Genome Atlas Study Pinpoints Ovarian Cancer Genetic Defects

Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Research Network and analyses were reported in the June 30, 2011, issue of the journal Nature. TCGA is jointly funded and managed by the [US] National Cancer Institute (NCI) and the [US] National Human Genome Research Institute (NHGRI), both part of the [US] National Institutes of Health (Bethesda, MD, USA).

Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85% percent of all ovarian cancer deaths. TCGA investigators completed whole-exome sequencing, which examines the protein-coding regions of the genome, on an unprecedented 316 tumors. They also completed other genomic characterizations on these tumors and another 173 specimens.

Among the specific findings was the confirmation that mutations in a single gene, TP53, were present in more than 96% of all such cancers. TP53 encodes a tumor suppressor protein that normally prevents cancer formation. Mutations in the gene disrupt this protein’s function, which contributes to uncontrolled growth of ovarian cells.

Also found were 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.

Results of the study made clear how sets of genes were expressed in a fashion that could predict patient survival by identifying patterns for 108 genes associated with poor survival and 85 genes associated with better survival. Patients with tumors carrying a gene-expression signature associated with poor survival lived for a period that was 23% shorter than patients whose tumors did not have such a signature.

To identify opportunities for targeted treatment, the investigators searched for existing drugs that might inhibit amplified or over-expressed genes that were suggested to play a role in ovarian cancer. The search identified 68 genes that could be targeted by existing [US] Food and Drug Administration-approved or experimental therapeutic compounds. The findings indicated that one type of drug, a PARP (Poly ADP ribose polymerase) inhibitor, might be able to suppress the DNA repair gene observed in half of the ovarian tumors studied. While it is known that this type of drug may be effective against the disease, this study revealed that 50% percent of tumors might be responsive to drugs that exploit the genetic instability of the tumors and induce the cancer cells to die.

“We found that ovarian cancer has a dramatic pattern of genomic disruption," said contributing author Dr. Richard Gibbs, professor of molecular and human genetics at the Baylor College of Medicine (Houston, TX, USA). “A globally disrupted genome is the common theme in this cancer. Large-scale amplifications and deletions of chromosome segments make this cancer very complex.”

Related Links:
[US] National Institutes of Health
Baylor College of Medicine