Gastric cancers of Western European and African patients show different patterns of genomic instability

<p>Abstract</p> <p>Background</p> <p>Infection with <it>H. pylori </it>is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of <it>H. pylori </it>infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level.</p> <p>Methods</p> <p>DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis.</p> <p>Results</p> <p>Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients.</p> <p>Conclusions</p> <p>Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.</p

High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers

DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status

Genomic imbalances in 5918 malignant epithelial tumors: an explorative meta-analysis of chromosomal CGH data

BACKGROUND: Chromosomal abnormalities have been associated with most human malignancies, with gains and losses on some genomic regions associated with particular entities. METHODS: Of the 15429 cases collected for the Progenetix molecular-cytogenetic database, 5918 malignant epithelial neoplasias analyzed by chromosomal Comparative Genomic Hybridization (CGH) were selected for further evaluation. For the 22 clinico-pathological entities with more than 50 cases, summary profiles for genomic imbalances were generated from case specific data and analyzed. RESULTS: With large variation in overall genomic instability, recurring genomic gains and losses were prominent. Most entities showed frequent gains involving 8q2, while gains on 20q, 1q, 3q, 5p, 7q and 17q were frequent in different entities. Loss "hot spots" included 3p, 4q, 13q, 17p and 18q among others. Related average imbalance patterns were found for clinically distinct entities, e.g. hepatocellular carcinomas (ca.) and ductal breast ca., as well as for histologically related entities (squamous cell ca. of different sites). CONCLUSION: Although considerable case-by-case variation of genomic profiles can be found by CGH in epithelial malignancies, a limited set of variously combined chromosomal imbalances may be typical for carcinogenesis. Focus on the respective regions should aid in target gene detection and pathway deduction

Nature meets nurture: molecular genetics of gastric cancer

The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed