👤 Mark van Duin

Amplification of 8q is frequently found in gastroesophageal junction (GEJ) cancer. It is usually detected in high-grade, high-stage GEJ adenocarcinomas. Moreover, it has been implicated in tumor progression in other cancer types. In this study, a detailed genomic analysis of 8q was performed on a series of GEJ adenocarcinomas, including 22 primary adenocarcinomas, 13 cell lines and two xenografts, by array comparative genomic hybridization (aCGH) with a whole chromosome 8q contig array. Of the 37 specimens, 21 originated from the esophagus and 16 were derived from the gastric cardia. Commonly overrepresented regions were identified at distal 8q, i.e. 124-125 Mb (8q24.13), at 127-128 Mb (8q24.21), and at 141-142 Mb (8q24.3). From these regions six genes were selected with putative relevance to cancer: ANXA13, MTSS1, FAM84B (alias NSE2), MYC, C8orf17 (alias MOST-1) and PTK2 (alias FAK). In addition, the gene EXT1 was selected since it was found in a specific amplification in cell line SK-GT-5. Quantitative RT-PCR analysis of these seven genes was subsequently performed on a panel of 24 gastroesophageal samples, including 13 cell lines, two xenografts and nine normal stomach controls. Significant overexpression was found for MYC and EXT1 in GEJ adenocarcinoma cell lines and xenografts compared to normal controls. Expression of the genes MTSS1, FAM84B and C8orf17 was found to be significantly decreased in this set of cell lines and xenografts. We conclude that, firstly, there are other genes than MYC involved in the 8q amplification in GEJ cancer. Secondly, the differential expression of these genes contributes to unravel the biology of GEJ adenocarcinomas. Show less

Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. Eight nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH) analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent probe amplification (MLPA) analysis for EXT1. EXT1 locus-specific fluorescent in situ hybridization (FISH) was performed on nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine which parts of the tumor are of clonal origin. Array-CGH analysis of tumor DNA revealed that all eight osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma. EXT1 functions as a classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas. Show less