and maternal chromosomes. A: Number of telomeric allelic imbalances (NtAI) counts the number of subtelomeric regions with allelic imbalance, that start beyond the centromere and extend to the telomere. B: Large-scale state transitions (LST) counts the number of chromosomal breaks between adjacent regions of at least 10 Mb. C: Homologous recombination deficiency score (HRD-LOH) measures the number of regions with LOH which are larger than 15 Mb, but shorter than the whole chromosome.
Figure 2
Figure 2
Distribution of signature scores across 15 cancer types. A: Distribution of NtAI scores. B: Distribution of LST scores. C: Distribution of HRD-LOH scores. Horizontal black lines indicate 25th, 50th and 75th percentiles.
Figure 3
Figure 3
Distribution of NtAI, LST and HRD-LOH signature scores by MSI status in colon, gastric and endometrial cancer. Tumors are grouped by MSI (microsatellite instable) or MSS (microsatellite stable). Horizontal black lines indicate 25th, 50th and 75th percentiles.
Figure 4
Figure 4
Comparison between signature scores. A: Spearman correlation coefficients for signature pairs. B: Venn diagram showing the overlap of genomic scars counted by the three signatures. All breakpoints measured by one or more signatures were counted, and each area gives the percentage of those breakpoints that were measured by each signature or combination of signatures.
Figure 5
Figure 5
Comparison of signature scores to other measures of genome instability. Spearman correlation coefficients between each of the three HR signatures (NtAI, LST and HRD-LOH) and each of three alternative genomic signatures (wGII, FLOH and Nmut, see text for details).
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