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Microsatellite Instability in Gastric Cancer Is Associated with Tumor Location and Family History in a High-Risk Population from Tuscany¹

Department of Oncology and Neurosciences, University "Gabriele D'Annunzio," 66013 Chieti [L. O., R. M-C., A. Cam.]; Epidemiology Unit, Centro Studio Pavenzione Oncologica, A. O. Careggi, Florence [D. P., C. S., F. C.]; Department of Experimental Medicine and Pathology, University of Rome "La Sapienza," 00161 Rome [M. F., C. D., C. T., L. D. M.]; Department of Pathology, University of Florence, 50131 Florence [A. A., A. Cal.]; and Epidemiology Satellite Unit, Istituto per lo Studio e cure dei Tumori Genoa, CSPO, Florence [G. M.], Italy

We studied the presence of microsatellite instability (MSI) in a series of 108 gastric cancers (GCs) previously identified in an epidemiological study carried out in a high-risk area around Florence. To investigate associations between MSI and GC family history, 34 cases (31.5%) who had a GC-affected first-degree relative were included in the series. A family history positive for colorectal cancer was reported quite rarely (5.6%). The analysis of 6 microsatellite loci in DNA from paired normal tissue and tumor samples microdissected from paraffin-embedded specimens revealed varying degrees of instability: 56 cases (51.8%) did not show instability at any of the 6 loci; 19 (17.6%) showed instability at 1 locus; 16 (14.8%) showed instability at 2 loci; 11 (10.2%) showed instability at 3 loci; 4 (3.7%) showed instability at 4 loci; and 2 (1.9%) showed instability at 5 loci. The replication error-positive (RER+) phenotype, defined as the presence of MSI at 2 or more loci, had a frequency of 30.6% (33 of 108) and tended to be positively associated with female sex, intestinal histological type, advanced tumor stage, vascular invasion, positive GC family history, and blood group of A type. No correlation emerged between age at diagnosis and RER+ phenotype, whereas a significant association with the RER+ phenotype was shown by the antral location. A multivariate analysis adjusting for a selected group of potential confounding factors confirmed the strong association of the RER+ phenotype with the antral location (P = 0.001) and with a positive GC family history (P < 0.05). Survival analyses at 5 and 8 years showed no difference between RER+ and RER- patients, even when corrected for stage distribution.

By the microdissection technique, we also used microsatellite allele patterns to investigate intratumoral heterogeneity and genetic relationships between tumors and adjacent dysplasia and/or intestinal metaplasia. Areas of metaplasia and dysplasia demonstrated MSI only in cases with MSI-positive tumors. In MSI-positive tumors, there was consistent evidence of intratumoral microsatellite allele heterogeneity, indicating the presence of genetically divergent tumor cell clones within the same neoplasm.

¹ Supported by Grant 95.00325.PF39 from the Consiglio Nazionale delle Ricerche (finalized project: Applicazioni Cliniche della Ricerca Oncologica), by the Associazione Italiana per la Ricerca sul Cancro special project "Hereditary Colorectal Tumors," and by grants from the Italian Ministry for Scientific and Technological Research and from Regione Toscana.

² To whom requests for reprints should be addressed, at Department of Oncology and Neurosciences, University "Gabriele D'Annunzio," Via dei Vestini 1, 66013 Chieti, Italy. Phone: 39-871-355325; Fax: 39-871-355322; E-mail: cama@unich.it.

Received 5/16/97. Accepted 8/14/97.

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