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Prostate tumors that carry a "signature" of four molecular markers
have the potential to become dangerously metastatic if not treated
aggressively, researchers at Dana-Farber Cancer Institute report in a
study published online today by the journal Nature. The
discovery lays the groundwork for the first gene-based test for
determining whether a man's prostate cancer is likely to remain dormant
within the prostate gland, or spread lethally to other parts of the
By analyzing prostate cancer tissue from hundreds of men
participating in a national health study, dozens of whom died of the
disease, investigators led by Ronald DePinho, MD, Lynda Chin, MD, and Zhihu Ding, PhD, of Dana-Farber, in collaboration with Massimo Loda, MD,
of Dana-Farber and Brigham and Women's Hospital, and Lorelei Mucci,
PhD, of Brigham and Women's and Harvard School of Public Health, found
that the four-gene/protein signature more accurately predicted which
patients would die from metastatic spread than did the conventional
method. The standard measure of prostate cancer's aggressiveness, known
as the Gleason score (which is based on cancer cells' appearance under a
microscope), is accurate about 60 to 70 percent of the time depending
on the skill of the pathologist. The four-gene signature method alone
was accurate 83 percent of the time. Combining the markers and Gleason
methods produced an accuracy of approximately 90 percent.
"It's widely recognized that many prostate cancer patients are
treated unnecessarily," says DePinho, who is the director of
Dana-Farber's Belfer Institute for Applied Cancer Science.
"The vast majority of prostate cancers would not become
life-threatening, even if left untreated. But because we can't
accurately forecast which are likely to spread and which aren't, there
is a tendency to unnecessarily subject many men to draconian
The result, DePinho says, is that approximately 48 men are treated
for prostate cancer for every life saved. The cost of such overtreatment
is estimated at more than $600 million a year in the United States
alone. There is a physical price as well. The main forms of prostate
cancer treatment — surgery and radiation therapy — can produce a range
of lasting complications, such as impotence and urinary problems,
The main obstacle to developing better prognostic tests for prostate
cancer has been the lack of uniformity of cells in different tumors, and
even within a single tumor. In 85 percent of prostate cancer cases,
the prostate gland holds more than one tumor focus, each of which may
contain a different assortment of cancer cells with a distinct set of
gene abnormalities. Such diversity makes it difficult to identify genes
or other features that reliably indicate a tumor's potential to spread.
In the current study, researchers began with the well-established fact that prostate cancers without a working copy of the Pten gene tend to remain fairly idle and don't trespass beyond the prostate gland itself. Researchers theorized that the loss of Pten in turn activates a collection of genes — a pathway — functioning to
constrain the tumor's growth and invasion. If that pathway was shut
down, they reasoned, the tumor would begin to break loose from the
prostate and spread insidiously through the body.
Using computational biology techniques to analyze gene activity in mouse prostate cancer cells with inactive Pten,
the investigators found a few pathways that seemed to play a
constraining role. One, known as TGFβ-SMAD4 (for some of the genes that
comprise it), was particularly intriguing as this pathway had been
implicated in the metastasis of other tumor types in the past. When
researchers conducted confirmatory molecular signaling studies to see
what happens when Pten is knocked out of commission, signaling
in the TGFβ-SMAD4 pathway "shot through the roof," DePinho says,
suggesting that the pathway had sprung into action.
When researchers generated mice whose prostate cells lacked both Pten and the Smad4 gene, the animals developed large, fast-growing tumors that spread to
their lymph nodes and beyond. Guided by these insights, they then
examined whether something similar was happening in human prostate
Comparing the gene expression profiles of indolent versus aggressive
mouse prostate cancers, they found about 300 genes that distinguished
the two groups. "We then categorized them for known functions," DePinho
says. "We were encouraged to see that the top functional category were
genes playing that have roles in cell division and movement" — actions
that are needed for cancer cells to grow and spread with lethal
The researchers conducted an elaborate series of experiments to
identify the genes most closely linked to the aggressive biology of
prostate cancer. Among the hundreds of genes analyzed, two such genes
stood out: SPP1 and CyclinD1, both of which, intriguingly, are close working partners of Smad4.
The four-gene signature — Pten, Smad4, SPP1, and CyclinD1 — showed its effectiveness as a predictive tool for survival when
researchers drew on data from the Physicians' Health Study, which has
been tracking the health of thousands of U.S. physicians for nearly 30
years. When the investigators screened prostate cancer samples from
study participants for the four-gene/protein signature, it was more
accurate in predicting the ultimate course of the illness than
conventional methods were.
"By integrating a variety of techniques — computational biology,
genetically engineered model systems, molecular and cellular biology,
and human tissue microarrays — we've identified a signature that has
proven effective in distinguishing which men with prostate cancer are
likely to progress and die from their disease and those who are not,"
DePinho remarks. "Efforts are already underway to use this knowledge to
develop a clinical test — which we hope will occur within a year or so —
that will enable doctors and patients to make more accurate treatment
decisions and avoid unnecessary aggressive interventions which adversely
impact on quality of life and deplete over-extended healthcare
resources. This science holds potential to illuminate a long-sought
answer for optimal management of this complex disease."
The paper's other co-authors are Chang-Jiun Wu, MD, PhD, Gerald C.
Chu, MD, Yonghong Xiao, PhD, Dennis Ho, Samuel R. Perry, Emma S. Labrot,
Xiaoqiu Wu, Rosina Lis, MD, Y. Alan Wang, David E. Hill, PhD Baoli Hu,
PhD, Shan Jiang, PhD, Hongwu Zheng, PhD, Alexander H. Stegh, PhD,
Kenneth L. Scott, PhD, Dana-Farber; Jingfang Zhang, University of
Wisconsin, Madison; Yujin Hoshida, MD, PhD, and Todd R. Golub, MD,
Dana-Farber and the Broad Institute of Harvard and MIT; David Hiller,
PhD, and Wing H. Wong, PhD, Stanford University; Sabina Signoretti, MD,
Dana-Farber/Harvard Cancer Center; Nabeel Bardeesy, PhD, Massachusetts
General Hospital Cancer Center; and Meir J. Stampfer, MD, DrPH, Brigham
and Women's Hospital and Harvard School of Public Health.
The research was funded in part by the Belfer Institute for Applied Cancer Science and the National Cancer Institute.
The Belfer Institute for Applied Cancer Science at Dana-Farber Cancer
Institute consists of leading academic and industry seasoned scientists
working as multidisciplinary teams supported by powerful platforms in
computational science, oncogenomics, engineered model systems,
clinicopathological analyses, and drug discovery. The Belfer Institute's
mission is to convert insights gleaned from cancer genomics and deep
biology research into the next generation of highly effective drugs and
drug combinations, as well as breakthrough diagnostics for improved
patient management. The Belfer Institute technology has launched a new
biotechnology company, Metamark Genetics, and has enabled cancer drug
discovery through highly productive strategic alliances within the
pharmaceutical sector, including Merck and Sanofi-Aventis.