Researchers propose “disruptive” new system to reclassify tumors

Researchers with The Cancer Genome Atlas (TCGA) have analyzed more than 3500 tumors on multiple genomic technology platforms, revealing a new approach to classifying cancers.  This largest-of-its-kind study, published online August 7th in Cell featured major contributions by Buck faculty Christopher Benz, MD and Senior Staff Scientist Christina Yau, PhD.

TCGA scientists analyzed the DNA, RNA and protein from 12 different tumor types using six different TCGA “platform technologies” to see how the different tumor types compare to each other. The study showed that cancers are more likely to be molecularly and genetically similar based on their cell type of origin as opposed to their tissue type of origin (e.g. breast, kidney, bladder, etc.). Benz, a senior author on the paper points out that most of our tissues are composed of many different types of epithelial and non-epithelial cells.  “This disruptive genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” said Benz. “Examples like the proposed reclassification of bladder cancer into several different cancer classes, each with distinct clinical outcomes, help explain why patients often respond very differently when treated with the same systemic therapy for their seemingly identical cancer type.”

The study team suggests that at least one in ten cancer patients would be classified differently under this new system. But Benz thinks this fraction of tumors needing reclassification will swell when more samples and additional tumor types are included in the next round of analysis, anticipated to involve more than 20 different tumor types. “We’re just appreciating the tip of the iceberg when considering the potential of this multi-platform type of genomic analysis. It could be that as many as 30 or 50 percent of cancers need to be reclassified.”

Particularly striking results were apparent with the bladder and breast cancers. At least three different subtypes of bladder cancer were identified–  one subtype virtually indistinguishable from lung adenocarcinomas, and another most similar to squamous cell cancers arising from the head-and-neck and lungs. The study also highlighted and confirmed known differences between subtypes of breast cancer – but revealed the new and surprising finding that basal-like breast cancers actually constitute their own cancer class. Basal-like breast cancers, commonly referred to as triple-negative breast cancer, are particularly aggressive and life threatening, and are more prevalent among African-American and younger women. “Even though these basal-like cancers arise in the breast, on the molecular level they have more in common with ovarian cancers and cancers of squamous cell origin than to other subtypes of breast cancer,” said Yau, a co-lead author of the study who also directs bioinformatics efforts in the Benz lab, which largely focuses on developing new targeted therapeutics and molecular diagnostics for breast cancer.

Benz thinks this study – and future iterations of it – will fuel better clinical trial designs whereby patients become eligible for novel therapeutics based on this type of genomic reclassification of tumors.  “Although follow-up studies are needed to validate and refine this newly proposed cancer classification system, it will ultimately provide the biologic foundation for that era of personalized cancer treatment that patients and clinicians eagerly await.”

About The Cancer Genome Atlas (TCGA) Research Network

This study was performed as part of the TCGA’s Buck Institute-UCSC Genome Data Analysis Center (GDAC), co-led by Benz and UC Santa Cruz investigators, Josh Stuart and David Haussler. The study’s corresponding authors along with Benz and Stuart includes Charles Perou from the University of North Carolina, Chapel Hill. The TCGA Research Network includes over 150 researchers at many different institutions across the country; and a full list of TCGA consortia participants in this study is provided in the publication. All TCGA-generated data are freely available in advance of publication at the TCGA Data Portal, http://tcga-data.nci.nih.gov/tcga, and CGHub, https://cghub.ucsc.edu. The TCGA Research Network is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health. Additional details about TCGA, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics and a media library of images can be found at http://cancergenome.nih.gov.