Buck Institute and UC Santa Cruz Collaborators Make Significant Contribution to Landmark Breast Cancer Study

After doing multiple types of genomic analysis from samples from 825 breast cancer patients, researchers have demonstrated the existence of four main classes of a disease that claims 450,000 deaths world-wide each year. The most recent study from The Cancer Genome Atlas (TCGA) appears in the September 23^rd  issue of Nature; it gives both researchers and oncologists a more refined view of the most common forms of breast cancer and adds to a body of knowledge that increasingly sees this and other cancers as a disease defined not by its tissue of origin, but by the genetic characteristics that also make it vulnerable to treatment. TCGA collaborators at the Buck Institute and the University of California Santa Cruz (UCSC) made a significant contribution to the research, identifying molecular pathways that are different among the four main breast cancer classes as well as identifying pathways common to one particularly aggressive class of breast cancer and an aggressive type of ovarian cancer.

The TCGA, which involves more than 200 researchers working at multiple sites across the country, is in the midst of a sweeping effort aimed at generating comprehensive, multi-dimensional maps of the key genomic changes in major types and subtypes of at least 20 different cancer types over the next five years. The research - which has already reported on glioblastoma brain, ovarian serous and colorectal and squamous lung cancer - is expected to result in a flood of discoveries that will hopefully lead to more powerful and personalized treatments based on targeting the genetic vulnerabilities of tumors. The Buck Institute and UCSC have partnered to create one of seven Genome Data Analysis Centers (GDACs) which provide the highest level of integrated analysis of comprehensive datasets derived from in-depth assays of the DNA, RNA and protein from nearly 500 cases of each cancer type.

“In this transformative breast cancer paper, TCGA identified at least 40 possible drug targets, many of which would not have been considered breast cancer targets, but are instead borrowed from other areas of oncology,” said Buck professor Christopher Benz, MD, who is the co-principal investigator of the UCSC-Buck Institute GDAC. Benz, who is also a practicing oncologist at UCSF’s Carol Franc Buck Breast Care Center, said the unprecedented analysis, which involves the integration of information across six different technology platforms, allows researchers to go beyond genetic mutations associated with breast cancer. “We’re now able to delve into the downstream molecular pathways that may or may not be activated in a particular tumor,” Benz said. “This is what is going to get us into personalized, precision medicine where we can tailor treatments to very specific breast cancer sub types,” he said. “There is a lot of work still to be done, we need to validate these novel pathways, but this study is a major step that will propel therapeutic advances in this direction.”

Working with collaborators at UCSC, Buck Institute staff scientist Christina Yau, PhD, was instrumental in identifying molecular pathways that are commonly activated in basal-like breast tumors and serous ovarian cancers, both of which are known to be particularly aggressive. “There is currently no targeted therapy for basal-like breast cancer, which is more common in African American and younger women,” said Yau, who pointed out that TCGA authors suggest that therapies now used to treat ovarian cancer should be considered for patients diagnosed with basal-like breast cancer.  “This discovery definitely offers new treatment opportunities for breast cancer patients,” said Yau.

The Buck Institute-UCSC GDAC is into its third year of operation. The Buck Institute brings a clinical and biological perspective to UCSC’s bioinformatics expertise and computing power. David Haussler, PhD, UCSC distinguished professor of biomolecular engineering, and co-PI Josh Stuart, PhD, associate professor of biomolecular engineering, lead the bioinformatics effort. Their team is pioneering methods in bioinformatics for TCGA and established the Cancer Genomics Hub (CGHub), a large-scale data repository and user portal for TCGA and the National Cancer Institute's other cancer genome research programs. “More than 300 gigabytes of data are generated for each tumor genome,” Haussler said. “It’s essential that researchers can transfer, access and store this information.” The UCSC team also developed PARADIGM, an analytic software program that is playing a key role in TCGA. “We’ve been able to read mutations but we haven’t been able to understand them,” said Haussler. “PARADIGM allows us to look at multiple sources of data from patient samples and figure out which genetic pathways are altered from their normal function.” In this newly publicized work, the UCSC team was able to use inferences about pathways to draw connections between subtypes of breast cancer with subtypes of multiple other tumor types. “The analysis points to common molecular circuitry between cancers arising in different tissues. Such connections may inform us about new directions for therapy,” Stuart said.

“The Buck Institute’s collaboration with UCSC represents a unique synergy of expertise,” said Benz. “When we put our heads together we can identify which genomic changes are relevant in various tumor types and explore how we might bring our therapeutic arsenal to bear on these cancers,” Benz said. “It’s a very exciting time to be involved in cancer research.”

Contributors to the work:
More than 200 scientists are named as contributors to the research. Other Buck Institute researchers involved in the study include Gary K. Scott, Christina Yau, Janita Thusberg and Sean Mooney.  Other collaborators from UCSC include Joshua M. Stuart, Stephen C. Benz, Jinchun Zhu, Christopher C. Szeto, Evan O. Paull, Daniel Carlin, Christopher Wong, Artem Sokolov, Sam Ng, Theodore C. Goldstein, Kyle Ellrott, Mia Gifford, Christopher Wilks, Singer Ma and Brian Craft. This work was supported by the following grants from the USA National Institutes of Health: U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003079, P50CA116201 and P50CA58223. Additional support was provided by the Susan G. Komen for the Cure, the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the Breast Cancer Research Foundation.