Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas

DNA multiploidy may involve specific DNA ploidy states with respect to gene tic alterations such as oncogenes, tumor suppressor gene mutation and micro satellite instability. To clarify the role of DNA multiploidy in colorectal cancer, we analysed allelic imbalance involving the ATM gene, localized to chromosome 11q22-23 and thought to be involved in genetic stability, in a series of multiploid colorectal carcinomas. In addition, p53 gene mutation (exons 5 - 8) and allelic imbalance at 11q24 loci distal to the ATM locus w ere also examined. The crypt isolation technique coupled with DNA cytometri c sorting and polymerase chain reaction assay using 10 microsatellite marke rs tightly linked to the ATM gene were used to study ATM allelic imbalance in 55 colorectal carcinomas (15 diploid, 13 aneuploid, 27 multiploid). Whil e allelic imbalance at the ATM locus was rarely observed in diploid and ane uploid carcinomas, multiploid carcinomas exhibited a high frequency of ATM allelic imbalance. In multiploid carcinoma samples, diploid subpopulations showed a smaller range of allelic imbalance at the loci tested compared to aneuploid subpopulations that demonstrated allelic imbalance over a relativ ely large region. Also, the frequency of AI at 11q24 showed a similar tende ncy to that at the ATM locus for each DNA ploidy state. An association betw een p53 gene mutation and ATM allelic imbalance in multiploid carcinoma was also observed. Our results suggest that ATM allelic imbalance and p53 gene mutations occur during the progression from diploid to aneuploid cell popu lations in multiploid colorectal carcinomas.