Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies

Blood. 2006 Sep 1;108(5):1684-9. doi: 10.1182/blood-2005-11-011486. Epub 2006 May 11.

Abstract

To identify the mechanism of loss of heterozygosity (LOH) and potential modifier gene(s), we investigated the molecular basis of somatic NF1 inactivation in myeloid malignancies from 10 children with neurofibromatosis type 1. Loci across a minimal 50-Mb region of primarily the long arm of chromosome 17 showed LOH in 8 cases, whereas a less than 9-Mb region of loci flanking NF1 had LOH in the remaining 2 cases. Two complementary techniques, quantitative polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), were used to determine whether the copy number at loci that showed LOH was 1 or 2 (ie, deleted or isodisomic). The 2 cases with LOH limited to less than 9 Mb were intrachromosomal deletions. Among the 8 leukemias with 50-Mb LOH segments, 4 had partial uniparental isodisomy and 4 had interstitial uniparental isodisomy. These isodisomic cases showed clustering of the centromeric and telomeric LOH breakpoints. This suggests that the cases with interstitial uniparental isodisomy arose in a leukemia-initiating cell by double-homologous recombination events at intervals of preferred mitotic recombination. Homozygous inactivation of NF1 favored outgrowth of the leukemia-initiating cell. Our studies demonstrate that LOH analyses of loci distributed along the chromosomal length along with copy-number analysis can reveal novel mechanisms of LOH that may potentially identify regions harboring "cryptic" tumor suppressor or modifier genes whose inactivation contributes to tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age of Onset
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 17*
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Leukemia, Myeloid / genetics*
  • Loss of Heterozygosity
  • Male
  • Neurofibromatosis 1 / genetics*
  • Neurofibromin 1 / genetics*
  • Recombination, Genetic
  • Uniparental Disomy / genetics*

Substances

  • Neurofibromin 1