Overlapping Tumor Suppressor Genes Independently Involved in Melanoma
Mutations in the p14ARF tumor suppressor gene (ARF) may play a role in melanoma, independent of the effect of the p16 gene.
ARF and p16 are overlapping genes at a location on chromosome 9 that is frequently mutated in melanomas. Although researchers have previously demonstrated that inactivation of the p16 tumor suppressor gene occurs frequently in melanomas, it has been less clear whether alterations in ARF occur independently of p16 in human melanoma.
In the current study, David Polsky, M.D., Ph.D., of the New York University School of Medicine and colleagues examined the two genes in 60 metastatic melanoma tumors from 58 patients.
They found two or more alterations in the ARF gene in 26 of the tumors (43 percent) and two or more alterations in the p16 gene in 13 of the samples (22 percent). In 18 tumor samples (30 percent), ARF was inactivated in the presence of the most common form of p16.
The researchers conclude that loss of ARF can promote melanoma development, even in the presence of normal p16. “Human and mouse data provide strong evidence that ARF plays an important independent role in the pathogenesis of human melanoma,” the authors write.
In an accompanying editorial, Gordon Peters, Ph.D., of Cancer Research UK London Research Institute provides a broad review of mouse and human data regarding the complex p16/ARF locus and melanoma. Although there are more data pointing to p16’s role in melanoma, Peters concludes that researchers should not ignore ARF’s possible contribution. “For now, we should be content to let them share the limelight,” he writes.
Aggressive Subclass of Prostate Cancer May be Driven By Estrogen Signaling
Aggressive prostate cancers that harbor a particular gene fusion are a distinct molecular subtype of the disease and their growth may be regulated by estrogen signaling.
Prostate cancers that carry the TMPRSS2-ERG gene fusion, which links the regulatory region of one gene to the protein-coding region of another, tend to be aggressive. The molecular mechanism by which the fusion gene impacts pathogenesis has been unknown.
Mark Rubin, M.D., of Weill Cornell Medical College in New York and colleagues examined the expression pattern of 6,144 genes in tumor samples from 455 patients from the Swedish Watchful Waiting cohort and the Physicians Health Study cohort from the United States.
Overall the investigators found that 103 tumors contained the fusion gene. When they compared the gene expression pattern in the tumors with the TMPRSS2-ERG fusion and those lacking it, they identified an 87-gene signature that correlated with the fusion gene. Many of the genes in the signature respond to estrogen signaling. In vitro experiments with prostate cancer cell lines indicated that drugs that stimulate one type of estrogen receptor (ER) promoted cancer cell growth, while drugs that activated another type of estrogen receptor (ER) increased cell death.
“Our results suggest a mechanism by which prostate cancers might develop androgen independence from an initial androgen-dependent state,” the authors write.
Contact: Andrew Klein, office of public affairs, Weill Cornell Medical College, email@example.com
Addition of Paclitaxel to Standard Chemotherapy Improves Outcome in Early Breast Cancer
Early breast cancer patients treated with standard chemotherapy followed by paclitaxel had better disease-free survival compared with patients treated with standard therapy alone, according to the final results from a randomized phase III trial.
Paclitaxel and other taxanes are among the most active agents in metastatic breast cancer. Researchers are now testing the drugs in patients with early, non-metastatic breast cancer.
In the current study, Miguel Martín, M.D., of the Spanish Breast Cancer Research Group and colleagues randomly assigned 1,246 women to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or FEC followed by weekly paclitaxel (FEC-P).
The estimated 5-year survival rate was 78.5 percent in the FEC-P arm and 72.1 percent in the FEC arm. There was a trend toward improved overall survival, but it did not reach statistical significance. “Because distant relapse-free survival is usually associated with overall survival, a statistically significant benefit in overall survival may become evident with a more protracted follow-up,” the authors write.
A retrospective analysis of the data failed to detect a subgroup of patients who were more likely to respond to taxane therapy on the basis of their tumor’s expression of the estrogen receptor and HER2.
In an accompanying editorial, Clifford Hudis, M.D., and Chau Dang, M.D., of Memorial Sloan-Kettering Cancer Center in New York review several trials that tested the potential benefit of adding taxanes to existing adjuvant therapy. From that point of view, the study by Martín and colleagues is important because it is well designed and uses a good regimen and schedule of drugs.
They emphasize that retrospective analyses should be considered hypothesis generating only, particularly when the results from several similar analyses are inconsistent “If you accept that the taxanes are effective, hormone receptor and HER2 status should not routinely guide your selection of patients for this therapy,” the editorialists conclude.
Also in May 27 JNCI:
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