Cancer Genome Atlas Provides Detailed Ovarian Cancer Analysis

Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Research Network and analyses are reported in the June 30, 2011, issue of the journal Nature. Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85% of all ovarian cancer deaths. TCGA researchers 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.

TCGA is jointly funded and managed by the US National Cancer Institute (NCI; Bethesda, MD, USA) and the US National Human Genome Research Institute (NHGRI; Bethesda, MD, USA), both part of the National Institutes of Health (NIH). “This landmark study is producing impressive insights into the biology of this type of cancer,” said NIH director Francis Collins, MD, PhD “It will significantly empower the cancer research community to make additional discoveries that will help us treat women with this deadly disease. It also illustrates the power of what's to come from our investment in TCGA.”

Among the specific findings is the validation that mutations in a single gene, TP53, are 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. Moreover, TCGA identified a multitude of less-frequent mutations in other genes.

TCGA researchers also established how sets of genes are expressed in a way that can predict patient survival--identifying patterns for 108 genes associated with poor survival and 85 genes associated with better survival. Patients whose tumors had a gene-expression signature tied to poor survival, lived for a period that was 23% shorter than patients whose tumors did not have such a signature. The overall five-year survival rate for ovarian cancer is 31%, which means that 69% of patients diagnosed in 2011 will not be alive in 2016, highlighting the urgent need for a better understanding of the disease.

“The new knowledge of the genomic changes in ovarian cancer has revealed that the molecular catalysts of this disease are not limited to small changes affecting individual genes,” said NCI director Harold E. Varmus, MD “Also important are large structural changes that occur in these cancer genomes. Cancer researchers can use this comprehensive body of information to better understand the biology of ovarian cancer and improve the diagnosis and treatment of this dreaded disease.”

To identify opportunities for targeted treatment, the investigators looked for existing drugs that might inhibit amplified or overexpressed 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 investigators noted that one type of drug, a PARP (poly ADP [adenovirus death protein] ribose polymerase) inhibitor, might be able to counteract the DNA repair gene seen in half of the ovarian tumors examined. Whereas researchers have known that these drugs could be effective against the disease, this study revealed that 50% of tumors might be responsive to drugs that exploit the genetic instability of the tumors and trigger the cancer cells to die.

“Like all cancers, ovarian cancer results from genomic derangements,” said Eric D. Green, MD, PhD, NHGRI director. “The efforts of TCGA are confirming that the more we learn about genomic changes in tumor cells, the more we will be able to care for the people affected by cancer.”

The results of this study support the existence of four diverse subtypes of the disease, based on the patterns seen in the transcription of RNA from DNA. They also support the existence of four related subtypes based on the patterns of DNA methylation--a chemical reaction in which a small molecule called a methyl group is added to DNA, altering the activity of individual genes. These patterns in all probability reflect the functional changes associated with ovarian serous adenocarcinoma, but are not strongly associated with survival duration.

Mutations in BRCA1 and BRCA2 genes, which are linked with some forms of breast cancer, also confer increased risk for ovarian cancer. In this study, about 21% of the tumors showed mutations in these genes. Analysis of these tumors confirmed observations that patients with mutated BRCA1 and BRCA2 genes have better survival odds than patients without mutations in these genes. Significantly, investigators identified that the process by which the BRCA1 and BRCA2 genes become defective also relates to survival. If either of the BRCA1 and BRCA2 genes is mutated, there is improved survival duration. However, if BRCA1 activity is instead reduced by methylation, there is no improved survival duration. “The integration of complex genomic data sets enabled us to discover an intricate array of genomic changes and validate one specific change that occurs in the vast majority of all ovarian cancers,” said lead author Paul T. Spellman, PhD, Lawrence Berkeley Lab (Berkeley, CA, USA). “Significantly, we have also found new information regarding the role that the BRCA1 and BRCA2 genes play in determining survival.”

In this latest study, the TCGA researchers built upon the approach they utilized in 2008 to characterize the genome of gliobastoma multiforme, the most common form of brain cancer.

TCGA, launched in 2006, is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA data are being made rapidly available to the research community through a database. The database provides direct access to most analytic datasets, with other data, such as patient treatment records and raw DNA sequence data, available to qualified researchers through an NIH review and approval process.

Related Links:
The Cancer Genome Atlas
US National Cancer Institute
US National Human Genome Research Institute