April 15 Cancer Research Highlights

Selected Articles from the April 15, 2008 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the April 15 issue of Cancer Research.

DICER Required to Maintain Hypermethylation in Cancer Cells

Ting et al.

Page 2570

Aberrant promoter hypermethylation is a common occurrence in cancer; however, the mechanism(s) behind the initiation and maintenance of this phenomenon is largely undefined. By comparing demethylated colon cancer cells with cells genetically rendered hypomorphic for DICER, Ting and colleagues identified a group of epigenetically silenced genes that became reactivated in the absence of DICER. This reactivation is specifically associated with a loss of promoter hypermethylation. The authors’ results demonstrate a requirement for intact DICER to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in colon cancer cells. This is the first link in humans between aberrant promoter hypermethylation and DICER, the small RNA processing enzyme, and suggests a connection between noncoding RNAs and epigenetic silencing.

Secondary Mutations of BRCA1 and Chemosensitivity

Swisher et al.

Page 2581

Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian cancer. However, acquired resistance to these drugs occurs and the mechanisms are largely unknown. BRCA1 is required for cellular resistance to cisplatin, and BRCA1-deficient cells are hypersensitive to cisplatin. Swisher and colleagues show that secondary mutations of BRCA1 that restore the reading frame of the BRCA1 protein frequently occur in BRCA1-mutated ovarian cancer with platinum resistance, suggesting that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors. This study provides an insight into molecular mechanisms of drug resistance mediated by a tumor suppressor gene in cancer therapy.

Autozygosity Signatures in Genome Correlate with Cancer Incidence

Bacolod et al.

Page 2610

The presence of long regions of homozygosity (known as autozygosity) in the genome of an individual suggests common ancestry in the parents. Bacolod and colleagues have shown that these identity-by-descent (IBD) regions are more prevalent in colorectal cancer (CRC) patients in than controls. This finding may help explain the higher incidence of CRC among individuals of Jewish background. IBD regions are likely to harbor important CRC-related genes with low-penetrance SNPs and/or mutations. Two recently identified CRC predisposition SNPs in the 8q24 region were confirmed to be homozygous in one particular patient carrying an IBD segment covering the region.

Imaging Transgene Activity

Gade et al.

Page 2878

Effective gene therapy requires adequate concentrations of a functioning transgene within the targeted tissue. The paucity of non-destructive and quantitative strategies for delineating transgene function presents a major obstacle to the further development of gene therapy. Gade and colleagues describe a novel molecular imaging platform that enabled noninvasive and absolute measurements of local enzyme concentration and activity within tissues of interest. Magnetic resonance spectroscopic images demonstrated regional heterogeneities in cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) activity that correlated well with the percentage of CD-UPRT⁺ cells and the biological effect of this enzyme. This strategy offers the potential to gain essential insights into transgene function noninvasively, in both preclinical and clinical settings.

Platform Technology to Generate Human T Cells with Redirected Specificity

Singh et al.

Page 2961
Gene transfer of a chimeric antigen receptor (CAR) is being tested in clinical trials to redirect specificity of clinical-grade T cells. Recombinant viruses, although efficient at expressing CAR, can be cost-prohibitive to manufacture as clinical-grade material. In comparison, the cost effectiveness associated with electrotransfer of DNA plasmid(s) is an attractive approach for early-phase T-cell trials. To overcome the low efficiency of plasmid integration, Singh and colleagues demonstrate that Sleeping Beauty (SB) transposon/ transposase DNA plasmids can introduce a CD19-specific CAR and that immortalized designer artificial antigen presenting cells (aAPC) can be used to selectively propagate CD19-specific CD4⁺ and CD8⁺ effector and memory T cells. By combining SB transposition of T cells with aAPC to numerically expand CAR⁺ T cells, the authors have developed a new platform technology to generate genetically modified T cells with a desired specificity that can be readily adapted to development of clinical-grade cells.

EGFR Gender-Related Survival Differences in Metastatic Colon Cancer

Press et al.

Page 3037
Evidence supports gender-related differences in the development of colonic carcinomas. EGFR expression is linked with poor prognosis in colon cancer. Press and colleagues explored the role of two functional polymorphisms of EGFR in 318 metastatic colon cancer patients, 177 males and 141 females. Gender-related survival differences were associated with both a HER-1 R497K polymorphism and an EGFR dinucleotide (CA)_n repeat polymorphism. The gender-related survival differences were opposite in males and females. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer and the divergent prognostic implications of these variants for men and women.

April 15 Cancer Research Highlights

Selected Articles from the April 15, 2008 Issue

DICER Required to Maintain Hypermethylation in Cancer Cells

Secondary Mutations of BRCA1 and Chemosensitivity

Autozygosity Signatures in Genome Correlate with Cancer Incidence

Imaging Transgene Activity

Platform Technology to Generate Human T Cells with Redirected Specificity

EGFR Gender-Related Survival Differences in Metastatic Colon Cancer

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