The stage of gastrointestinal cancers has been correlated with the loss of heterozygosity (LOH) and the presence of microsatellite instability (MSI). This study delineated the category of the extent of LOH and the presence of MSI for the genetic classification of the intestinal-type and diffuse-type gastric cancers that frequently exhibited intralesional heterogeneity. A total of 390 tumor foci from 116 gastric cancers were screened using a panel of 40 microsatellite markers on chromosomes 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. One MSI-positive gastric cancer accompanying a LOH-positive focus and 19 gastric cancers with an intralesional LOH heterogeneity with a similar extent were identified. One hundred and sixteen gastric cancers were categorized based on the presence of MSI (16 cases) and the extent of LOH (100 cases) in a representative focus. A large fraction of MSI-positive cases was found in the intestinal-type (94%), late-onset (mean age 68 years), early-stage (75%) diseases (P<0.05). The diffuse-type gastric cancers with a baseline-level loss involving zero or one chromosome showed a correlation with the earlier onset (mean age 45 years), advanced-stage (81%) diseases (P<0.0001). In both the intestinal-type and diffuse-type gastric cancers, a low-level loss involving 0-3 chromosomes (2-3 chromosomes in the diffuse type) and a high-level loss involving 4-7 chromosomes were predominant in the early (69%) and advanced (86%) stages, respectively (P<0.0001), at similar mean ages of onset (61 years and 65 years). Gastric cancers were categorized into low-risk (MSI and low-level LOH) and high-risk (baseline-level and high-level LOH) genotypes displaying cell-type- and age-dependent oncogenicity.
Mutator phenotype tumors provide unique opportunities to unravel malignant progression because of various gene alterations acquired during clonal tumor evolution. Gastric carcinomas, which have been known to show frequent genetic instability, would be composed of initial gene alterations shared by most tumor areas and subsequent alterations restricted to particular tumor sites. To analyse the timing of genetic events, we examined separate sites of tumor tissue obtained from a given gastric carcinoma patient with microsatellite instability (MSI). Our study included 95 normal/tumor area pairs from 25 patients. Six of the 25 patients (24%) demonstrated various levels of MSI ranging from 7% (two of 30) to 97% (28 of 29) of markers tested in multiple tumor sites. Of the six patients, ®ve manifested frameshift mutations in a tract of ten deoxyadenosines within transforming growth factor b receptor type II and four demonstrated frameshift mutations in a tract of eight deoxyguanosines within BAX. These mutations were common to all tumor sites regardless of the various level of MSI phenotype, indicating initial events. Two of the six patients exhibited frameshift mutations in mononucleotide repeats of mismatch repair genes, hMSH3 and hMSH6, and the insulin-like growth factor II receptor in restricted tumor areas, indicating additional alterations. Insulin-like growth factor II receptor mutations appear to be caused by hMSH3 and hMSH6 mutations because the former mutations were con®ned to tumor portions with the latter two mismatch repair lesions. These results provide genetic progression evidence for gastric carcinomas of the mutator pathway. In this pathway, mismatch repair insuciency initially targets mononucleotide tracts of transforming growth factor b receptor type II and BAX. During tumorigenesis, primary mismatch repair failure may give rise to the secondary mismatch repair lesions, frameshift mutations of hMSH3 and hMSH6, which result in another tumorigenic mutation in the insulin-like growth factor II receptor.
A mixed glandular-neuroendocrine gastric carcinoma shows discrete, juxtaposed areas of adenocarcinoma and neuroendocrine carcinoma. In order to gain insight into the genetic events and clonality associated with the dual differentiation of a mixed gastric carcinoma, eight cases (two true composite and six neuroendocrine-dominant carcinomas) were examined by analyzing the genome-wide loss of heterozygosity (LOH). Of the eight mixed gastric carcinomas, one true composite and five neuroendocrine-dominant carcinomas showed a primary LOH that was shared by both the glandular and neuroendocrine components and a secondary LOH or mutations that were restricted to the neuroendocrine components. The glandular components contained mixed cell populations with or without primary LOH events, suggesting that a primary LOH arose during adenocarcinoma progression and that the LOH-positive cell served as a precursor for a neuroendocrine carcinoma. The neuroendocrine components were of a homogeneous population with various genetic alterations such as a LOH, p53 mutations, and microsatellite instability-associated transforming growth factor (TGF)-beta RII mutation. Therefore, most (six of eight cases) mixed glandular-neuroendocrine gastric carcinomas were likely to have sequentially evolved from a glandular precursor to a genetically heterogeneous adenocarcinoma and then to neuroendocrine differentiation. Two components of the other true composite carcinomas were shown to have reciprocally lost different alleles of identical loci on multiple chromosomes, suggesting that, occasionally (one of eight cases), dual differentiation concurrently arises from a single precursor, possibly as a result of non-disjunctional cell division.
To gain an insight into the genetic events underlying morphological phenotypes, we analysed 58 gastric carcinoma tissues for the genome-wide allelotype study using microsatellite markers. Based on a binomial distribution, loss of heterozygosity (LOH) that was signi®cantly more frequent than expected (P50.05) thus interpreted as nonrandom LOH selected during tumorigenesis. The overall extent of chromosomes undergoing LOH i.e. fractional allelic loss (FAL, the ratio of LOHpositive markers to the total number of informative markers) was measured in each tumor patient. Nonrandom LOH was found on 17p (48.0%), 18q (38.4%), 13q (38.1%) and 9p (36.4%). Overall, there were no signi®cant phenotypes correlated with allelic loss on speci®c chromosome regions. Based on a bimodal distribution of FAL values with two peaks bordered by a mean of 0.233, tumors were classi®ed into LOHrelated (40.233) and LOH-unrelated (50.233) types. Among 24 patients with LOH-related tumors, increase in the in®ltrative type of growth pattern was found to correspond with a signi®cant trend of increasing FAL values. This study shows that the growth pattern of gastric carcinoma is correlated with FAL, suggesting that a malignant phenotype is in¯uenced by LOH event.
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