Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

To identify additional targets of p53, we used a cDNA microarray system to examine gene-expression patterns in response to enforced expression of exogenous p53 in p53-deficient cancer cells, and identified the aldehyde dehydrogenase 4 (ALDH4) gene as a direct target of p53. ALDH4 is a mitochondrial-matrix NAD + -dependent enzyme catalyzing the second step of the proline degradation pathway. Expression of ALDH4 mRNA was induced in HCT116 cells in response to DNA damage caused by adriamycin treatment, in a p53-dependent manner. ALDH4 contains a potential p53 binding sequence in intron1 and the interaction of p53 with the site was shown by EMSA and ChIP assays. We confirmed p53-dependent transcriptional activity of the binding site by means of a reporter assay. Inhibition of ALDH4 expression by antisense oligonucleotides was able to enhance cell death induced by infection with Ad-p53. H1299 cells transformed to overexpress ALDH4 showed significantly lower intracellular reactive oxygen species (ROS) levels than parental or control cells after treatment with hydrogen peroxide or UV. Those cells were also resistant to cell damage caused by hydrogen peroxide. These results suggest that p53 might play a protective role against cell damage induced by generation of intracellular ROS, through transcriptional activation of ALDH4.

No abstract

Although the biological functions of tumor-originated cell-free DNA have not been previously clarified , such molecular characteristics as mutations , hypermethylation , and microsatellite instability have confirmed its tumor origin. Therefore , to investigate the use of plasma DNA level as a biomarker of lung cancer, we compared plasma DNA concentrations in 102 patients with lung cancer and 105 healthy individuals using quantitative PCR analyses. The median plasma DNA concentrations for the healthy and cancer groups were 10.4 and 22.6 ng/ml , respectively (P < 0.0001), and elevated plasma DNA levels were also detected in patients with either stage I or II disease. Neither smoking status nor the number of packs per year had an effect on the level of circulating cell-free DNA. Increased concentrations of circulating cell-free DNA showed the potential power to discriminate lung cancer (area under the receiver operating characteristic curve ‫؍‬ 0.86 , 95% CI ‫؍‬ 0.81 to 0.91). When subjects were classified into three groups based on their plasma DNA concentrations, subjects in the upper tertile (ie, those with the highest concentration) had a significantly increased risk of lung cancer as compared with those in the lowest tertile (adjusted odds ratio ‫؍‬ 50.6, P < 0.001). These results suggest that elevated circulating plasma DNA levels may serve as a potential diagnostic indicator and be an important risk factor for lung cancer. Lung cancer is the leading cause of cancer-related death in Korea and across the globe. Despite the development of several advanced technologies with enhanced sensitivity for detecting cancer, current screening methods for the diagnosis of lung cancer at an early stage are insufficient. Recently, circulating cell-free DNA was detected in blood fractions from patients with cancer. Since then, efforts have been made to use circulating cell-free DNA as a diagnostic or prognostic factor for lung cancer.

Purpose: Circulating cell-free DNA (CFDNA) was investigated as potential screening or prognostic markers in a variety of cancers. This study investigated its clinical significance in a homogeneous group of lung cancer patients.Experimental Design: We analyzed the blood samples of 134 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy. The amount of plasma CFDNA was measured by real-time quantitative PCR targeting the human ACTB genomic sequence. The patients were divided into three groups according to the tertiles of baseline plasma CFDNA.Results: Baseline plasma CFDNA did not correlate with primary tumor size (P ¼ 0.961), whereas the number of metastatic sites correlated significantly with baseline plasma CFDNA (P ¼ 0.015). In the GP arm, the low-CFDNA group showed a lower response rate than the middle-or high-CFDNA group (26.1%, 57.9%, and 60.9%, respectively; P ¼ 0.035). However, in the gefitinib arm, there was no difference in response rate between the three CFDNA groups (57.1%, 47.4%, and 51.9%; respectively; P ¼ 0.825). The high tertile CFDNA group showed a significantly shorter survival than the low tertile CFDNA group (median overall survival, 16.0 vs. 28.6 months, respectively; P ¼ 0.030). The risk of death increased with increased baseline plasma CFDNA (HR ¼ 1.23, 95% CI, 1.01-1.50; P ¼ 0.045).Conclusion: High plasma CFDNA is associated with aggressive tumor behavior and poor survival outcomes in these patients. Clin Cancer Res; 17(15); 5179-87. Ó2011 AACR.