Determination of amplicon boundaries at 20q13.2 in tissue samples of human gastric adenocarcinomas by high‐resolution microarray comparative genomic hybridization

Abstract

Comparative genomic hybridization (CGH) of gastric adenocarcinomas frequently shows gains and amplifications of chromosome 20. However, the underlying genetic lesion is unknown and conventional CGH results do not allow specification of the target region. In order to investigate this chromosomal aberration with a higher resolution and sensitivity, microarray-based CGH was performed with both scanning and high-resolution arrays of chromosome 20 in a series of 27 gastric adenocarcinomas. Locus-specific fragments of genomic DNA from bacterial artificial chromosome (BAC) clones were spotted as microarrays. A scanning array contained a set of 27 BAC clones covering chromosome 20q. A high-resolution array contained 27 overlapping BAC clones at 20q13.2. This high-resolution array was used to narrow down the amplicon at 20q13.2 in tumours showing amplification of this chromosomal region with the scanning array. Positive copy number changes on chromosome 20q were detected in 12 of 27 cases (44%). These changes included gain of the whole arm of chromosome 20q in 8 of 27 (30%) cases, amplification restricted to 20q12.1 in one case, and amplifications restricted to 20q13 in three cases (11%). The three tumours showing amplification restricted to 20q13 were analysed further using the high-resolution array. In one tumour, the whole contig was amplified at a constant level. One of the other two tumours had a clear proximal breakpoint, while the other tumour had a clear distal breakpoint within the 20q13.2 region. The proximal and the distal breakpoint were approximately 800 kb apart. In the present study, an amplicon at 20q13.2 has been narrowed down to 800 kb which is likely to harbour one or more putative oncogenes relevant to gastric carcinogenesis, for which ZNF217 and CYP24 are good candidates.

Genomic profiling of gastric cancer predicts lymph node status and survival

“…This could be explained by higher tumour heterogeneity in gastric and colorectal cancer than in breast cancer. Fluorescence in situ hybridization experiments on gastric cancers on chromosome 20q support this idea (Weiss et al, 2003). Given their clinical relevance, a biological significance of these low-level changes must exist, but their effect in terms of gene expression remains to be determined.…”

“…Analysis of substantially larger series of cases will enable to narrow down the common regions of overlap for these discriminating chromosomal loci, which can then be explored with contig arrays. These contig arrays may reveal amplifications within such a common region of interest that otherwise could have been missed, and this can be a strong indication of the actual genes involved (Varis et al, 2002;Weiss et al, 2003). By means of fluorescent in situ hybridization analysis and expression analysis, these candidate genes can be validated (Varis et al, 2002).…”

Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression

“…45 In our study, gain of 20q was detected in 71 cases (70%) and was associated with the pattern of the cancer-stroma 51 and CYP24 (20q13.2). 52 Amplification and overexpression of the BTAK gene, which encodes breast tumor-amplified kinase (identical to aurora2, ARK1 and STK15), have been reported in primary gastric adenocarcinomas that were associated with aneuploidy and poor prognosis. 47 Moreover, amplification and overexpression of the AIB1 (amplified in breast cancer 1) gene, a member of the steroid receptor coactivator family, appears to be useful as a marker of poor prognosis in gastric cancer.…”

“…It was also been reported that the ZNF217 gene, which encodes a transcription factor, and the CYP24 gene, for a suppressor of the active form of vitamin D that inhibits cell growth, at 20q13.2 might be relevant to gastric carcinogenesis. 52 Thus, expressions of these genes at 20q12-13 are likely regulated not only by amplifications of these genes but also by other mechanisms such as transcriptional activation, and expressions of these genes might play an important role in the development and progression of gastric cancers. A gain in DNA copy number at 8q was the second most frequent gain, but it was not associated with clinicopathologic factors in our series.…”

Prediction of S-1-induced anemia

“…For the sex chromosomes, a log 2 ratio of 0.22-0.28 was suggested for a single copy change [29,30]. With an indirect study design, ranges of 0.2-0.6 had been suggested for a single copy change [31,32] and a log 2 ratio of 0.68 was suggested as the criterion for genome alterations, such as duplicated or deleted gene changes, regardless of differences in microarray study design (direct, indirect, sex-matched, sex-mismatched; Fig. 3) [28].…”