Gene signature helps predict melanoma outcome.
In the first large genomic study of primary melanomas, Dr. Spatz and his colleagues at the Gustave-Roussy Institute in Villejuif, France, correlated gene expression profiles with clinical outcome in a large cohort of patients who had undergone treatment for primary cutaneous melanoma.
The investigators analyzed 105 frozen cutaneous melanomas. Unsupervised clustering (no phenotypes specified) of 11,043 filtered genes from 83 of the primary melanomas with eligible RNA and appropriate follow-up showed that one large cluster of genes and one smaller cluster were associated with good and poor clinical outcomes, respectively.
A supervised analysis of the data in which the samples were phenotypically grouped revealed that 255 of the filtered genes had a differential expression between patients with fewer than 3 years of disease-free survival and those who survived disease-free for more than 3 years.
The investigators conducted an additional analysis that identified 60 genes with a high probability of predicting distant metastasis at 4 years.
"These 60 genes provided the best candidate signature for disease progression," Dr. Spatz said.
Gene activity within tumor thickening and the presence of gene-associated antibodies in patients who were tumor-free were among the criteria that the investigators used in testing for differential genetic expression.
"Because thickness is a manifestation of tumor progression, it can be expected that biological processes in the neoplastic cells vary according to the thickness of the primary melanoma," according to Dr. Spatz.
"We clustered the thickness-correlated genes into 11 functional groups and analyzed their expression across the 83 thicknesses of the melanomas," he explained. Some of the resulting functional groups of genes showed an expression pattern that increased substantially with increasing thickness of the primary melanoma, he said.
The investigators also carried out an assessment of gene-associated antibodies. "We studied 23 proteins from the gene set for immunoreactivity in tissue microar-rays," Dr. Spatz said.
"The median expression of 7 of the 23 antibodies was significantly associated with disease-free survival at 4 years," he reported.
One example is the increased expression of the stem cell gene MCM4, which is involved in the control of DNA replication. "A high clinical expression of MCM4 was associated with a poor prognosis," Dr. Spitz said. That finding led the investigators to hypothesize that the dysregulation of MCM4-related DNA replication may be an important potential therapeutic target for cutaneous melanoma.
To date, "the development of targeted therapies for melanoma has been impaired by the fact that key molecular events in disease progression are poorly understood," Dr. Spatz explained.
Improved insight into the biology of melanoma, such as the biologic events that are associated with tumor thickness, are crucial for devising improved prognostication methods and for pursuing the development of new potential therapeutic targets.
Because a number of the genes that are involved in the melanoma progression signature belong to the same cellular pathways as genes that are associated with the in vivo progression of other types of tumors, it is possible that inhibitors currently under development for other tumors could target some of the related proteins in melanoma, Dr. Spatz concluded.
BY DIANA MAHONEY
New England Bureau
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|Publication:||Internal Medicine News|
|Date:||Mar 1, 2006|
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