Chromosomal 20q gain in the DNA diploid component of aneuploid colorectal carcinomas

Abstract

The order of appearance of different genetic aberrations during the shift from diploidy/near-diploidy to aneuploidy in colorectal cancers is not yet clear. We studied genetic alterations in flow cytometrically-sorted DNA diploid and corresponding aneuploid epithelial cell populations from each of 20 colorectal tumors using comparative genomic hybridization, FISH, and PCR. Analysis of the 19 cases in which aberrations were found in the flow-sorted diploid population indicated that large-scale aneuploidization in colorectal cancer was preceded by amplification of oncogene(s) localized to chromosome 20q13.2 and by KRAS mutations, but not by TP53 deletions or losses of large chromosomal regions such as 4q, 8p and 18q. ' 2007 Wiley-Liss, Inc.Key words: DNA aneuploidy; DNA diploidy; flow-sorted colorectal tumors; CGH; chromosomal aberrations; FISH; 20q13 gain Colorectal tumorigenesis is characterized by the sequential accumulation of multiple and extensive genomic changes in normal colonic mucosal cells, 1 which ultimately lead to high-level aneuploidy in the majority of tumors. 2 The order of appearance of different genetic aberrations and the molecular mechanisms underlying the shift from diploidy to aneuploidy are not yet clear. The origin of high-level aneuploidy has been suggested to occur via tetraploidization of near-diploid aberrant colonic mucosal cells followed by chromosome loss. 3 Genes responsible for DNA double-strand break repair, chromosomal stability, chromosomal segregation and chromosome disjunction have also been suggested as likely candidates in the development of aneuploidy. 4,5 TP53 gene alterations may also be permissive for aneuploidy, 6 since the resulting loss of wild-type TP53 function may facilitate the formation and survival of cells with abnormal DNA content. Aneuploid colorectal tumors exhibit considerable chromosomal instability as evidenced by frequent gains of chromosomes 20 and 13 and frequent losses of chromosomes 18 and 4. 7,8 Late-stage colorectal adenomas harbor some of the same chromosomal aberrations as seen in colorectal carcinomas, although their incidence is less frequent. 7,9 The putative oncogenes and tumor suppressor genes localized to these frequently-amplified or -deleted chromosomal regions are still mostly unidentified.The resolution of flow cytometric DNA content measurements is limited to the detection of a variation in DNA content of about 5%. Thus cell populations with gain or loss of only 1 or 2 chromosomes may be measured by flow cytometry as having diploid DNA content, even if such near-diploid populations predominate in a cell sample. Flow cytometric DNA content histograms of aneuploid tumors typically show a cell population with ''diploid'' DNA content (Figure 1a). This DNA diploid cell population consists of infiltrating leucocytes and colonic mucosal cells. Some of these colonic mucosal cells may possibly be late-stage adenoma cells or abnormal cells (with some few chromosomal aberrations) that are at an early stage of tumor progression, and which may stil...

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