The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

Background

Ovarian cancer is the fifth leading cause of cancer death among women in the US, with 21,880 new cases and 13,850 deaths predicted for 2010 1. Most deaths are of patients presenting with advanced stage, high grade serous ovarian cancer (HGS-OvCa) 2, 3 (~ 70%). The standard of care is aggressive surgery followed by platinum/taxane chemotherapy. After therapy, platinum resistant cancer recurs in approximately 25% of patients within 6 months 4 and overall 5-year survival is 31% 5. Approximately 13% of HGS-OvCa is attributable to germline mutations in BRCA1 or BRCA2 6, 7, while a smaller percentage can be accounted for by other germline mutations. However, most ovarian cancer can be attributed to a growing number of somatic aberrations 8.