The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.

The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research.

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.Experimental Design: We obtained pre-and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4 þ T cells showed enhanced IFNg production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8 þ T-cell and CD45RO þ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3 þ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in postversus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. Ó2016 AACR.

Genomic complexity from profound copynumber aberration has prevented effective molecular stratification of ovarian and other cancers. Here we present a method for copynumber signature identification that decodes this complexity. We derived eight signatures using 117 shallow wholegenome sequenced highgrade serous ovarian cancer cases, which were validated on a further 497 cases. Mutational processes underlying the copynumber signatures were identified, including breakagefusionbridge cycles, homologous recombination deficiency and wholegenome duplication. We show that most tumours are heterogeneous and harbour multiple signature exposures. We also demonstrate that copy number signatures predict overall survival and changes in signature exposure observed in response to chemotherapy suggest potential treatment strategies. 2. CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/174201 doi: bioRxiv preprint first posted online Aug. 9, 2017;The discrete mutational processes that drive copynumber change in human cancers are not readily identifiable from genomewide sequence data. This presents a major challenge for the development of precision medicine for cancers that are strongly dominated by copynumber changes, including highgrade serous ovarian (HGSOC), oesophageal, nonsmallcell lung and triple negative breast cancers 1 . These tumours have low frequency of recurrent oncogenic mutations, few recurrent copy number alterations and highly complex genomic profiles 2 .HGSOCs are poor prognosis carcinomas with ubiquitous TP53 mutation 3 . Despite efforts to discover new molecular subtypes and targeted therapies, overall survival has not improved over two decades 4 . Current genomic stratification is limited to defining homologous recombinationdeficient (HRD) tumours 57 , and classification using gene expression does not currently have clinical utility 8,9 . Detailed genomic analysis using whole genome sequencing has shown frequent loss of RB1, NF1 and PTEN by gene breakage events 10 and enrichment of amplification associated foldback inversions in nonHRD tumours 11 . However, none of these approaches has provided a broad mechanistic understanding of HGSOC, reflecting the challenges of detecting classifiers in extreme genomic complexity.Recent algorithmic advances have enabled interpretation of complex genomic changes by identifying mutational signatures genomic patterns that are the imprint of mutagenic processes accumulated over the lifetime of a cancer cell . Importantly, these studies show that tumours typically harbour multiple mutational processes requiring computational approaches that can robustly identify coexistent mutational signatures. Quantification of the exposure of a tumour to specific mutational signatures provides a rational framework to personalise therapy 14 but currently is not readily applicable to copynumber driven tumours. We hypothesized that specific feat...