Abstract A60: DNA copy-number alterations in primary ovarian serous cystadenocarcinoma encoding for cell transformation and predicting survival and response to platinum therapy throughout the course of the disease.

Abstract

Abstract Purpose: To examine patterns of primary ovarian serous cystadenocarcinoma (OV) copy-number alterations (CNAs), each of which is correlated with a patient's overall survival (OS) and response to platinum-based chemotherapy at the time of initial diagnosis, over the course of the disease, i.e., in the subpopulations of patients of increasing progression-free survival (PFS) time intervals, from the end of the initial therapy targeting the primary tumor to a diagnosis of tumor recurrence or progression. The patterns of DNA CNAs, across the chromosome arms 7p and, separately, Xq, and across the combination of the two chromosome arms 6p+12p (together but not separately) were recently discovered by using DNA copy-number, i.e., genomic profiles of 249 primary OV tumors, mostly high-grade, from the Cancer Genome Atlas (TCGA) [Sankaranarayanan, Schomay, Aiello and Alter, PLoS One 10 (4), article e0121396 (2015); doi: 10.1371/journal.pone.0121396]. Segmentation of the patterns of DNA CNAs, gene ontology enrichment analyses of the corresponding differential mRNA expression, and mapping of the corresponding differential microRNA and protein expression to the DNA CNAs, linked each pattern with one of three hallmarks of cancer: DNA instability in 7p, cellular immune response suppression in Xq, and a cell's transformation and immortality in 6p+12p (where loss of the p21-encoding CDKN1A and the p38-encoding MAPK14 and gain of KRAS, together but not separately, can lead to transformation of human normal to tumor cells). Survival analyses showed and computationally validated that a combination of the three patterns makes a better predictor of OV survival than the tumor's stage, in the general as well as in the high-grade OV patient population. For >30 years prior, the best predictor of OV survival at the time of initial diagnosis was the tumor's stage. About 25% of primary OV tumors are resistant to platinum therapy, the first-line treatment, yet no diagnostic existed to distinguish resistant from sensitive tumors before the treatment. Methods and Results: By using survival analyses, we find and computationally validate that in the general as well as in the high-grade OV patient population, the three patterns of DNA CNAs are each statistically significantly (log-rank test P-value<0.05) correlated with survival and response to platinum throughout the course of the disease, independent of the primary tumor's stage and other indicators that are determined during treatment, i.e., the residual disease after surgery, the outcome of subsequent therapy, and the neoplasm status, as well as the PFS interval to tumor recurrence or progression. For example, the Kaplan-Meier (KM) median survival times of the 89 high-grade and high-stage patients in the validation set of 148 patients, that were diagnosed with tumor recurrence or progression at any time after the completion of the initial therapy, i.e., PFS>0 months, classified by the combination of the three patterns into three groups A, B, and C, are 72, 55, and 34 months, respectively, such that the median survival time of group A is >3 years greater than, and more than twice that of group C. The KM median survival times of the 56 patients among them with a PFS of >11 months, classified into the same groups, are 72, 58, and 45 months, respectively, such that the median survival time of group A is >2 years greater than that of group C. Conclusion: We find that a primary OV tumor's chromosome arm-wide DNA CNAs, across 7p, Xq, and 6p+12p, can predict a patient's survival and response to platinum beyond the time of initial diagnosis, and throughout the disease, even in patients experiencing complete remission after the treatment of the primary tumor, and independent of the time interval to tumor recurrence or progression. Citation Format: Orly Alter. DNA copy-number alterations in primary ovarian serous cystadenocarcinoma encoding for cell transformation and predicting survival and response to platinum therapy throughout the course of the disease. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A60.