Abstract AP23: A PLATINUM–RESISTANT SUBTYPE OF HIGH–GRADE SEROUS OVARIAN CANCER IDENTIFIED BY A NETWORK OF SOMATIC MUTATIONS
Authors: Shen John Paul , Bojorquez-Gomez Ana , Huang Justin , Hofree Matan , Klepper Kristin , Beckett Alex , Saenz Cheryl , Kreisberg Jason , Ideker Trey 
Published: June 2017

PURPOSE: Like many solid tumors, high grade serous ovarian carcinoma (HGSOC) is a heterogeneous entity with a widely variable clinical course even among patients of the same stage and histological subtype. Although most patients will achieve remission with platinum-based chemotherapy, approximately 20% will display primary platinum resistance. If it were possible to platinum resistance from the molecular profile of a tumor, patients with platinum resistant tumor could be identified for alternative therapy, however, currently no such biomarker exists.

METHODS: We have recently developed an analysis method called Network-based Stratification (NBS), which combines genome-scale somatic mutation profiles with genetic interaction networks. Briefly, somatic mutations for each patient are mapped onto a network, and then the influence of each mutation is propagated over its network neighborhood to give each gene a propagated mutation score (PM score). Unsupervised clustering is then used to assign the propagated networks into subtypes.

RESULTS: Using NBS a high risk subtype consisting of approximately 20% of the patients was identified in both TCGA (n=330) and the ICGC (n=92) HGSOC cohorts. The median overall survival (OS) for the high risk (HR) subtype was a year less than standard risk (SR) subtype (36 vs. 48 mo, Log rank p = 1.6x 10-5) in TCGA cohort and similarly shorter (22 mo vs. not-yet-reached, p = 3.6x10-4), see figure 1. These survival differences were independent of age, tumor stage and residual tumor after surgical resection. The PM scores of the HR tumors from TCGA and ICGC cohorts we remarkably correlated (Pearson r2 = 0.94, p &lt; 0.001). In contrast, the correlation of PM scores from the full TCGA to ICGC cohorts was 0.58, and within the TCGA the correlation between HR and SR was only 0.18. The network of frequently mutated genes for the HR subtype was enriched for genes in the nucleoskeleton, caspase, and FGFR pathways.

We then built a classifier to identify molecularly matched cell line models for in vitro study. The three cell lines with mutation profiles match the HR subtype (Kuramochi,Ovkate, OAW28) were significantly more resistant to cisplatin relative to cell lines characteristic of SR tumors (COV318, TYK-NU, OVCAR4), (IC50 14.4 vs. 3.3 µM, p &lt; 0.0001). There was no significant difference in sensitivity to paclitaxel. Figure 1.Kaplan-Meier plots of Overall Survival, A TCGA, B ICGCFigure 1. Kaplan-Meier plots of Overall Survival, A TCGA, B ICGC

CONCLUSIONS: NBS can be used to identify a molecular distinct subtype of HGSOC characterized by poor patient survival and primary platinum resistance.

Citation Format: John Paul Shen, Ana Bojorquez-Gomez, Justin Huang, Matan Hofree, Kristin Klepper, Alex Beckett, Cheryl Saenz, Jason Kreisberg, Trey Ideker. A PLATINUM–RESISTANT SUBTYPE OF HIGH–GRADE SEROUS OVARIAN CANCER IDENTIFIED BY A NETWORK OF SOMATIC MUTATIONS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP23.