UNMC, National Researchers Discover Common Cancer
is Two Distinct Diseases
For pathologists, distinguishing among the many types of B-cell lymphoma
has always been a challenge. Current tumor classification systems
are based on subtle differences in the appearance of these immune cells
under a microscope, leaving many to wonder whether looks sometimes might
be deceiving.
But today in the weekly international journal, Nature, a team of scientists
report that in the future, there may be a new way around this old problem.
Using DNA microarray technology — a powerful new research tool that can
record the expression patterns of thousands of genes at once — the group
was able to show that, as currently defined, diffuse large B-cell lymphoma,
the most common form of non-Hodgkins lymphoma is actually two distinct
diseases.
Researchers at the University of Nebraska Medical Center, and collaborators
from five other institutions across the United States, say this information
may ultimately be used to predict the prognosis of patients with lymphoma.
Besides UNMC, other institutions involved in the research include: the
National Institutes of Health, Washington, D.C.; Stanford University School
of Medicine in Palo Alto, Calif.; Research Genetics in Huntsville, Ala;
Johns Hopkins School of Medicine in Baltimore; and Walter Reed Army Medical
Center in Washington, D.C.
Through this pilot project, we believe that genetic profiling will
be able to predict which lymphoma will have a good or poor prognosis for
the patient, said Wing (John) Chan, M.D., a pathologist and professor
in the UNMC Department of Pathology and Microbiology. Dr. Chan is principal
investigator of the grant at UNMC. One type of tumor may require aggressive
treatment while another may require less aggressive treatment, which would
reduce the potential complications involved with treatment. If we can find
out the genetic factors that determine prognosis and response to treatment,
then we may be able to use this information as a target to design new therapies
to attack the disease, Dr. Chan said.
Louis Staudt, M.D., Ph.D., a scientist at the National Cancer Institute
(NCI) and the senior author on the paper, said this finding helps to explain
why about 40 percent of patients with this type of NHL can be cured with
standard chemotherapy regimens, while other patients who seemingly have
the same disease often relapse. Its a case of mistaken identity,
Dr. Staudt said. The tumor cells might look very similar, but this
study offers strong
evidence that their molecular engines work very differently.
This weeks paper also adds to the growing interest among scientists
to create molecular profiles of common cancers. This finding offers
one of the first glimpses into how cancer will be diagnosed in the future,
said NCI Director Richard Klausner, M.D. It will be based on well-characterized
biological differences among tumor cells that tell us more precisely how
aggressive a tumor will be and how best to treat it.
As the experiments proceeded, the scientists discovered something interesting.
The diffuse large B-cell lymphoma (DLBCL) samples showed distinct differences
in their expression of hundreds of genes, suggesting that DLBCL might be
more than one cancer.
An analysis showed two distinct patterns of gene expression, signifying
that they were looking at two subtypes of the cancer. In one of the
subtypes, called GC B-like, the expression of germinal center genes was
largely congruent with that of normal B cells. But in the second subtype,
known as activated B-like, these genes were expressed at low or undetectable
levels. This finding that the subtypes express germinal center genes
differently–pointed to major biological differences among them.
In a pilot study of 42 previously untreated DLBCL patients who were
being treated with anthracycline-based chemotherapeutic regimens, the scientists
discovered significant differences in five-year survival rates among the
subtypes. For patients with GC B-like, three-fourths were alive
at the five-year mark; for activated B-like, only 16 percent were still
living.
Ron Levy, M.D., an author on the paper and a scientist at the Stanford
University Medical Center, agrees. As this finding shows, genetic profiling
of tumors will offer extra power in predicting which patients will do well
and which will do poorly, he said. This more precise diagnosis of a developing
cancer should help in the future in more accurately guiding a patients
treatment decisions.
A five-year, $3.24 million grant was funded by the NIH at UNMC and collaborating
insititutions to verify and extend the groups finding, a standard practice
in science. Diffuse large B-cell lymphoma is diagnosed in over 25,000
Americans each year. At a time when many cancers are decreasing in
the United States, this lymphoma is increasing, making it a growing public
health concern.
The study also prompted a planned expansion of involvement from three
institutions in the United States and Canada to potentially eight in the
U.S., Canada and Europe. To confirm our initial finding, we need to have
a large number of cases to study. This would give us statistical power
to get a more firm conclusion, Dr. Chan said.
Four other UNMC researchers and clinicians also are involved in the
study. They are Timothy Greiner, M.D., Dennis Weisenburger, Ph.D., James
O. Armitage, M.D., and James Lynch, Ph.D.
UNMC is the only public academic health science center in the state.
Through its commitment to research, education, outreach and patient care,
UNMC has established itself as one of the country’s leading centers for
cancer research and treatment, solid organ transplantation and arthritis.
Nearly $32 million in research grants and contracts were awarded to UNMC
scientists during the past fiscal year. In addition, UNMCs educational
programs are responsible for training more health professionals practicing
in Nebraska than any other institution.