New TCGA project finds cancer-driving changes shared across tumor types

Pan-Cancer initiative looks across organ-site research silos to classify diseases genomically

MD Anderson News Room 09/26/13

HOUSTON – The Cancer Genome Atlas, a massive collaborative effort tracking down the genomic abnormalities that drive cancer in 12 different organs, is now directing its research firepower to examine how those aberrations occur commonly across tumor types.

Scientists aligned with The Cancer Genome Atlas (TCGA), a joint project of the National Cancer Institute and the National Human Genome Research Institute, describe the TCGA’s Pan-Cancer Initiative and report first research findings in two papers and two commentaries today in the journal Nature Genetics.

“With TCGA finding genomic drivers of cancer in those 12 cancer types, now the Pan-Cancer project will identify shared patterns of molecular abnormalities across cancers.  That will help us apply discoveries in one disease to another,” said John Weinstein, M.D., Ph.D., chair of Computational Biology and Bioinformatics at The University of Texas MD Anderson Cancer Center. Weinstein is co-author of a Nature Genetics commentary that describes the pan-cancer analysis initiative.

“One of more exciting possibilities for this research is that we can take therapies effective in one tumor type, for example HER2 protein inhibitors for HER2-positive breast cancer, and check their effectiveness  in other cancer types that we now know also have that mutation or overexpress that protein,” Weinstein said. Groups of patients with glioblastoma, endometrial, gastric, bladder and lung cancers have been found to have HER2 abnormalities.

Pan-cancer analysis also can help researchers identify small groups of patients affected by a specific genomic abnormality who might be missed in single-cancer research but emerge in a larger cross-cancer study.   “This puts it all together rather than relying solely on piecemeal studies of this or that cancer type,” Weinstein said.

Crossing the silos

The authors note that until recently cancer care and research have been siloed by tumor type, which made sense, “but the results of molecular analysis are now calling this view into question.”  Cancers of different organs have many shared features while, conversely, cancers from the same organ are often quite distinct.

Genomic diversity among cancer cells in tumors in the same organ fuels resistance to treatment and cancer progression.

To address this issue, TCGA launched the Pan-Cancer analysis project in October 2012. A dataset totaling 5,074 tumor samples with data from six different types of genomic and epigenomic research platforms was assembled from individual TCGA projects.

Primary cancers included are glioblastoma multiforme, acute myeloid leukemia, head and neck and lung squamous cell cancers; and breast, lung, kidney, ovarian, bladder colon, rectal cervical and endometrial adenocarcinomas – cancers that form in epithelial tissue that lines or covers organs.  Adenocarcinomas make up 80-plus percent of all solid tumors.

Papers find new gene copy alterations, 30 subclasses of tumors

The two Nature Genetics research papers, by scientists at other institutions, examined patterns of gene copy deletions or amplifications in 4,934 tumors from the Pan-Cancer data set and genomic and epigenetic features in 3,299 tumors.

The first paper identified 140 genomic regions with recurrent copy number alterations, 102 of which had no known oncogene or tumor-suppressor gene targets and 50 of which had significantly mutated genes.

The second paper stratified tumors by their genomic and epigenomic features, finding two major classes of tumor, one driven by mutations and the other mainly by gene copy alterations.  They also found that cancer-promoting gene signatures identified 30 subclasses of tumor independent of tissue of origin.

While different cancer types share genomic alterations, it’s known that protein activity and clustering is affected by tissue type.  By analyzing 12 cancers, researchers expect individual tissue effects to drop out, exposing tissue-independent activity.

More to come

Weinstein is the commentary’s first individual author after listing of The Cancer Genome Atlas Research Network, representing hundreds of scientists, as first author.  Gordon Mills, M.D., Ph.D., chair of Systems Biology, and Kenna Shaw, Ph.D., executive director of the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT) are the other MD Anderson co-authors.

Mills has been involved with 11 of the 12 TCGA projects addressing individual tumor types.  He also leads or co-leads a number of silo-breaking research projects, including a Stand Up to Cancer Dream Team addressing the PI3K pathway in endometrial, breast and ovarian cancers and an MD Anderson moon shot examining triple-negative breast cancer and high-grade serous ovarian cancer. He is co-director of the IPCT.

Shaw came to MD Anderson in 2013 after serving as director of the TCGA program office.

The second Nature Genetics commentary includes MD Anderson co-authors Yuan Yuan, a graduate student, and Han Liang, Ph.D., an assistant professor, both in Computational Biology and Bioinformatics. Their paper describes the software platform used to perform integrative analysis of the 12 tumor types.

Weinstein said there are about 80 more Pan-Cancer papers in the pipeline by TCGA researchers.  And work continues on individual cancer types – Weinstein is senior author of a bladder cancer analysis in the publication pipeline.

The commentary lists a dozen questions addressable by additional Pan-Cancer analysis. Necessary follow-up will include functional studies to determine how genomic abnormalities identified actually affect cancer. Josh Stuart, Ph.D., of the Department of Biomolecular Engineering at the University of California, Santa Cruz, is corresponding author of the commentary.

“There’s a lot more to come,” Weinstein said. “We can wring a certain amount of information and knowledge from these results now.  The real value will come over time as informaticians and experts on particular cancer types feast on the data to generate important hypotheses -- and important conclusions for the benefit of cancer patients and their families.”