Patterns Of Tumor Evolution In High Grade Serous Ovarian Carcinoma

BACKGROUND High grade serous ovarian cancer (HGS-OvCa) is the fifth leading cause of cancer death amongst women in the United States and is characterized by a 25% rate of recurrence within six months after the end of treatment. To gain insight into the mechanisms used by tumor cells to evade the toxic effects of DNA damaging therapy, we genomically characterized sixteen triplets of tumor primary, tumor recurrence and normal samples using whole exome sequencing, DNA copy number arrays, methylation arrays and gene expression arrays. RESULTS Fifteen out of sixteen recurrent samples acquired both somatic mutations as well as DNA copy number alterations, and the number of novel abnormalities acquired was correlated with the time elapsed between primary and recurrence. Interestingly, nine of sixteen recurrence samples harbored only a subset of the mutations identified in the primary tumor. Similarly, these cases appeared to have lost a subset of the copy number alterations with which the primary sample originally presented, suggesting that primary and recurrent tumors were derived from an ancestral clone rather than to have evolved from the dominant clone present at diagnosis. The remaining seven recurrent samples contained all abnormalities found at time of diagnosis and are thus likely to have evolved from the dominant diagnostic clone. The time to recurrence was shorter for ‘diagnostic clone’ patients than for ‘ancestral clone’ patients, with borderline significance (likelihoodratio test p-value 0.08). Analysis of mutation allele fractions suggested a higher degree of tumor heterogeneity in primary tumor samples than in recurrent tumor samples. Recurrence was not associated with a specific mutation or copy number alteration. Tumors from patients whose interval between end of platinum therapy and recurrence was less than six months were not characterized by specific patterns of abnormalities. DISCUSSION Analysis of genomic alterations in primary and recurrent ovarian cancer tumor samples suggests that recurrences can be classified into two dominant groups: recurrences derived from an ancestral clone and recurrences originating from the same dominant clone present at time of diagnosis. Analysis of mutation allele fractions provided further insights into the clonality of primary and recurrent tumor samples. These findings shed light on the mechanism by which tumors overcome the effects of DNA damaging agents and may lead to development of therapies that specifically address the clonal origin properties of recurrent tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4922. doi:1538-7445.AM2012-4922