Researchers have long recognized cancer is not a single disease. Rather, the term encompasses hundreds of different diseases — all with one common characteristic: unchecked cell growth.

Even though scientists typically classify cancers according to where they start in the body — breast cancer in the breast, lung cancer in the lung, and so on — they are increasingly relying on molecular characteristics to define narrower and more clinically relevant categories.

"Every single patient's tumor is unique in some way," says Andrew Feldman, M.D., a Mayo Clinic pathologist. "The question is finding that sweet spot between an overly superficial classification that just has a few big groups that provide clinicians with limited information and an overly granular classification where there are not enough patients in any one group to understand how they will do clinically or what therapies they might respond to."

Feldman's laboratory is helping redefine the classification of T-cell lymphomas, a group of malignant tumors of the immune system that are often fatal. Although B cells and T cells can give rise to malignancies or lymphomas, T-cell lymphoma is the rarer disease, making up less than 15% of all Non-Hodgkin lymphomas, and is less well-understood.

"Mayo has created an exceptional environment that facilitates studying a rare disease," says Dr. Feldman. "There's a huge biobanking effort here that is pretty much unparalleled. And there's very active clinical engagement with patients, through the NCI-funded (National Cancer Institute) Lymphoma SPORE (specialized program of research excellence), the Mayo Clinic Comprehensive Cancer Center, and participation in large national and international consortia."

Like cancer writ large, T-cell lymphomas are a diverse and heterogeneous bunch, with the World Health Organization listing over 30 subtypes.

"It's not simply a rare disease, but rather many very rare diseases, which compounds the difficulty in characterizing them," says Dr. Feldman. "As practicing pathologists, we need diagnostic tools that differentiate among these different entities."

For example, Dr. Feldman would like to identify subgroups that behave aggressively so that he can guide clinicians in how to best treat individual patients.

His team has focused on a particular subtype of T-cell lymphoma called anaplastic large cell lymphoma. By examining anaplastic large cell lymphoma tumors at the genetic level, his team discovered that the system for classifying these tumors was limited. Initially, anaplastic large cell lymphoma tumors were categorized based on the presence or absence of one genetic feature, a chromosomal rearrangement of a gene known as ALK. According to Dr. Feldman, the tumors that were positive for the ALK rearrangement had been well-studied, whereas the ones that were negative for the rearrangement were poorly understood. So his team decided to zero in on the ALK-negative tumors.

So far, researchers have identified several subclasses within the ALK-negative group. Two of these subclasses arise from chromosomal rearrangements in two genes — DUSP22 and TP63 —with vastly different consequences.

Patients whose tumors harbor the DUSP22 rearrangement do well clinically — to the point that some clinicians have suggested that they may require less aggressive treatment.

"Actually, in almost every parameter we have looked at, these tumors are different," says Dr. Feldman. Under the microscope, the tumors display distinct morphologic features.

In addition to the DUSP22 rearrangements, these less aggressive tumors have unique epigenetic alterations, which affect the way the genome is read by molecules in the cell without changing the underlying DNA sequence. Specifically, Dr. Feldman's team noticed alterations in a process called DNA methylation, which alters how genes are expressed.

"The result is the expression of many genes that normally would not be expressed in tumors," says Dr. Feldman. "What we think is happening — and are still working on proving — is that the expression of these additional genes becomes a target for the immune system."

As Dr. Feldman explains, normally the immune system in a patient with cancer tries to recognize and eliminate the cancer by identifying unique aspects of that cancer and saying: "Hey, these cells don't belong here. Let's get rid of them.” He believes that the DNA methylation that goes awry in tumors with DUSP22 rearrangements might cause genes known as cancer testis antigens — normally only turned on in the testis — to be expressed and allow the tumor to be recognized by the immune system.

"That may be why these patients tend to do well," says Dr. Feldman. "And that's important not only in terms of the prognosis of the patient, but also because it may uncover opportunities for types of therapy that could augment the immune response in patients where the tumors lack DUSP22 rearrangements and evade recognition."

Based on these and other findings, the new International Consensus Classification of lymphomas recently recognized the DUSP22 rearrangement as defining a unique genetic subtype of anaplastic large cell lymphoma. In addition, this subtype has been incorporated into the treatment guidelines of the National Comprehensive Cancer Network, providing patients with the DUSP22 rearrangement with an option for less intensive therapy.

However, patients with the other subtype Dr. Feldman's laboratory has defined — that is, chromosomal rearrangements in a gene called TP63 — have a more dismal prognosis. This gene is closely related to TP53, one of the most frequently altered genes in human cancers.

Dr. Feldman has found that fusion proteins derived from the chromosomal rearrangement of the TP63 gene are associated with aggressive cancer. Almost all patients with this subtype fail their initial chemotherapy or have a recurrence of cancer and die soon thereafter.

"Their very poor prognosis does give clinicians some idea of how the tumor will behave, which might allow them to choose a more intensive therapeutic regimen or potentially consider clinical trials of novel agents for patients who aren't predicted to do well with conventional therapy," says Dr. Feldman.

Some anaplastic large cell lymphoma tumors lack all three genetic alterations, and are negative for ALK, DUSP22 and TP63 chromosomal rearrangements. Dr. Feldman has recently set his sights on characterizing these "triple-negative" cases, which he says have further heterogeneity.

"Again, it's not just one group, but even within those there are further subgroups," he says.

To tease apart this heterogeneity, Dr. Feldman and his team are looking at other molecular changes besides genetics. "At Mayo, we call this 'beyond DNA,'" he says.

That means using "multi-omics" technology that incorporates genomics; transcriptomics, which is the study of RNA within a cell; proteomics, which is the study of proteins in the body; epigenomics, which is the impact of environment on genes; and metabolomics, which is the study of small molecules in organisms.

"As we've gained new and more sophisticated tools, our classification systems can also become more sophisticated," Dr. Feldman says.

Through an international consortium called the Lymphoma/Leukemia Molecular Profiling Project, funded by the National Cancer Institute and co-led by Mayo, his team is working to develop a new and improved molecular classification system for anaplastic large cell lymphoma.

"Looking across all of these 'omics,' we are dissecting the subclasses and biology of how these tumors differ with the idea of further improving classification and developing novel therapies," he says.

 — Marla Broadfoot, Ph.D.

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