Integrated genomic analyses of ovarian carcinoma¶
Why this mattered¶
TBD
Abstract¶
A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further 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 microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. The Cancer Genome Atlas (TCGA) project reports here its analysis of messenger RNA and microRNA expression, promoter methylation, DNA copy number and exome sequences in 489 high-grade serous ovarian adenocarcinomas. The analyses help establish new tumour subtypes. Among other insights is the finding that while the gene encoding p53 tumour suppressor is mutated in almost all tumours, nine other loci including NF1, BRCA1, BRCA2, RB1 and CDK12 carry recurrent albeit low-prevalence mutations. Homologous recombination is defective in about half of the tumours studied, and Notch and FOXM1 signalling are involved in the pathophysiology.
Related¶
- cite ← An integrated map of genetic variation from 1,092 human genomes — The 1000 Genomes integrated map cites TCGA ovarian carcinoma analysis as an example of using large-scale genomic variation data to interpret cancer genomes.
- cite ← Comprehensive molecular portraits of human breast tumours — TCGA's breast cancer study follows the ovarian carcinoma paper's integrated multi-platform genomic analysis strategy.
- cite ← Comprehensive molecular characterization of human colon and rectal cancer — The colon and rectal cancer TCGA study follows the ovarian carcinoma TCGA template of integrated multi-platform genomic characterization.
- cite ← Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing — Gerlinger et al. cite TCGA ovarian carcinoma analysis as evidence that bulk tumor genomics can define cancer alterations but may miss spatial intratumor heterogeneity.