A holistic view of ovarian cancer

Published September 01 2016

The American Cancer Society estimates that about 22,280 women this year will receive a first-time diagnosis of ovarian cancer. The cancer, which has various forms, is the most lethal disease of the female reproductive system.

In a paper published in the journal Cell on June 29, researchers presented one of the largest studies ever done of the most malignant type of ovarian cancer. The scientists carried out proteomic analyses of highly malignant tumors and then integrated their data with genetic and clinical information. The detailed view of the tumors gave the researchers a better understanding of what makes these tumors so aggressive.

In 2011, The Cancer Genome Atlas, a project undertaken by the National Cancer Institute, provided a list of genetic mutations in ovarian cancers. “The Cancer Genome Atlas did a fantastic job of cataloging the genomic aberrations associated with many different cancer types, including the most lethal form of ovarian cancer,” which is high-grade serous carcinoma, or HGSC, says Karin Rodland at the Pacific Northwest National Laboratory. She co-led the study published in Cell with Daniel W. Chan at Johns Hopkins University.

The researchers, who came from nine institutions across the U.S. and were funded by the NCI, were interested in how genetic defects affected proteins, which are one of the workhorses in the cell. “We were also interested in protein phosphorylation as a marker of information flow in the cancer cell and as a way of telling which signaling pathways were most activated in HGSC,” says Rodland.

Rodland adds that the researchers wanted to compare cases of HGSC that had the worst outcomes, where the women died in less than three years, with cases in which patients lived for five years or longer. The hope was that the comparison would give scientists fresh clues about the disease.

The team examined 169 tumor samples and identified 9,600 proteins from all the samples. They focused on 3,586 proteins common to all the samples and combined their analyses with genetic and clinical data. The team found that a critical malfunction in HGSC involved changes in DNA where parts either were deleted or copied more than once.

Duplications of sections in chromosomes 2, 7, 20 and 22 caused 200 proteins to be produced in greater numbers. When they looked more closely at those 200 proteins, the researchers found “the affected proteins were highly enriched for functions related to cell motility, invasion and immunity,” says Rodland. These functions help make a cancer more aggressive.

Proteins undergo post-translational modifications, which influence their functions. By looking at the copies of proteins produced as well as their post-translational modifications, the investigators were “able to derive a signature from the pattern of affected proteins that could discriminate between patients with short and long overall survival with a highly significant probability,” says Rodland. This signature was much better at predicting survival outcomes of the women with ovarian cancer than other prognostic signatures.

Moreover, Chan explains that the Hopkins group of researchers selected 122 of the 196 samples based on a deficiency in homologous recombination, a process that is supposed to repair damaged DNA. Ovarian cancer patients with the deficiency usually get treated with a particular drug.

Chan notes that the study revealed several protein post-translational modifications that were associated with the deficiency that “might help explain why not every patient with the homologous recombination deficiency responds to the same drug treatment,” he says. “This finding could help select patients for the right therapy.”

The researchers now are working to validate their observations using a completely different set of patients, but Rodland says that the current study unequivocally shows the importance of a holistic view. “You have to look at the whole flow of information, from genome to transcriptome to proteome and phosphoproteome, in order to get a complete picture of cancer biology,” she says. Rodland points out that the protein phosphorylation data helped the team identify activated pathways that provided “an additional level of information about cancer biology that cannot be derived from genomic data alone.”

Rajendrani Mukhopadhyay Rajendrani Mukhopadhyay is the chief science correspondent for the American Society for Biochemistry and Molecular Biology. Follow her on Twitter.