Integrated Genomic Analyses of Ovarian Carcinoma

Author

The Cancer Genome Atlas Research Network

Doi

10.1038/nature10166

PMID: 21720365 · DOI: 10.1038/nature10166 · Journal: Nature (2011)

TL;DR

The Cancer Genome Atlas comprehensively profiled 489 high-grade serous ovarian carcinomas (HGS-OvCa) using whole-exome sequencing, copy number arrays, mRNA/miRNA expression, and DNA methylation. The study found TP53 mutated in 96% of tumors with few other recurrently mutated genes, identified four transcriptional subtypes, and showed that homologous recombination defects are present in approximately half of tumors, providing a rationale for PARP inhibitor therapy.

Cohort & data

  • 489 clinically annotated stage II-IV HGSOC samples from ov_tcga_pub.
  • Whole-exome sequencing on 316 tumors with matched normals (~180,000 exons from ~18,500 genes).
  • DNA copy number via Affymetrix SNP6 and Agilent arrays for all 489 samples.
  • mRNA expression from three platforms (Agilent, Affymetrix HuEx, Affymetrix U133A), miRNA expression, and Illumina 27K methylation arrays.
  • GISTIC used for focal copy number analysis.
  • All patients received platinum-based chemotherapy; 94% received a taxane.

Key findings

  • TP53 was mutated in 303/316 (96%) of sequenced HGS-OvCa samples.
  • Only 9 genes were significantly mutated above background: TP53, BRCA1, BRCA2, NF1, RB1, CDK12, CSMD3, FAT3, GABRA6.
  • BRCA1 germline mutations in 9% and BRCA2 in 8% of cases, with additional somatic mutations in 3% each.
  • 113 significant focal DNA copy number aberrations identified; most common focal amplifications: CCNE1, MYC, MECOM (each >20% of tumors).
  • Four transcriptional subtypes identified: Immunoreactive, Differentiated, Proliferative, Mesenchymal.
  • Three miRNA subtypes identified; miRNA subtype 1 associated with significantly longer survival.
  • A 193-gene transcriptional signature predictive of overall survival was validated across four independent datasets.
  • Homologous recombination (HR) pathway defective in ~50% of tumors (BRCA1/2 mutation 20%, BRCA1 methylation 11%, EMSY amplification/mutation 8%, PTEN deletion/mutation 7%, RAD51C methylation 3%, ATM/ATR mutation 2%, Fanconi anemia gene mutation 5%).
  • RB1 pathway deregulated in 67% of cases; PI3K/RAS in 45%.
  • FOXM1 transcription factor network activated in 87% of cases.
  • Notch signaling pathway altered in 23% of samples.
  • CCNE1 amplification mutually exclusive with BRCA inactivation (8% vs. 26% in BRCA-wildtype, FDR-adjusted P = 0.0048).
  • BRCA-mutated cases showed better overall survival than BRCA-wildtype; BRCA1 epigenetically silenced cases had survival similar to wildtype (median OS 41.5 vs. 41.9 months, P = 0.69).

Genes & alterations

Gene Alteration Finding
TP53 Somatic mutation Mutated in 96% of HGS-OvCa; 302 validated mutations
BRCA1 Germline/somatic mutation, promoter methylation Germline 9%, somatic 3%, methylation 11.5%; methylation mutually exclusive with mutation
BRCA2 Germline/somatic mutation Germline 8%, somatic 3%
NF1 Somatic mutation, focal deletion 13 validated mutations; homozygous deletion in >=2%
RB1 Somatic mutation, focal deletion 6 validated mutations; homozygous deletion in >=2%
CDK12 Somatic mutation 9 mutations; 5 nonsense/indel (loss of function), 4 missense in kinase domain
CCNE1 Focal amplification >20% of tumors; associated with shorter survival trend (P = 0.072)
MYC Focal amplification >20% of tumors
MECOM Focal amplification >20% of tumors; enriched in Immunoreactive subtype
KRAS Somatic mutation (G12D), amplification Rare driver; amplified in >=10%
NRAS Somatic mutation (Q61R) Rare driver
BRAF Somatic mutation (N581S) Rare driver
PIK3CA Somatic mutation (E545K, H1047R) Rare driver
PTEN Focal deletion, mutation Deletion/mutation in 7%; potential PARP inhibitor sensitivity
FOXM1 Transcriptional activation Network activated in 87%; likely driven by TP53 loss
CREBBP Focal deletion, mutation 5 non-synonymous + 2 frameshift mutations
RAD51C Promoter methylation Hypermethylated in 3% of tumors

Clinical implications

  • Approximately 50% of HGS-OvCa harbor HR defects, providing a rationale for PARP inhibitor therapy (e.g., olaparib) beyond germline BRCA carriers.
  • BRCA-mutated tumors have better overall survival, likely reflecting platinum sensitivity.
  • BRCA1 epigenetic silencing does not confer the same survival advantage as BRCA1/2 mutations, suggesting mechanism of inactivation matters clinically.
  • CCNE1 amplification survival disadvantage may be confounded by the better survival of BRCA-mutated cases rather than being an independent prognostic factor.
  • 22 amplified, over-expressed genes are targets of existing therapeutic inhibitors, including MECOM, MAPK1, CCNE1, and KRAS.
  • Commonly deregulated pathways (RB, RAS/PI3K, FOXM1, NOTCH) represent therapeutic opportunities.

Limitations & open questions

  • Median follow-up of only 30 months limits mature survival analyses.
  • Transcriptional subtypes did not show statistically significant survival differences in this cohort.
  • BRCA1 methylation confers different biology than BRCA1/2 mutation despite both disrupting HR; the mechanism is unclear.
  • GABRA6 and FAT3 appear statistically significantly mutated but are not expressed in HGS-OvCa, questioning their functional relevance.
  • DNA methylation clusters showed only modest stability.
  • The study does not include functional validation of the identified driver mutations or pathway alterations.

Citations from this paper used in the wiki

  • “TP53 was mutated in 303 of 316 samples (283 by automated methods and 20 after manual review)”
  • “BRCA1 and BRCA2 had germline mutations in 9% and 8% of cases, respectively, and both showed somatic mutations in an additional 3% of cases”
  • “Overall, HR defects may be present in approximately half of HGS-OvCa, providing a rationale for clinical trials of PARP inhibitors”
  • “the FOXM1 transcription factor network… significantly altered in 87% of cases”
  • “CCNE1 amplification in cases with BRCA inactivation (8% of BRCA altered cases had CCNE1 amplification v. 26% of BRCA wild type cases, FDR adjusted P = 0.0048)”
  • “epigenetically silenced BRCA1 cases exhibited survival similar to BRCA1/2 WT HGS-OvCa (median OS 41.5 v. 41.9 months, P = 0.69, log-rank test)”

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