© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
Potential Selection Bias in Intervention Studies
Studies that evaluate the effects of proposed interventions to reduce the risk of disease among carriers of a highly penetrant mutation are important. In a commentary, Wacholder (p. 1204) argues that some of these studies may be susceptible to a serious selection bias when they are based in clinics that care for people at high risk for the disease. He explains how a study design in which a large fraction of the case patients were diagnosed before being seen at the clinic and in which all control subjects are people previously seen at the clinic can create a false impression of intervention efficacy if, as is likely, mutation carriers seen at the clinic were more likely to receive the intervention than mutation carriers in the general population.
Gene Hypermethylation and Neuroblastoma Prognosis
Neuroblastoma, the most common extracranial solid tumor of infancy and childhood, displays high clinical diversity. Several prognostic biomarkers, such as MYCN amplification, have been identified, but additional markers are needed. In this issue, Alaminos et al. (p. 1208) report that profiling the status of CpG island methylation may help distinguish clinically relevant groups of neuroblastomas. Cluster analysis of 10 neuroblastoma cell lines on the basis of hypermethylation of 45 genes distinguished lines of higher and lower malignant potential (based on MYCN amplification). Subsequent unsupervised cluster analysis of 145 tumors based on hypermethylation of the 10 most informative genes separated clinically relevant groups of tumors. In addition, for several single genes, promoter hypermethylation had prognostic ability. The authors note that clustering of hypermethylation genes may ultimately prove complementary to microarray analysis for molecular profiling of human tumors.
In an editorial, Ross and Spengler (p. 1192) point out that analyzing specific methylation changes in neuroblastomas is complicated by their cellular heterogeneity, with each cellular component having its own methylation profile. Nevertheless, they conclude, methylation patterns may be of prognostic value in neuroblastoma and other cancers.
Therapeutic Potential of Heparanase Targeting
Heparanase degrades heparan sulfate, the key polysaccharide in the extracellular matrix and basement membrane. Expression of heparanase is associated with the invasive, angiogenic, and metastatic potential of diverse malignant tumors and cell lines. Edovitsky et al. (p. 1219) used two gene-silencing strategies (ribozyme and small interfering RNA [siRNA]) to explore the therapeutic potential of targeting heparanase. The authors found that, compared with cells transfected with control constructs, cells transfected with the anti-heparanase ribozyme or siRNA vectors had decreased heparanase levels and reduced invasion and adhesion in vitro, regardless of cell type. In vivo, tumors produced by cells transfected with the anti-heparanase ribozyme or siRNA vectors were less vascularized and metastasized to a much lower extent than tumors produced by cells transfected with the control vectors. Moreover, heparanase silencing resulted in extended survival of the tumor-bearing mice. The authors conclude that heparanase is a potential target for anti-cancer drug development.
In an accompanying editorial, Boyd and Nakajima (p. 1194) consider both biologic (functional overlap or redundancy mechanisms) and clinical (the majority of patients already have disseminated disease at diagnosis) limitations that need to be overcome in determining whether heparanase could be a new target in cancer therapy.
MEN2A-Derived RET and Medullary Thyroid Carcinoma
Dominant activating mutations in the RET proto-oncogene, a receptor tyrosine kinase, have been identified as a cause of medullary thyroid carcinoma. Drosten et al. (p. 1231) used a dominant negative truncated form of RET that inhibits oncogenic RET activity to investigate the role of oncogenic RET in maintaining the neoplastic phenotype of medullary thyroid carcinoma. They found that transfection of medullary thyroid cancer cells with truncated RET reduced cell viability, abolished phosphorylation of downstream signaling molecules, reduced cell cycle progression, and stimulated apoptosis. They also found that the size of tumors in transgenic mice with medullary thyroid carcinomas was statistically significantly reduced 2 weeks after injection of a vector carrying truncated RET. They conclude that specific disruption of oncogenic RET signaling in medullary thyroid carcinoma is associated with loss of its neoplastic phenotype and should be investigated further as the basis for new therapies for this disease.
Prostate Cancer Susceptibility Genes
One of the most well-established risk factors for prostate cancer is a family history of this disease. However, efforts that use genetic linkage analysis methods to find prostate cancer susceptibility alleles have been hindered by a number of factors. Gillanders et al. (p. 1240) performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer study populations to search for prostate cancer susceptibility genes. They found evidence for a prostate cancer linkage at chromosome region 17q22. Several additional chromosomal regions that are likely to harbor prostate cancer susceptibility genes were found among specific subsets of hereditary prostate cancer families, including 15q11 among families with late-onset disease and 4q35 among families with four or more affected family members. The authors conclude that fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.
Macrophage Inhibitory Cytokine–1 and Prostate Cancer
Inflammation has been suggested to have a role in prostate cancer development. Lindmark et al. (p. 1248) investigated whether macrophage inhibitory cytokine–1 (MIC-1), a regulator of inflammation, was associated with prostate cancer risk in a case–control study of 2163 Swedish men. The authors found that men carrying a MIC-1 gene mutation that changes the amino acid sequence of the protein had a statistically significantly lower risk of developing sporadic or familial prostate cancer compared with those carrying the normal gene. They conclude that inflammatory gene variation may contribute to prostate cancer susceptibility.
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