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Background: Germline mutation in the cell adhesion molecule E-cadherin is known to be associated with the development of undifferentiated or diffuse-type familial gastric cancers, but the prevalence of this contribution seems to be low in Japanese familial cases, so far., Methods: We screened all exons of the E-cadherin gene for mutations in 101 Japanese patients having an intense family history of gastric cancers., Results: An abnormal band pattern was found in exon 9 in three patients (Y6, B21, B37) from two families by PCR-SSCP. DNA sequencing analysis of these three patients revealed isoleucine-leucine substitution at codon 415 in exon 9. B21 and B37 are siblings and the other three brothers died of gastric cancer and another brother (B36) has not been affected by gastric cancer to date. This case (B36) did not have this alteration in the exon 9 of E-cadherin., Conclusion: Although the mechanistic basis is not clear, our findings may provide a possibility that this additional missense mutation in germline E-cadherin gene may contribute to gastric cancer predisposition.

Papillary adenocarcinoma of the stomach is a relatively uncommon histological type, and it is often detected in the early stage. We recently characterized the papillary type of gastric cancer and found frequent microsatellite instability and associated mutations. In this study we analyzed the centromere numerical abnormality (CNA) of 18 chromosomes (chromosomes 1-4, 6-12, 15-18, 20, X, and Y) in the papillary and papillotubular types of gastric cancer by a modified fluorescence in situ hybridization technique with microwave treatment. All 3 cases (100%) of papillary adenocarcinoma had high microsatellite instability (MSI-H), and low CNA, and 41% (7 cases) of the 17 cases of papillotubular adenocarcinoma exhibited MSI-H and all 7 cases had low CNA. Further 8 cases (47%) had extensive CNA. In these 15 cases, all the MSI-H cases had lower CNA, and low microsatellite instability (MSI-L) and MSS cases had higher CNA. The remaining two cases showed low CNA and MSI-L and MSS. These profiles were different from those of tubular type gastric cancer, which always had extensive CNA and no MSI. Although the numbers of the cases in this series are limited, our data may suggest that a modest CNA may be another characteristic of gastric cancer with papillary structure.

Purpose: We have previously reported that EPHB2 is overexpressed in gastric cancer; however, the expression profiles of its ligands, EFNB1 and EFNB2, are unknown. This study was designed to investigate the expression of EPHB2 and its ligands, EFNB1 and EFNB2, in human gastric cancer., Methods: Semi-quantitative RT-PCR using (32)P was performed on human gastric cancer tissues and corresponding normal tissues (29 gastric cancer patients)., Results: EPHB2 was more highly expressed in tumor tissues than in normal tissues in 21 out of 29 (72.4%), in gastric cancer patients ( P = 0.01); EFNB1 and EFNB2 were highly expressed in 21 out of 29 (72.4%) ( P = 0.037) and 14 out of 29 (48.3%) patients, respectively. The overexpression of EPHB2 was frequently detected in both well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma [10/13 (76.9%) and 9/14 (64.3%), respectively]. On the other hand, the overexpression of EFNB1 was more frequently detected in poorly differentiated adenocarcinoma than in well-differentiated adenocarcinoma [12/14 (85.7%) and 7/13 (53.8%), respectively. P =0.027]. Elevated levels of EPHB2 and EFNB1 were detected in substantial subsets of early gastric cancers. Genomic alterations to these three genes in gastric cancer specimens were either not found or rarely found except for several rare variations of EPHB2., Conclusions: These findings suggest that not only the expression of EPHB2, but the expression of its ligand EFNB1 may have some relation with the oncogenesis of gastric cancer.

beta-PIX, a newly identified p21-activated kinase (PAK)-interacting exchange factors (PIX), encodes a guanine nucleotide exchange factor for Rho guanosine triphosphatases. Characterization of beta-PIX gene was performed using the BAC Library method. The beta-PIX gene has 17 exons and an A/T polymorphism at the 32nd base upstream of the intron/exon junction of exon 7. The frequencies of genotypes A/T, A/A and T/T were 23.6% (13/55), 72.7% (40/55) and 3.6% (2/55), respectively; these frequencies are in Hardy-Weinberg equilibrium. Two out of 14 informative tumors (14.3%) were shown to have lost their heterozygosity at this locus, but no mutations in the remaining alleles were detected. In addition, we examined the gene-expression profile in another set of 30 gastric samples, but no significant over-expression of either the beta-PIX gene or the alpha-PIX gene was found. Though the beta-PIX gene has been speculated to potentially have tumor-related biological characteristics, the findings of the present study suggest that the involvement of beta-PIX gene in human gastric carcinogenesis is minimal.

PAK-interacting exchange factor (PIX) has been reported to mediate the recruitment of PAK into focal adhesions and activate Rac, thus creating a feedback loop that stimulate PAK and other targets. This pathway is thought to be related to cellular changes, such as transformation and migration, that are often encountered in cancer cells. Here, we report the genomic structure of alpha-PIX, one of the PAK- interacting exchange factors, including the identification of the promoter region, which consisted 772 amino acids in 22 exons, spanning about 100 kb on genome of X chromosome. All splice sites conformed to the GT-AT rule. To investigate the role of alpha-PIX in carcinogenesis, we screened 60 cases of gastric cancer for mutations and polymorphisms using an intron-primer that covered all the exons, but no mutations or polymorphisms were found in the coding region. However an 18 bp repeat of thymidine tract was present in 50 bp downstream from exon 12 and the deletion of variable numbers of mononucleotide repeats was observed in seven out of the 60 gastric cancer tissue specimens that were examined. These seven cases all exhibited a mutator phenotype, suggesting that the deletions are passenger mutations. Thus our results revealed that alpha-PIX probably does not play any primary role in human gastric carcinogenesis.