NCI Scientists Create Model That Predicts Follicular Lymphoma Survival
Scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, have created a model that predicts the
survival of follicular lymphoma patients based on the molecular characteristics of their tumors at diagnosis. The model is based on two sets
of genes--called survival-associated signatures--whose activity was found to be associated with good or poor prognosis for patients with the
cancer. The scientists' results, to be published in the November 18, 2004, New England Journal of Medicine* , suggest that immune cells
infiltrating follicular lymphoma tumors have an important impact on survival--both signatures came from such immune cells.
The progression rate of follicular lymphoma, the most common non-Hodgkin lymphoma, varies widely. "In some patients the disease progresses
slowly over many years, whereas in others progression is rapid, with the cancer transforming into aggressive lymphoma and leading to early
death," explained principle investigator Louis M. Staudt, M.D., Ph.D., of NCI's Center for Cancer Research. "Understanding the molecular
causes of such differences in survival could provide a more accurate method to determine patient risk, which could be used to guide treatment
and may suggest new therapeutic approaches."
To create their model, Staudt and associates used follicular lymphoma biopsies taken from 191 untreated patients. The biopsies were taken
between 1974 and 2001 and came from North American and European institutions that are part of the NCI-sponsored Lymphoma/Leukemia Molecular
Profiling Project**. Following their biopsies, all patients received standard treatments. The NCI scientists examined their subsequent medical
records to determine survival. Biopsies were divided into two groups balanced for survival and institution: 95 went into a group used to
uncover gene expression patterns associated with survival; the other 95 were used to test the predictive power of these patterns.
NCI scientists first used a DNA micro array to determine which genes were expressed (active) in the first group of 95 tumor biopsies, and at
what levels. They then determined which of these genes were statistically associated with survival. They called those associated with long
survival "good prognosis genes" and those associated with short survival "poor prognosis genes."
Next, the researchers identified subsets of both kinds of genes that tended to be expressed together. These they named "survival-associated
signatures." Two signatures--one which indicated poor prognosis, the other good--had strong synergy and together predicted survival better than
any other model tested. Unexpectedly, both came from nonmalignant immune cells infiltrating the tumors. The good prognosis signature genes
reflect a mixture of immune cells that is dominated by T cells. T cells react to specific threats to the body's health. In contrast, the
poor prognosis signature genes reflect a different group of immune cells dominated by macrophages and/or dendritic cells--which react to
nonspecific threats--rather than T cells.
The two signature model allowed NCI scientists to divide patients into four equal groups with disparate average survival rates of 3.9, 10.8,
11.1, and 13.6 years. For the 75 percent of patients with survival rates 10 years or longer, "watchful waiting is appropriate," Staudt said.
"These patients would benefit from knowing that they may not need treatment for quite some time. On the other hand, those patients in the
group with the lowest survival rate should be considered for newer treatments and clinical trials," added Staudt.
The fact that the most predictive signatures came from immune cells suggests an important interplay between the host immune system and
malignant cells in follicular lymphoma. "One possibility is that the immune cells with the good-prognosis signature are attacking the
lymphoma and keeping it in check," Staudt speculated. "Another possibility is that these immune cells may provide signals that encourage the
cancer cells not to leave the lymph node, preventing or delaying the spread of the cancer," he added. Knowing more about the signals that may
delay the spread of follicular lymphoma could provide new therapeutic targets.
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For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer
Information Service at 1-800-4-CANCER (1-800-422-6237).
* Dave SS, Wright G, et al. A Molecular Predictor of Survival Following Diagnosis of Follicular Lymphoma Based on the Profile of Non-Malignant
Tumor-Infiltrating Immune Cells. New England Journal of Medicine. November 18, 2004.
** Participating institutions in the Lymphoma/Leukemia Molecular Profiling Project include: Center for Cancer Research, National Cancer
Institute, USA; University of Nebraska Medical Center, USA; Southwest Oncology Group, USA; British Columbia Cancer Agency, Canada; Norwegian
Radium Hospital, Norway; University of Wuerzburg, Germany; University of Barcelona, Spain; and St. Bartholomew's Hospital, UK.
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