DNA copy number changes in young gastric cancer patients with special reference to chromosome 19

Only a few cytogenetic and genetic studies have been performed in gastric cancer patients in young age groups. In the present study we used the comparative genomic hybridisation (CGH) method to characterise frequent DNA copy number changes in 22 gastric cancer patients of 45 years or younger and three gastric cancer cell lines established from patients younger than 45 years. Analysis of DNA copy number changes revealed frequent DNA copy number increases at chromosomes 17q (52%), 19q (68%) and 20q (64%). To confirm the CGH results and to characterise the amplicon region on the most frequently amplified chromosome, chromosome 19, we carried out fluorescence in situ hybridisation (FISH) analysis and Southern blot analysis. Fluorescence in situ hybridisation with the bacterial artificial chromosome (BAC) clone mapped to 19q12 indicated a copy number increase in all eight tumour specimens studied. Southern blot analysis of six tumour specimens and three tumour cell lines, with five probes mapped to the 19q12-13.2 region, suggested cyclin E to be one of the candidate target genes in the 19q region for gastric cancer tumorigenesis. Cyclin E protein overexpression was verified in tumours with amplification on chromosome 19. Further studies are required to investigate the biological and clinical significance of 19q amplicon and cyclin E upregulation in gastric cancer of young patient

IκBα polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese

<p>Abstract</p> <p>Background</p> <p>Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of <it>IκBα </it>to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.</p> <p>Methods</p> <p>A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in <it>IκBα </it>were analyzed by TaqMan SNP genotyping assay.</p> <p>Results</p> <p>Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, <it>P </it>= 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, <it>P </it>= 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, <it>P </it>= 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, <it>P </it>= 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, <it>P </it>= 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.</p> <p>Conclusions</p> <p><it>IκBα </it>rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.</p

Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates

Racial and ethnic colorectal cancer patterns affect the cost-effectiveness of colorectal cancer screening in the United States.

Background &amp; aimsColorectal cancer screening beginning at age 50 is recommended for all Americans considered at "average" risk for the development of colorectal cancer.MethodsWe used 1988-1995 California Cancer Registry data to compare the cost-effectiveness of two 35-year colorectal cancer screening interventions among Asians, blacks, Latinos, and Whites.ResultsAverage annual age-specific colorectal cancer incidence rates were highest in blacks and lowest in Latinos. Screening beginning at age 50 was most cost-effective in blacks and least cost-effective in Latinos (measured as dollars spent per year of life saved), using annual fecal occult blood testing (FOBT) combined with flexible sigmoidoscopy every 5 years and using colonoscopy every 10 years. A 35-year screening program beginning in blacks at age 42, whites at age 44, or Asians at age 46 was more cost-effective than screening Latinos beginning at age 50.ConclusionsColorectal cancer screening programs beginning at age 50, using either FOBT and flexible sigmoidoscopy or colonoscopy in each racial or ethnic group, are within the $40,000-$60,000 per year of life saved upper cost limit considered acceptable for preventive strategies. Screening is most cost-effective in blacks because of high age-specific colorectal cancer incidence rates

Modulation of angiogenic biomarkers in patients treated on a phase I study of TRC105 (anti-CD105 antibody) monotherapy for advanced solid tumors

This journal suppl. entitled: ASCO Meeting Abstracts Part 1BACKGROUND: CD105 (endoglin) is an important mediator of tumor angiogenesis that is upregulated by hypoxia and VEGF inhibitors. TRC105 is an anti-CD105 monoclonal antibody currently being evaluated in clinical trials as an anti-angiogenic cancer therapy. METHODS: In this first-in-human phase I study, pts with advanced, incurable solid tumors were treated with escalating doses of TRC105, iv every 2 wks, until disease progression. Serial plasma samples were analyzed via a novel multiplex ELISA platform optimized for cancer patients. 39 candidate biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month, and at end of study (EOS). RESULTS: 19 pts treated with TRC105 at 0.01-1 mg/kg were evaluable for biomarker analysis. Spearman’s rank correlation coefficients were calculated for pairs of analytes with known interactions. Wilcoxon signed rank tests indicated that the following analytes were significantly down-regulated at one month when compared with baseline: IGFBP-3 (p=0.001), VEGF-C (p=0.002), VEGF-D (p=0.003), FGFb (p=0.008), PDGF-AA (p=0.011), PDGF-BB (p=0.039), and PIGF (p=0.045). By EOS, significant increases from the 1 month nadir were observed for the following analytes: VEGF-C (p=0.027), VEGF-D (p=0.034), and IGFBP-3 (p=0.043). CONCLUSIONS: This is the first systematic investigation of the effect(s) of TRC105 on angiogenic biomarkers in the clinical setting. Multiplex analyses indicate that TRC105 therapy is associated with down-regulation of key modulators of angiogenesis that later increase at the time of disease progression. Based on these preliminary findings, additional analyses are planned for pts treated at higher TRC105 doses as well as pts treated on phase Ib and phase II studies of TRC105 in combination with VEGF inhibitors and other standard-of-care cancer therapies

A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach

Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs E-cadherin to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment