BOSTONGene expression profiling may help predict survival
outcomes for patients with diffuse large B-cell lymphoma (DLBCL), the most
common lymphoid malignancy, according to a study reported by Margaret Shipp,
MD, director of the Lymphoma Program at Dana-Farber Cancer Institute in Boston.
In the study, gene expression profiling was able for the first time to identify
curable and noncurable lymphomas from a pool of intermediate-risk patients.
"Using gene expression profiling is a powerful way of
understanding the biological basis of lymphoma, and assessing differences in
outcomes among patients," Dr. Shipp said. The study also identified
individual genes and molecular mechanisms that could play a part in the
development of incurable lymphoma.
In the future, such discoveries could help target therapies to
cancer patients based on their molecular profiles, and help develop novel
molecular targets for medications, Dr. Shipp predicted.
While 40% of DLBCL patients are cured of their disease, the
majority ultimately succumb to progressive lymphoma. In the past few years,
studies have looked at the cellular and molecular basis of the disease using
RNA expression profiling. The goal is to understand the disease more
completely, and determine the prognosis for individual patients in order to
treat them more successfully.
In the 5-year study, genetic material from the tumors of 58
DLBCL patients were subjected to RNA expression profiling. In this technique,
fluorescently labeled RNA from a tumor specimen is used to probe a gene chip to
determine which genes the cancer cells express. Patterns of gene expression in
various tumor specimens are compared using a variety of computerized tools.
A review of 6,817 genes from the tumors of the DLBCL patients
identified two categories of patients with dramatically different 5-year
overall survival rates of 72% vs 9%. Patients included those in low-,
intermediate-, and high-risk groups. Thirty patients had achieved complete
remissions, 23 had died of lymphoma, 2 had died of other causes, and 3 had
recurrent refractory disease.
Most significantly, the researchers were able to separate
intermediate-risk patients into two discrete groups, who also had widely
varying survival rates of 71% vs 7% based on their genetic profiles. Since most
DLBCL patients fall into the intermediate-risk group, such categorization can
be tremendously valuable in planning therapy, Dr. Shipp said.
Several Methods Work
"We used several different algorithms to achieve our
results," Dr. Shipp explained. These included a weighted voting prediction
algorithm and a support vector machine algorithm. All methods used were
similarly predictive of disease outcome. "The value of using several
different algorithms is that we now know that more than one method works to
identify curable and deadly lymphomas," Dr. Shipp said.
The algorithms also allowed identification of a number of genes
that were commonly underexpressed or overexpressed in fatal vs curable tumors.
These genes had functions that influenced mechanisms like cell adhesion,
apoptosis, ras signaling, and immunity to tumors.
"Once we identify genes that are expressed in curable vs
noncurable tumors, we can find the genetic or molecular pathways that might be
sensitive to standard treatments," Dr. Shipp said. "We might also
find ways to interrupt molecular pathways that contribute to fatal
The study was a collaborative effort among Dana-Farber Cancer
Institute and Brigham and Women’s Hospital in Boston, the Whitehead Institute
in Cambridge, Massachusetts, and St. Bartholomew’s Hospital in London.