Abstract POSTER-TECH-1119: Phylogenetic portraits of high grade serous ovarian cancer

Abstract

Abstract High Grade Serous Ovarian Cancer (HGSOvCa) is characterized by genomic instability resulting from deficient DNA repair processes primarily due to TP53 mutation and BRCA abnormalities. Genomic instability has been shown to result in significant intratumoral heterogeneity, with temporally and spatially separated tumours exhibiting unique mutational profiles. A key unanswered question is whether genomic instability produces functionally relevant driver mutations, or whether the tumours complement of driver mutations predates the emergence of instability. We sought to reconstruct the evolutionary histories of the tumours of 8 HGSOvCa patients using spatial and temporal profiling of somatic mutations. For each patient, we collected multiple tumour biopsies resected from primary and metastatic sites at the time of surgery. We then used whole genome shotgun sequencing to identify somatic point mutation, rearrangement and copy number changes present at each site. We used novel computational techniques to unmix the signal produced by sequencing of a mixture of tumour cells, and infer the genomic architecture of clonal populations in each tumour sample. Additionally, we used phylogenetic inference techniques to reconstruct the ancestral relationships between the genomically distinct clones identified in each patient. We classified mutations as occurring ancestrally (before clonal divergence) or occurring on a descendent lineage. We identified multiple well known driver mutations occurring in descendent lineages of the tumour phylogeny, including mutations in CDKN2A, BCL6 and ERBB2. Aberrant site specific expression patterns were concomitant with genomic changes. Furthermore, we identified instances of convergent evolution, including independent deletion of wild type RAD51B in a patient with a germline RAD51B mutation. Reconstruction of clonal phylogenies enabled inference of metastatic spread. In one patient, a minor subclone of a right ovary tumour acquired an ERBB2 amplification, then subsequently populated all other metastatic sites sampled by the experiment. Finally, from our analyses we concluded that in many HGSOvCa, genomic instability and associated copy number changes result in the deletion of a significant number of point mutations, with implications for phylogenetic reconstruction using traditional techniques. Citation Format: Andrew McPherson, Andrew Roth, David Huntsman, Jessica McAlpine, Sohrab Shah. Phylogenetic portraits of high grade serous ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1119.