Alterations of chromosomal copy number during progression of diffuse-type gastric carcinomas: metaphase- and array-based comparative genomic hybridization analyses of multiple samples from individual tumours.

The application of comparative genomic hybridization (CGH) has led to the rapid accumulation of cytogenetic information on gastric carcinoma (GC), but there is little information on the time sequence of cytogenetic changes. In the present study, degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR) and CGH were applied to multiple samples microdissected from 19 diffuse-type GCs including eight early cancers. Recurrent gains were detected at 8q, 3q, 7q, and 8p, and loss at 17p (in more than 50% of the cancers), the frequencies of which were fairly similar between the samples with (SIG) and those without (POR) abundant signet ring cells. Earlier stemline changes (8q+, 8p+, 1q+, 17p-, etc), with breakpoints that were common to all the samples, were discriminated from later sideline changes (2q+, 11q+, 17q-, 21q-, etc) in individual tumours. The changes were generally common to early and advanced cancers, except for 7p+, 15q+, 3p-, and 18q-, which were largely sideline changes and more frequently detected in advanced cancers (p<0.05). Because the samples with 7p+ had a greater number of copy-number changes than those without 7p+ (p<0.01), 7p+ may play a role in tumour progression by acceleration of chromosomal instability. Fifteen different chromosomal loci with amplification were detected in ten cases, mostly as sideline changes in advanced cancers. By microarray-based CGH, KRAS, MDM2, and FGFR2 were confirmed in the amplicons at 12p, 12q, and 10q, and FES at 15q26, for the first time in GC. These results support the notion that SIG and POR are of a genetically single lineage in both early and advanced diffuse-type GC and that the majority of advanced cancers derive from early cancers through the accumulation of various sideline changes in addition to stemline changes. Copyright 2003 John Wiley & Sons, Ltd.