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TCGA Reports on Integrated Genomic Findings for Ovarian Cancer

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a study appearing online today in Nature, researchers involved in The Cancer Genome Atlas reported on findings from their integrated genomic analyses of high-grade serous ovarian cancer.

The TCGA team's genomic analyses relied on whole-exome sequencing of more than 300 high-grade serous ovarian adenocarcinomas and matched normal samples, along with messenger RNA, microRNA, methylation, and copy number analyses on nearly 500 tumor-normal pairs.

While they found relatively few genes containing recurrent mutations in the ovarian cancer, the researchers tracked down numerous copy number changes and several frequently mutated pathways, along with microRNA, methylation, and transcription signatures that appear to hold promise for categorizing ovarian cancer and predicting survival outcomes.

"We have compiled a short list of mutations that occur commonly in ovarian tumors as well as a much longer list of mutations that occur much less frequently," co-author Richard Wilson, director of the Washington University Genome Institute, said in a statement. "This new knowledge sets the stage for future discoveries to help improve the diagnosis and treatment of this devastating disease."

TCGA researchers used Agilent, Illumina, and Affymetrix arrays to look at copy number, messenger RNA expression, microRNA expression, and methylation profiles in 489 clinically annotated stage II to stage IV tumor samples.

They also did whole-exome sequencing on a subset of these. After capturing coding sequences from the genomes of 316 ovarian cancer tumors and matched normal samples, the team sequenced 236 of matched tumor-normal exomes with the Illumina GAIIx platform. The remaining 80 pairs were sequenced with the ABI SOLiD 3 platform.

Overall, the tumors contained roughly 61 somatic mutations each, on average. Nearly all of the tumors tested — some 96 percent — harbored mutations affecting the tumor suppressor gene TP53, they reported. Nine other genes showed recurrent mutations, though at lower frequency than TP53.

Among them: BRCA1 and BRCA2, which were somatically mutated in three percent of the tumors. Consistent with past studies linking ovarian cancer risk to BRCA1/2 germline mutations, the team also detected BRCA1 germline mutations in nine percent of ovarian cancer cases and BRCA2 germline mutations in eight percent.

Within the broader set of 489 ovarian tumors, meanwhile, the researchers identified eight recurrent regional chromosomal gains, including five found in more than half of the tumor samples. Meanwhile 18 of the 22 recurrent losses of chromosomal regions appeared in at least 50 percent of the tumors. The team also found 63 smaller, focal amplifications and 50 significant focal deletions.

"A globally disrupted genome is the common theme in this cancer," co-author Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center, said in a statement. "Large-scale amplifications and deletions of chromosome segments make this cancer very complex."

The genomic analyses also revealed several high-grade serous ovarian cancer sub-types — four with distinct promoter methylation patterns and three sub-types with different microRNA patterns. Another four sub-groups, dubbed immunoreactive, differentiated, proliferative, or mesenchymal, sprung up from the group's expression studies.

Meanwhile, another set of 193 genes had expression patterns that corresponded to improved or reduced survival outcomes, they reported. Within this 193-gene signature, 108 genes corresponded to poor overall survival outcomes, while 85 coincided with improved survival.

By bringing together the data on the ovarian cancer cases assessed by both whole-exome sequencing and other genomic approaches, the team also got clues about the biological pathways that tend to get altered in ovarian cancer. These included genes in the RB, PI3K/RAS, or NOTCH signaling pathways, as well as genes involved in homologous recombination pathways and in the FOXM1 transcription factor network.

Along with insights into ovarian cancer biology, those involved in the study say the findings may eventually lead to improved treatment for some forms of the disease, since many of the genes or pathways identified in the study can be targeted with drugs that are already approved by the US Food and Drug Administration or which are currently being tested.

"Overall, these discoveries set the stage for approaches to the treatment of [high-grade serous ovarian cancer] in which aberrant genes or networks are detected and targeted with therapies selected to be effective against these specific aberrations," the researchers concluded.