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

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.

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…The median telomeric imbalance score for the 18 DCIS cases was 8 (range 0-22), slightly lower than the median of 12 in invasive breast cancer. 34 In our previous cohort of 53 DCIS with molecular inversion probe array data, the median was 8.5, thus we do not think the score is reduced by not having allelic imbalance information available. The telomeric imbalance score was significantly associated with TP53 mutation (Figure 4, P = 0.001) and high nuclear grade (P = 0.01).…”

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…Progression-free survival was signifi cantly longer in the BRCA mutant subgroup (HR 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high subgroup (HR 0·62, 0·42-0·90, p=0·011) than in the LOH low subgroup (fi gure 2A). 12 month progressionfree survival was higher in the BRCA mutant subgroup (50%, 95% CI 33-65) and LOH high subgroup (28%, 18-39) than in the LOH low subgroup (10%, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The proportionality of hazards assumption was not violated (appendix pp [4][5]15).…”

“…4−6 Half of all high-grade serous ovarian carcinomas are estimated to have homologous recombination defi ciency, with about 15% of carcinomas harbouring a germline BRCA mutation, 6% a somatic BRCA mutation, and 20% a mutation in, or epigenetic silencing of, another homologous recombination gene. 7,8 Even without an identifi able mutation in BRCA or other known homologous recombination gene, many high-grade serous ovarian carcinomas show BRCA mutant-like genomic signatures, 6,9 which could serve as a downstream marker of homologous recombination defi ciency.…”

Novel targets in the treatment of advanced gastric cancer: a perspective review

“…Defects in DNA damage repair lead not only to point mutations but also to loss of part or whole chromosomes [Watkins et al 2014;Marquard et al 2015]. The presence of such genomic scars is associated with platinum sensitivity, and also sensitivity to poly ADP ribose polymerase (PARP) inhibitors.…”