Chromosomal instability in flat adenomas and carcinomas of the colon

Abstract

Flat adenomas are flat or slightly elevated dysplastic lesions of the colorectal mucosa, mostly with a tubular architecture. Compared with polypoid adenomas of similar size, flat adenomas show a higher frequency of high-grade dysplasia and rapid submucosal invasion. The aim of this study was to survey whether flat colorectal lesions differ in their pattern of chromosomal aberrations from their polypoid counterparts. Six flat adenomas and 12 flat carcinomas were analysed by comparative genomic hybridization (CGH) and the pattern of chromosomal aberrations was compared with a previously published series of 112 polypoid adenomas and 82 polypoid carcinomas. In addition, multiplex ligation-dependent probe amplification (MLPA) for identifying DNA copy number changes of 25 individual genes on chromosome 20 was performed on 14 flat and 15 polypoid tumours. With CGH, flat adenomas showed on average 1.8 gains (range 1-4) and 3.2 losses (range 0-4), and the flat carcinomas 4.5 gains (range 0-8) and 3.5 losses (range 1-6). In both adenomas and carcinomas, high frequencies of 20q gain (83% and 92%, respectively) and 18q loss (83% and 92%, respectively) were found. This correlation between 20q gain and 18q loss had previously been observed in a subgroup of polypoid colorectal tumours. Both flat and polypoid colorectal tumours with 20q gains by CGH showed similar patterns of copy number ratios for the individual genes tested. TOP1, BCL2L1, and E2F1 had median copy number ratios of 2 or higher, while ZNF217 had a ratio around 3. In conclusion, flat adenomas and carcinomas of the large intestine show a similar pattern of chromosomal aberrations to that observed in a specific subgroup of polypoid lesions. The transcription factor ZNF217 is an important candidate for driving the 20q gain.

Chromosome 5q Loss in Colorectal Flat Adenomas

“…In this study, chromosome 18 loss was less frequently found in flat adenomas and was associated with HGD, which is consistent with earlier findings of high prevalence of 18q in a series of flat adenomas enriched for high-grade lesions (38). Deletion of chromosome 18q has also been described as an important event in the transition from adenoma to carcinoma (42), which could indicate that flat adenomas acquire chromosome 18 loss later in their tumorigenesis.…”

“…Many alterations observed in this study for flat and polypoid adenomas have been described before including gains on chromosome 7, 13, and 20, however not yet using a high resolution platform with multiple probes per gene (14,34,(37)(38)(39). Supervised testing of chromosomal aberrations between flat and polypoid adenomas revealed that flat adenomas harbor a specific loss of 5q15.5-q31.1 and rarely show other losses that frequently occur in polypoid adenomas, that is, 1p36.32-p35.3, 10q25.3, 17p12, and chromosome 18.…”

Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas

“…Using multiplex ligation-mediated probe amplification, we previously found increased copy numbers for this gene in 15 of 15 cervical carcinomas (22). Frequent copy number gains of TOP1 were also found in colorectal cancer using the same technique (42).…”

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

“…CNAs at the chr16p loci have generally not been reported in previous copy number studies of colorectal neoplasia, 11,18,23,[26][27][28][29][30] maybe because the region is located close to the p-terminus where it traditionally have been difficult to identify CNAs using conventional CGH. 31 Although a few studies have reported on losses of the short arm of chr16 in CRC, this has not received much attention. 12,[32][33][34][35] Our analyses indicate that the genomic rearrangement leading to chr16p-loss is an early event occurring in $ 30% of adenomas.…”