Prostate Cancer Viewed as Condition Linked to Fused Chromosomes

ANN ARBOR, Mich., Aug. 1 -- Prostate cancer may be an umbrella term for a variety of neoplastic conditions traced to fused chromosomes, according to genetic findings here.

A series of experiments, primarily with experimental animals, showed that prostate neoplasia springs from the fusion of genes on separate chromosomes, according to Arul Chinnaiyan, M.D., Ph.D., of the University of Michigan and colleagues.

But the experiments also showed there are different kinds of gene fusion that act as on-switches for malignant growth, potentially requiring different approaches to treatment, Dr. Chinnaiyan and colleagues reported in the Aug. 2 issue of Nature.

"Each of these switches, or gene fusions, represents a different molecular subtype," Dr. Chinnaiyan said. "This tells us there's not just one type of prostate cancer."

"It's a more complex disease and potentially needs to be treated differently in each patient," he added.

Such gene fusions are known to be involved in the pathogenesis of hematological and mesenchymal malignancies. Indeed, one of the great cancer success stories in recent years has been the development of imatinib (Gleevec), which targets the so-called Philadelphia chromosome, a fused chromosome that causes chronic myelogenous leukemia.

Genetic fusions of that sort have not been demonstrated in epithelial cancers, the researchers said.

The researchers had previously reported that the fusion of the prostate-specific gene TMPRSS2 and the members of the E26 transformation-specific (ETS) family of genes occurs in most prostate cancers.

The fused genes are androgen-driven, causing over-expression of the ETS proteins and leading to a neoplasm, the researchers said.

In the current study, they identify four other genes that fuse with ETS genes:

• A prostate-specific gene that is induced by androgen called SLC45A3.
• A prostate-specific gene dubbed C15orf21 that is repressed by androgen.
• An endogenous retroviral element called HERV-K_22q11.23.
• And a strongly expressed housekeeping gene, HNRPA2B1.

Because not all of them are driven by androgen, the discovery "may be important for management, particularly with respect to the effects of androgen ablation," Dr. Chinnaiyan and colleagues said.

All the newly identified genes fuse with an ETS gene called ETV1, whose effect in the prostate is to confer what the researchers called "neoplastic phenotypes."

Fusions between the gene TMPRSS2 and the ETS family are "the predominant class" of genetic on-switches, the researchers said, but at least two of the new genes represent previously unknown classes.

For instance, C15orf21 is "markedly overexpressed in prostate cancers," the researchers said, yet it is repressed by androgen. Also, the gene HNRPA2B1 is neither prostate-specific nor driven by androgen.

Further investigation, the researchers said, may reveal still more types of gene fusion involved in the development of prostate cancer.

Also, they concluded, the findings "suggest a generalized role for chromosomal rearrangements in common epithelial cancers" including, but not limited to, other hormone-driven malignancies, such as breast cancer.