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Diffuse gastric cancer (DGC) is one of the two primary types of stomach cancer. Carriers of germline mutations in the gene encoding E-cadherin are predisposed to DGC. The primary aim of the present study was to determine if genomic instability is an early event in DGC and how it may lead to disease progression. Chromosomal aberrations in early intramucosal hereditary diffuse gastric cancer (eHDGC) were assessed using array comparative genomic hybridization (array CGH). Notably, no aneuploidy or other large-scale chromosomal rearrangements were detected. Instead, all aberrations affected small regions (< 4.8 Mb) and were predominantly deletions. Analysis of DNA sequence patterns revealed that essentially all aberrations possessed the characteristics of common fragile sites. These results and the results of subsequent immunohistochemical examinations demonstrated that unlike advanced DGC, eHDGCs is characterized by low levels of genomic instability at fragile sites. Furthermore, they express an active DNA damage response, providing a molecular basis for the observed indolence of eHDGC. This finding is an important step to understanding the pathology underlying natural history of DGC and supports a revision of the current definition of eHDGC as a malignant disease.

Background: We have recently reported an inverse relationship between colon cancer progression and tumour proliferative activity. Here, we extend our findings by evaluating the proliferative activity of liver metastatic lesions and primary colorectal cancers (CRC) that differ in their metastatic potential. Methods: Using an earlier established multi-gene proliferation signature (GPS), proliferative levels were analysed in 73 primary CRCs and 27 liver metastases. Results: Compared with primary CRCs, we observed a significantly lower expression of the GPS in liver metastases and confirmed their lower proliferative levels by quantitative RT–PCR and Ki-67 immunostaining. No difference could be detected in apoptotic indices as assessed by M30 immunostaining, indicating that the net growth rate is lower in metastases relative to primary tumours. Notably, relapsed primaries or those with established metastases had significantly lower proliferative activity than CRCs that were non-metastatic and did not relapse. Conclusion: Our results suggest that slow proliferation is a biological characteristic of both liver metastases and those primary tumours with the ability to metastasise. The delineation of the mechanisms underlying the inverse association between proliferation and CRC aggressiveness may be important for the development of new therapeutic strategies.

Compromised quality of formalin-fixed paraffin-embedded (FFPE)-derived DNA has compounded the use of archival specimens for array-based genomic studies. Recent technological advances have led to first successes in this field; however, there is currently no general agreement on the most suitable platform for the array-based analysis of FFPE DNA. In this study, FFPE and matched fresh-frozen (FF) specimens were separately analyzed with Affymetrix single nucleotide polymorphism (SNP) 6.0 and Agilent 4x44 K oligonucleotide arrays to compare the genomic profiles from the two tissue sources and to assess the relative performance of the two platforms on FFPE material. Genomic DNA was extracted from matched FFPE–FF pairs of normal intestinal epithelium from four patients and were applied to the SNP and oligonucleotide platforms according to the manufacturer-recommended protocols. On the Affymetrix platform, a substantial increase in apparent copy number alterations was observed in all FFPE tissues relative to their matched FF counterparts. In contrast, FFPE and matched FF genomic profiles obtained via the Agilent platform were very similar. Both the SNP and the oligonucleotide platform performed comparably on FF material. This study demonstrates that Agilent oligonucleotide array comparative genomic hybridization generates reliable results from FFPE extracted DNA, whereas the Affymetrix SNP-based array seems less suitable for the analysis of FFPE material.

Background Inherited genetic factors such as E-cadherin (CDH1) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for CDH1 transcription has been identified in CDH1 intron 2. Methods We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using χ2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis. Results We observed a significant (p < 0.0004) association of the CDH1 163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09–9.93) and 1.38 (95%CI = 0.75–2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H. pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied. Conclusion The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.