Integrative Analysis of Genomic Aberration and Gene Expression Suggests That MPD with Loss of Heterozygosity or Gain of Chromosome 9 Represents a Distinct Entity

Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) can all be associated with the JAK2V617F gain of function mutation. MPDs are also associated with gross cytogenetic anomalies including genomic gain/loss or loss of heterozygosity (LOH) due to mitotic homologous recombination. To determine whether genomic anomalies may be associated with JAK mutation status/disease phenotype we subjected genomic DNA from the granulocytes of 87 patients with PV, ET or IMF to analysis using high resolution Affymetrix 250K Nsp SNP arrays with an average probe spacing of 12Kb. Firstly this analysis precisely mapped previously identified anomalies in MPD patients such as gain of chromosome 1q chromosome 9 (Chr9), chromosome 8, and deletion of 20q and 13q indicating the robustness of the technique. By removing genomic Copy Number Polymorphisms (CNPs) ascertained from 90 normal individuals from the HapMap dataset, we further detected a number of novel alterations such as frequent gain of Chr9p33–34 harboring among other genes, Notch1. MPD patients heterozygous for the JAK V617F mutation exhibited higher genomic instability than JAK2 V617 homozygous or wild type patients. IMF patients had overall more aberrations than PV or ET patients but unsupervised hierarchical clustering of chromosomal anomalies could not distinguish patients with PV, ET or IMF. Whole chromosomal gain or loss was equally frequent among the three diseases, however IMF patients had more frequent alteration of 10Mb or greater when compared to ET or PV (p