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

Andrea M Marquard,Zoltan Szallasi,Aron C Eklund,Zhigang C Wang,Daniel P Silver,Francesco Favero,Tejal Joshi,Marcin Krzystanek,Andrea L Richardson,Nicolai J Birkbak

doi:10.1186/s40364-015-0033-4

Andrea M Marquard, Zoltan Szallasi + Show 8 more

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https://doi.org/10.1186/s40364-015-0033-4

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Abstract

BackgroundOvarian 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.ResultsWe 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.ConclusionsWithin 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40364-015-0033-4) contains supplementary material, which is available to authorized users.

Highlights

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
We find that cases with high levels of each signature can be found in 12 of the 15 cancer types, suggesting that it may be possible to use genomic scar signatures to identify patients with DNA repair deficiency predictive of platinum chemotherapy sensitivity prior to initiating therapy
This shows that the type of chromosomal aberrations that are counted by each signature is not restricted to a single or a few types of cancer, but rather represents a general aberration pattern that can be found across most cancer types

Summary

Introduction

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. Personalized medicine in cancer aims to improve treatment outcome by matching the specific biological characteristics of a tumor with the most appropriate therapeutic option One such biological characteristic is a defect in one of the DNA repair systems, which often leads to the accumulation of genomic damage, such as point mutations and short indels, as well as gross copy number aberrations, termed genomic scars, that may be gain or loss of large chromosomal regions, or even whole chromosomes [1,2]. Depending on the type of DNA repair defects present, cancers may show increased sensitivity to treatment with certain DNA-damaging agents or drugs that interfere with other parts of the DNA repair system This has been shown in particular with BRCA1 and BRCA2, key genes in both the homologous recombination (HR) and Fanconi Anemia (FA) pathways [4,5,6]. As the patterns of genomic scars may be DNA repair pathway-specific rather than genespecific, drug response signatures based on genomic scars may be reliable biomarkers for DNA repair deficiency and could be used to identify patients that would benefit from specific types of anti-cancer therapy [15]

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