Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.