Non-Hodgkin's Lymphoma Panel: (left to right) Stephen Chanock, Michael Lenardo, Sophia Wang, Nathaniel Rothman, Patricia Hartge, and Sandeep Dave

The prognosis for patients with follicular lymphoma has been notoriously unpredictable. But gene expression profiling at the time of diagnosis, NIH scientists are saying, may change that by revealing genes associated with good and poor immune response and corresponding survival.

"Morphologic similarities can mask a surprising degree of molecular heterogeneity that underlies outcome differences," Sandeep Dave observed, citing outcome data related to molecular subtype gathered in Lou Staudt's NCI lab, where he is a clinical fellow.

Subtypes of diffuse large B cell lymphoma (DLBCL) that "look the same under the microscope" nonetheless exhibit different oncogene mechanisms, respond differently to treatment, and carry a different prognostic message.

Five-year survival for the ABC subtype, which expresses NF-kB, is 31 percent; five-year survival for the GCB subtype, which does not express NF-kB, is 60 percent. NF-kB, Dave said, might thus be a therapeutic target in the ABC subtype of DLBCL.

Dave was one of the panelists at a Research Festival symposium that explored the expanding repositories of data — genetic, environmental, and medical — related to the risk of non-Hodgkin's lymphoma (NHL). The need now, they agreed, is to determine which factors and combinations of factors can inform preventive and therapeutic strategies in the clinical setting.

According to data from the SEER case-control study of NHL, Sophia Wang noted, NF-kB is indeed "emerging as a signficant player" in DLBCL risk.

The SEER data, she said, focused on 15 single-nucleotide polymorphisms  from seven genes for inflammatory cytokines and uncovered two — TNF-G308A and LTA-252G — that singly and, especially, in combination were significantly associated with DLBCL. A follow-up study is exploring gene-environment interactions, said Wang, an investigator in the Division of Cancer Epidemiology and Genetics, NCI.

Patricia Hartge, deputy director of the DCEG Epidemiology and Biostatistics Program, itemized environmental and host factors that have been implicated in the etiology of NHL — the incidence of which, in contrast to Hodgkin's disease and independent of the advent of AIDS, with which it is associated — has been steadily increasing since 1950.

SEER data, Hartge said, suggest that chlordane insecticides, but not herbicides, are associated with NHL and that foods containing antioxidants and folates may be protective.

Among risky host factors are immune suppression; a family history of NHL, Hodgkin's disease, or multiple myeloma; autoimmune diseases such as Sjögren's syndrome, lupus, and rheumatoid arthritis; and hepatitis C.

Genetics, she said, may elucidate susceptibility and mechanisms. She predicted new large epidemiological studies that would look at survival and cause, a major advance over previous studies.

A newly described genetic disorder of programmed cell death — autoimmune lymphoproliferative syndrome (ALPS) — can presage lymphoma, Michael Lenardo, a senior investigator in the Laboratory of Immunology, NIAID, reported.

Characterized by the loss of a general antineoplastic mechanism associated in 75 percent of cases with an FAS receptor mutation, ALPS patients typically present with lymphadenopathy and splenomegaly by the age of 5 — and there  is typically a delay of 10 to 40 years between ALPS onset and lymphoma.

In a study of 130 individuals in 39 families with ALPS and FAS mutations, 10 people eventually developed 11 instances of B and T cell lymphomas, Lenardo said.

Jumping from the United States to the world stage of molecular epidemiological data, Nathaniel Rothman pointed to the International Lymphoma Consortium (InterLymph), as a growing source of "solid clues that could translate to clinical implications for survival."

Established in the late 1990s, InterLymph has amassed data from about 9,000 cases in North America, Australia, and Europe, said Rothman, a DCEG senior investigator.

The Genetic Polymorphism Working Group has been studying Th1 and Th2 proinflammatory response and has found a consistent association with lymphoma risk for haplotypes with both TNF and LTA variants and, to a less consistent extent, with an IL-10 variant.

With the ability to conduct whole genome scans, it will become possible to distinguish associations that are real from those that are not, Rothman said.

Stephen Chanock, a senior investigator and head of the Genomic Variation Section, NCI, observed that the population groups most extensively studied to date are Caucasian. Asian and African groups, he said, need similar scrutiny, which will elucidate what genetic variants are common across populations and the role of environmental factors.  n

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