Selective Advantage of the Recurrent Isodicentric Chromosome 20 in Myeloid Disease

Interstitial deletion of the long arm of chromosome 20 is a common genomic imbalance associated with myeloid hematologic disorders. Originally identified by conventional cytogenetics and fluorescent in situ hybridization, it has been hypothesized that deletion of 20q results in haploinsuffciency of tumor suppressor gene(s) causing a proliferative advantage. The advent of microarray analysis has revolutionized the detection of copy number gains and losses associated with a variety of oncogenic mechanisms. Initial studies using microarray analysis have shown significant heterogeneity in the breakpoints associated with interstitial deletions of 20q, ruling out the possibility of a recurrent genomic fusion, but establishing a critical region which appears to support a tumor suppressor gene loss model. We have documented six individuals, referred for microarray analysis of myelodysplasia, with alterations of chromosome 20 involving a similar complex rearrangement. The rearrangement is an isodicentric chromosome 20 consisting of 1) a deletion of the majority of the short arm pter to p11.1, 2) retention of the region flanking the centromere from p11.1 to q11.21, and 3) an adjacent interstitial deletion of the long arm that can vary in size similar to the common 20q deletion. The breakpoints of the region flanking the centromere at 20p11.1 are within a block of segmental repeats and virtually identical in all 6 cases while the break points in 20q11.21 are within ~1.1 MB (30,785,977-31,887,129). In addition, one of the six cases shows additional copies of the region flanking the centromere from p11.1 to q11.21 consistent with supernumerary marker chromosomes found by conventional cytogenetics. These results suggest that there is a selective advantage associated with a gene(s) within the chromosome 20p11.1->q11.21 segment. The PDRG1 gene is localized to 20q11.21and has been shown to be upregulated in number of malignant cell types including colon, rectum, ovary, lung, stomach, breast and uterus. As our results show, PDRG1 is duplicated or amplified in all 6 cases with the isodicentric chromosome 20. Therefore, these results suggest PDRG1 upregulation may contribute to the pathogenicity of myelodysplasia by conferring a selective advantage in individuals with the isodicentric chromosome 20.