title: High-resolution 400K oligonucleotide array comparative genomic hybridization analysis of neurofibromatosis type 1-associated cutaneous neurofibromas.
abstract: Neurofibromatosis type 1 (NF1) is a genetic disorder where affected individuals develop benign or malignant nervous system tumors. To date, NF1 is caused by mutations in the NF1 tumor suppressor gene located at chromosome band 17q11.2. In this study, we aimed to characterize novel recurrent regional chromosomal imbalances and tumor-related candidate genes in NF1-associated cutaneous neurofibromas. Nine cutaneous neurofibromas from NF1 patients were screened for recurrent chromosomal imbalances using high-resolution 400K oligonucleotide array comparative genomic hybridization (aCGH). All the cases exhibited at least one sub-microscopic abnormality. Regions of recurrent chromosomal imbalances in a least one third of cases were loss of 1q13.2 (33%, FAM19A3), 1q21.1 (44%, RABGAP1L), 2q37.1 (56%, INPP5D), 3p25.1 (67%, CHCHD4), 4p15.32 (56%, FGFBP1), 5q11.2 (56%, ARL15), 6q22.31 (56%, NKAIN2), 6q22.33 (67%, ARHGAP18), 6q25.1 (67%, UST), 7q13 (56%, ADCY1), 12q13.13 (44%, KRT71), 19q13.32 (56%, GRLF1), and 20p11.21 (56%, NLP) and gain of 2p23.3 (76%, C2orf53), 8q22.3 (44%, ODF1) and 8q24.3 (67%, ARC). Several chromosomal imbalances, including loss of 7q11.23, 13q14.1, 14q32.13, 17p12, and 17q11.2 were detected at a lower frequency. We also confirmed that these chromosomal imbalances were not detected in the patient-matched lymphocyte DNAs. Amongst the 6 tumor-related candidate genes (RABGAP1L, ADCY1, SLIT2, GRLF1, UST, and ARC) identified in the regions of recurrent chromosomal imbalances, the gene expression changes of UST (down-regulation) and ARC (up-regulation) were found to be significantly associated with copy number alterations. The novel recurrent chromosomal imbalances and the altered expression levels of the tumor-related candidate genes may be associated with the development of NF1-associated benign cutaneous neurofibromas.
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan; Department of Plastic & Reconstructive Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Asai
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. Electronic address: aota@aichi-med-u.ac.jp.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan; Department of Internal Medicine Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Lhagvasuren
authors.initials: L
authors.lastname: Damdindorj
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Ekhtear
authors.initials: E
authors.lastname: Hossain
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Department of Plastic & Reconstructive Surgery, Daiyukai Daiichi Hospital, Ichinomiya, Aichi, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nagata
authors.affiliation: Department of Plastic & Reconstructive Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yokoo
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009455:Neurofibroma / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics*
keywords: Cutaneous neurofibroma; Gene expression; Neurofibromatosis type 1; Oligo-array CGH; Tumor-related gene