PNNL

Results: In what is believed to be the largest study of its kind, scientists at the Pacific Northwest National Laboratory (PNNL), Johns Hopkins University, and collaborators from institutions across the nation have examined the collections of proteins in the tumors of 169 ovarian cancer patients to identify critical proteins present in their tumors.

By integrating their findings about the collection of proteins (the proteome) with information already known about the tumors' genetic data (the genome), the investigators report the potential for new insights into the progress of the most malignant form of the disease. The work is published June 29, 2016, in the advance online edition of Cell.

Why It Matters: The researchers say their achievement illustrates the power of combining genomic and proteomic data - an approach known as proteogenomics - to yield a more complete picture of the biology of a cancer. Ovarian cancer accounts for 3 percent of all cancers in women and is the fifth leading cause of cancer deaths among women in the United States.

"Historically, cancer's been looked at as a disease of the genome," said Karin Rodland, a senior author of the study and chief scientist for biomedical research at PNNL. "But that genome has to express itself in functional outcomes, and that's what the proteomic data adds, because proteins do the actual work of the genome."

The authors say the findings will better enable researchers to identify the biological factors defining the 70 percent of ovarian cancer patients who suffer from high-grade serous carcinoma, the most malignant form of ovarian cancer. Currently, only one in six such patients lives five or more years beyond diagnosis.

Methods: Under the leadership of the National Cancer Institute, scientists around the nation created The Cancer Genome Atlas (TCGA), a collaborative effort to map cancer's genetic mutations. The task for ovarian cancer was completed in 2011. In the current study, the PNNL and the Johns Hopkins teams each studied subsets of 169 high-grade serous carcinoma tissue samples and accompanying genomic and clinical data from the TCGA.

The Johns Hopkins team initially selected 122 of the samples based on those tumors' ability to repair damaged DNA - known as homologous recombination deficiency - and characterized by changes in genes including BRCA1, BRCA2 and PTEN, mutations long linked to increased cancer risk and severity.

The PNNL team initially selected 84 samples based on overall patient survival times. "We examined the data for the shortest-surviving patients and the longest-surviving patients hoping to pinpoint biological factors associated with extremely short survival or better-than-average, longer survival," said Rodland.

Then, through their participation in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), another program of the National Cancer Institute which funded both teams, the two groups combined their efforts.

Using protein measurement and identification techniques based on mass spectrometry, the teams identified 9,600 proteins in all the tumors, and pursued study on 3,586 proteins common to all 169 tumor samples.

A detailed look at the activity of proteins in cancer biology gives researchers insight into specific molecular events that would otherwise remain unknown.

What's Next? New hypotheses about the disease, and how to treat it. New directions to test in the lab and clinic.

Acknowledgments

Sponsors: National Cancer Institute, National Institutes of Health

Research Area: Biological Systems Science

User Facility: EMSL

Research Team: Hui Zhang, Zhen Zhang, Bai Zhang, Jian-Ying Zhou, Li Chen, Shisheng Sun, Lijun Chen, Punit Shah, Paul Aiyetan, Yuan Tian, Caitlin Choi, Stefani Thomas, Lori Sokol, Heng Zhu, David W. Chan, Ie-Ming Shih, Leslie Cope, and Akhilesh Pandey of Johns Hopkins; Tao Liu, Samuel H Payne, Jason E McDermott, Vladislav A Petyuk, Debjit Ray, Feng Yang, Marina A Gritsenko, Therese R Clauss, Matthew E Monroe, Song Nie, Chaochao Wu, Ronald J Moore, and Richard D Smith of Pacific Northwest National Laboratory; Jing Wang, David L Tabb, and Bing Zhang of Vanderbilt University; Seong Won Cha, Sunghee Woo, and Vineet Bafna of the University of California, San Diego; Kun-Hsing Yu and Michael P  Snyder of Stanford University; David Fenyo of New York University; Yue Wang of Virginia Polytech; Henry Rodriguez, Emily S Boja, Tara Hiltke, and Robert C Rivers of the National Cancer Institute; and Douglas A Levine of Memorial Sloan Kettering Cancer Center.

Reference: Zhang H, T Liu, Z Zhang, SH Payne, B Zhang, JE McDermott, J-Y Zhou, VA Petyuk, L Chen, D Ray, S Sun, F Yang, L Chen, J Wang, P Shah, SW Cha, P Aiyetan, S Woo, Y Tian, MA Gritsenko, TR Clauss, C Choi, ME Monroe, S Thomas, S Nie, C Wu, RJ Moore, K-H Yu, DL Tabb, D Fenyö, V Bafna, Y Wang, H Rodriguez, ES Boja, T Hiltke, RC Rivers, L Sokoll, H Zhu, I-M Shih, L Cope, A Pandey, B Zhang, MP Snyder, DA Levine, RD Smith, DW Chan, KD Rodland, and the CPTAC investigators. 2016. "Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer." Cell, June 29, 2016. DOI: 10.1016/j.cell.2016.05.069