title: Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-associated glomus tumors.
abstract: Neurofibromatosis type 1 (NF1) is a common, autosomal dominant, tumor-predisposition syndrome that arises secondary to mutations in NF1. Glomus tumors are painful benign tumors that originate from the glomus body in the fingers and toes due to biallelic inactivation of NF1. We karyotyped cultures from four previously reported and one new glomus tumor and hybridized tumor (and matching germline) DNA on Illumina HumanOmni1-Quad SNP arrays (≈ 1 × 10(6) SNPs). Two tumors displayed evidence of copy-neutral loss of heterozygosity of chromosome arm 17q not observed in the germline sample, consistent with a mitotic recombination event. One of these two tumors, NF1-G12, featured extreme polyploidy (near-tetraploidy, near-hexaploidy, or near-septaploidy) across all chromosomes. In the remaining four tumors, there were few cytogenetic abnormalities observed, and copy-number analysis was consistent with diploidy in all chromosomes. This is the first study of glomus tumors cytogenetics, to our knowledge, and the first to report biallelic inactivation of NF1 secondary to mitotic recombination of chromosome arm 17q in multiple NF1-associated glomus tumors. We have observed mitotic recombination in 22% of molecularly characterized NF1-associated glomus tumors, suggesting that it is a not uncommon mechanism in the reduction to homozygosity of the NF1 germline mutation in these tumors. In tumor NF1-G12, we hypothesize that mitotic recombination also "unmasked" (reduced to homozygosity) a hypomorphic germline allele in a gene on chromosome arm 17q associated with chromosomal instability, resulting in the extreme polyploidy.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD 20852, USA. drstewart@mail.nih.gov
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
authors.forename: Alexander
authors.initials: A
authors.lastname: Pemov
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.forename: Eline
authors.initials: E
authors.lastname: Beert
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
authors.forename: Evgenia
authors.initials: E
authors.lastname: Pak
authors.forename: Amalia
authors.initials: A
authors.lastname: Dutra
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D016514:Genes, Neurofibromatosis 1; D005918:Glomus Tumor / Q000150:complications / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D019656:Loss of Heterozygosity; D008297:Male; D008938:Mitosis; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000235:genetics; D011123:Polyploidy; D011995:Recombination, Genetic