Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany.
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.
Ottini
L
L
Department of Oncology and Neurosciences, University Gabriele D'Annunzio, Chieti, Italy.
Palli
D
D
Falchetti
M
M
D'Amico
C
C
Amorosi
A
A
Saieva
C
C
Calzolari
A
A
Cimoli
F
F
Tatarelli
C
C
De Marchis
L
L
Masala
G
G
Mariani-Costantini
R
R
Cama
A
A
D000367:Age Factors; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics; D004247:DNA / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry; D005190:Family; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012016:Reference Values; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis
D004273:DNA, Neoplasm; D005819:Genetic Markers; D004247:DNA