High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations

Abstract

Single-nucleotide polymorphism arrays allow for genome-wide profiling of copy-number alterations and copy-neutral runs of homozygosity at high resolution. To identify novel genetic lesions in myeloproliferative neoplasms, a large series of 151 clinically well characterized patients was analyzed in our study. Copy-number alterations were rare in essential thrombocythemia and polycythemia vera. In contrast, approximately one third of myelofibrosis patients exhibited small genomic losses (less than 5 Mb). In 2 secondary myelofibrosis cases the tumor suppressor gene NF1 in 17q11.2 was affected. Sequencing analyses revealed a mutation in the remaining NF1 allele of one patient. In terms of copy-neutral aberrations, no chromosomes other than 9p were recurrently affected. In conclusion, novel genomic aberrations were identified in our study, in particular in patients with myelofibrosis. Further analyses on single-gene level are necessary to uncover the mechanisms that are involved in the pathogenesis of myeloproliferative neoplasms.

Figure 1.

(A) Matched-pair SNP-array profile of one post-essential thrombocythemia myelofibrosis patient with microdeletion in 17q. Allele-based analysis at the bottom of the figure differentiates SNP calls derived from germline (red) and tumor (green) material. Overlay of both profiles (blue) reveals one stretch of tumor-specific loss of heterozygosity in 17q11.2 (1.6 Mb). (B) Validation by fluorescence in situ hybridization with a representative cell from the same patient. One green fluoresence signal using a Neurofibromatosis-1- (NF1-) specific DNA-probe indicates monoallelic loss of the gene, whereas two red signals obtained with a TP53-specific control probe demonstrate the existence of both alleles.