Copy Number Alterations at Polymorphic Loci May Be Acquired Somatically in Patients with Myelodysplastic Syndromes.

Abstract 2782

Poster Board II-758

Myelodysplastic (MDS) clones are thought to arise from a primitive CD34+ hematopoietic cell as a result of disrupted genomic integrity. Although approximately 50% of low-risk MDS patients do not exhibit karyotypic alterations, recent studies have identified submegabase copy number alterations in a proportion (18–68%) of cytogenetically normal cases using genomic array platforms. Recently, we observed disease-associated copy number alterations in low-risk MDS patients that overlapped common loci known to be sites of copy number variants (CNV). These CNV or copy number polymorphisms are a source of structural variation in the genome of a normal population, and widely assumed to be constitutional and not relevant findings in malignant tissue. Here we show by whole genome array comparative genomic hybridization that copy number changes in the CD34+ MDS clone that occur at polymorphic loci are frequently somatic alterations rather than constitutional variants. Further, the extent of copy number variation is increased in CD34+ cells of MDS patients compared to CD34+ cells of age-matched controls. This increase in disease-associated copy number alterations at polymorphic loci shows a trend toward association with poorer overall survival. Our findings demonstrate that copy number alterations at known polymorphic loci in CD34+ cells from lower-risk MDS patients are frequently due to somatic changes rather than constitutional polymorphisms. Further, alterations in copy number at these sites are likely not benign, regardless of whether they represent constitutional or somatic alterations, and may contribute to disease progression.