Cancer categories recast in largest-ever genomic study

New research suggests that cancer would be more accurately diagnosed in 1 of every 10 patients if their tumors were defined by cellular and molecular criteria rather than by the tissues in which they originated, and that this information, in turn, could lead to more appropriate treatments. In the largest study of its kind to date, scientists analyzed molecular and genetic characteristics of more than 3,500 tumor samples of 12 different cancer types using multiple genomic technology platforms.

Cancers have traditionally been categorized according to their tissue of origin—such as breast, bladder, or kidney cancer. But tissues are composed of different types of cells, and the new work indicates that in many cases the type of cell affected by cancer may be a more useful guide to treatment than the tissue in which a tumor originates.

The study, published in Cell (2014; doi:10.1016/j.cell.2014.06.049), was conducted as part of The Cancer Genome Atlas (TCGA) initiative spearheaded by the National Cancer Institute and National Human Genome Research Institute, both part of the National Institutes of Health. TCGA was launched in 2006 with the goal of compiling genomic atlases of more than 20 types of cancer. As the project proceeded, however, commonalities across cancer types began to emerge, which led to the creation of the TCGA Pan-Cancer project, the source of the data used in the new study.

In this work, TCGA Research Network scientists analyzed DNA, RNA, and protein from 12 tumor types using six different genomic technologies to see how different tumor types compare to one another. The team arrived at a classification based on 12 cancer subtypes. Five of these matched up well with tissue-of-origin classifications, but several newly identified subtypes were seen to affect a variety of tissues.

Particularly striking results were seen in bladder and breast cancers. At least three different subtypes of bladder cancer were identified, one virtually indistinguishable from lung adenocarcinomas, and another most similar to squamous-cell cancers of the head and neck and of the lungs. (In the new study, these squamous cell cancers appeared to form their own subtype, whether they originated in the lungs or in the head and neck.) The findings may help explain why treatment response is very different in patients with bladder cancer when treated with the same systemic therapy for seemingly identical cancer type, Benz reported.

The study also confirmed known differences between basal-like and luminal subtypes of breast cancer. But because the researchers compared these cancers not just with one another but with many other types of cancer, they were able to reveal that these differences are quite profound, and that basal-like breast cancers constitute their own distinct class. "What's amazing is that basal breast cancer is as different from luminal breast cancer as it is from, say, kidney cancer," said co-lead author Denise Wolf, PhD, a research scientist at University of California San Francisco.

Commonly referred to as triple-negative, basal-like cancers are particularly aggressive and are more prevalent among African American women 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 with other subtypes of breast cancer," said co-lead author Christina Yau, PhD, of UCSF.

Senior co-author Christopher Benz, MD, of UCSF, is hopeful that these studies will fuel clinical trial designs based on genomic reclassification of tumors whereby patients become eligible for novel therapeutics. "Although follow-up studies are needed to validate and refine this newly proposed cancer classification system," Benz said, "it will ultimately provide the biologic foundation for that era of personalized cancer treatment that patients and clinicians eagerly await."

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