Posted: July 1, 2011
TCGA Researchers Report the Findings of their Comprehensive Characterization of the Ovarian Cancer Genome
Ovarian carcinoma, a cancer that develops in the ovaries, is the fifth leading cause of cancer death among women in the United States. Doctors lack methods for early detection and treatment, which means that many patients diagnosed with advanced ovarian cancer have poor prospects. Ovarian cancer patients are often diagnosed with a type of tumor called serous ovarian carcinoma, and these tumors are likely to recur in most patients after they have been treated. Only 31 percent of patients with this tumor type are expected to live for five years or more, but despite the grim outlook, a paper published in the June 30, 2011 issue of Nature1 by researchers from The Cancer Genome Atlas (TCGA) offers some hope that better treatments can be found. The scientists performed a wide-ranging analysis of the genomic changes that occur in these tumors and found several potential targets for medications.
The researchers found hundreds of genes that were abnormally deleted or duplicated, a phenomenon called copy-number variation. Of these hundreds of genes, 68 of the duplicated genes were matched with already-existing chemical compounds that can block activity of the excessively produced proteins that are made from these genes. Such a finding is cause for cautious optimism, as it gives scientists a jump start in the search for medications that could treat serous ovarian tumors.
Non-inherited Alterations in BRCA1 and BRCA2 Genes Play a Role in Ovarian Cancer
The researchers also speculated that many serous ovarian tumors could respond to PARP inhibitors, which are a class of drugs that are already used to treat breast and ovarian cancers with abnormal BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 are involved in most cases of inherited breast and ovarian cancer. However, changes in these genes can also play a role in breast and ovarian cancers that do not run in families. The current study confirmed that changes in BRCA1 and BRCA2 that were not inherited existed in a number of tumors, suggesting that treatment with PARP inhibitors could be extended to patients with non-inherited ovarian cancer. The researchers also confirmed a previous finding that the presence of BRCA1 or BRCA2 mutations is associated with better survival. A new finding by TCGA researchers added more detail to our understanding of these genes and their role in ovarian cancer. It appears that the way BRCA 1 and BRCA2 genes become defective also relates to survival. If a BRCA1 gene is methylated (as opposed to mutated), there is no improved survival. DNA methylation is a chemical reaction in which a small molecule called a methyl group is added to DNA, affecting whether genes are turned on or off.
TCGA researchers also found that which genes are expressed helps predict patient survival. They identified 108 genes associated with poor survival and 85 genes associated with better survival. Patients whose tumors had a gene-expression signature associated with poor survival lived for a period that was 23 percent shorter than patients whose tumors had the genes associated with better survival.
Different Cancers are Genetically Distinct
In addition to having a number of potential drug targets and gene changes predictive of survival, the serous ovarian tumors stood out among previously studied tumor types like glioblastoma in terms of the sheer number of genes that were duplicated or deleted. Compared to ovarian tumors, glioblastoma tumors are characterized less by copy number changes and more by the same genes having mutations, or changes in the DNA code, in many tumors. The researchers believe this distinction points to the differing balance of types of genetic changes that happen in each cancer type. Put another way, it suggests that all cancer does not arise from the same kinds of genomic changes and it validates TCGA’s approach to studying a long list of different cancers.
The next step for scientists will include experiments on the known drugs that matched some of the target genes to determine if they can indeed slow or block ovarian tumor growth. The hope is that clinical trials on some of these drugs, as well as PARP inhibitors, will quickly follow. Overall, the future holds promise for treatments targeted to a patient’s specific DNA changes.
1The Cancer Genome Atlas Research Network. (2011) Integrated genomic analyses of ovarian carcinoma. Nature. 474(7353): 609-615. View Author Manuscript