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Recurrent Chromosome 22 Deletions in Osteoblastoma Affect Inhibitors of the Wnt/Beta-Catenin Signaling Pathway

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Recurrent Chromosome 22 Deletions in Osteoblastoma Affect Inhibitors of the Wnt/Beta-Catenin Signaling Pathway Recurrent Chromosome 22 Deletions in Osteoblastoma Affect Inhibitors of the Wnt/Beta-Catenin Signaling Pathway Karolin H. Nord1*, Jenny Nilsson1, Elsa Arbajian1, Fredrik Vult von Steyern2, Otte Brosjö3, Anne-Marie Cleton-Jansen4, Karoly Szuhai5, Pancras C. W. Hogendoorn4 1 Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden, 2 Department of Orthopedics, Skåne University Hospital, Lund, Sweden, 3 Department of Orthopedics, Karolinska Hospital, Stockholm, Sweden, 4 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands, 5 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands Abstract Osteoblastoma is a bone forming tumor with histological features highly similar to osteoid osteoma; the discrimination between the tumor types is based on size and growth pattern. The vast majority of osteoblastomas are benign but there is a group of so-called aggressive osteoblastomas that can be diagnostically challenging at the histopathological level. The genetic aberrations required for osteoblastoma development are not known and no genetic difference between conventional and aggressive osteoblastoma has been reported. In order to identify recurrent genomic aberrations of importance for tumor development we applied cytogenetic and/or SNP array analyses on nine conventional and two aggressive osteoblastomas. The conventional osteoblastomas showed few or no acquired genetic aberrations while the aggressive tumors displayed heavily rearranged genomes. In one of the aggressive osteoblastomas, three neighboring regions in chromosome band 22q12 were homozygously deleted. Hemizygous deletions of these regions were found in two additional cases, one aggressive and one conventional. In total, 10 genes were recurrently and homozygously lost in osteoblastoma. Four of them are functionally involved in regulating osteogenesis and/or tumorigenesis. MN1 and NF2 have previously been implicated in the development of leukemia and solid tumors, and ZNRF3 and KREMEN1 are inhibitors of the Wnt/beta-catenin signaling pathway. In line with deletions of the latter two genes, high beta-catenin protein expression has previously been reported in osteoblastoma and aberrations affecting the Wnt/beta-catenin pathway have been found in other bone lesions, including osteoma and osteosarcoma. Citation: Nord KH, Nilsson J, Arbajian E, Vult von Steyern F, Brosjö O, et al. (2013) Recurrent Chromosome 22 Deletions in Osteoblastoma Affect Inhibitors of the Wnt/Beta-Catenin Signaling Pathway. PLoS ONE 8(11): e80725. doi:10.1371/journal.pone.0080725 Editor: Masaru Katoh, National Cancer Center, Japan Received August 1, 2013; Accepted October 16, 2013; Published November 13, 2013 Copyright: © 2013 Nord et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Magnus Bergvall Foundation, the Royal Physiographic Society (Lund, Sweden) and the Swedish Cancer Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. * E-mail: [email protected] Introduction osteomas). Osteoblastoma typically shows a non-infiltrative growth pattern and when resected with free margins Osteoblastoma is a bone forming tumor that is usually recurrences are uncommon. The treatment is therefore based located in the medullary cavity of the bone [1]. The disease can on surgery alone and the prognosis is excellent [1]. However, affect patients at any age but has a predilection for males in there is a group of intra-osseous osteoblastic tumors that can their teens and young adulthood. At the cellular level, the tumor be diagnostically challenging at the histopathological level [3]. is identical to osteoid osteoma; both tumor types show rich These tumors have been referred to as aggressive, epithelioid vascularization, irregular osteoid with osteoblasts and often or malignant osteoblastoma. Currently, they are considered osteoclast-type multinucleated giant cells. Differentiation within the morphological spectrum of osteoblastoma [1], and between the two tumor types is based on size [2]. Osteoid have the same clinical behavior. A very rare subtype of osteoma has a limited growth potential and seldom exceeds 1 osteosarcoma exists, so-called osteoblastoma-like cm in largest diameter. In contrast, lesions larger than 2 cm are osteosarcoma, which shares some morphological features with not considered to have a restricted growth potential and are osteoblastoma, but clinically behaves like conventional high- referred to as osteoblastomas (also known as giant osteoid grade osteosarcoma [4]. Osteosarcomas, including these rare PLOS ONE | www.plosone.org 1 November 2013 | Volume 8 | Issue 11 | e80725 Recurrent Chromosome 22 Deletions in Osteoblastoma Table 1. Clinical and cytogenetic features of eleven osteoblastomas. SNP array a b c Case Age/Sex Location Follow-up Karyotype analysis 43,X,-Y,der(1)t(1;?22)(p3?;q?),add(2)(q3?),-6,del(8)(p12),der(9)t(9;17) d 1 35/M Skull R 21, 53, NED 60 (p12;q11),-12,der(14)t(?1;14) Aberrant (?;q3?),-17,der(19)t(19;22)t(1;22)t(12;22)t(12;17),der(22)t(1;22)(?;q1?)[23]/46,XY[7] 44,X,-Y,add(1)(p34),del(1)(q21),del(2)(p21p23),+3,del(3)(p21)x2,del(6) e (q15),der(6)t(6;13)(q27;q12),+10,der(10)t(8;10)(q11;q26)x2,del(12) 2 13848:85 23/M Proximal humerus NED 168 Aberrant (p11),-13,+der(15)t(1;15)(q21;p13)ins(1;?)(q32;?),+16,-17,add(17)(q11),-18,-22,-22[16]/ 43,idem,-15[3] 3 14/M Vertebra NED 48 44-45,XY,-22[cp 43]/46,XY[25] No 4 17/F Proximal femur NED 25 48,XX,+2mar[9]/46,XX[17] No 5 20/M Proximal humerus R 18, NED 21 46,XY,add(18)(q2?3)[7]/46,XY[17] No 6 16/M Proximal femur NED 43 46,XY[25] Normal 7 10/F Sacrum R 9, NED 18 46,XX[25] Normal 8 37/M Os ilium NED 253 46,XY[25] Normal 9 44/M Vertebra NED 156 No Normal 10 42/M Vertebra NED 36 46,XY[18] Normal 11 30/M Aceta-bulum NED156 No Normal a. Previously published karyotypes are indicated by their reference and case numbers in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman). b. Follow-up time given in months. R = recurrence; NED = no evidence of disease. c. Karyotypes in cases 1 and 10 are based on data from COBRA FISH analysis. d. Epithelioid osteoblastoma. e. Aggressive osteoblastoma. doi: 10.1371/journal.pone.0080725.t001 variants, generally present highly complex karyotypes with Leiden, The Netherlands, the Skåne University Hospital, Lund, multiple aberrations [5]. Low-grade central osteosarcomas do Sweden and the Karolinska Hospital, Stockholm, Sweden. The not pose a histological differential diagnosis and are age of the patients ranged from 10-44 years and the majority (9 characterized at the genetic level by frequent gains of MDM2. of 11) of patients were male. Two of the tumors were classified In osteoblastoma the genetic findings are heterogeneous as epithelioid or aggressive and the remaining cases were ranging from single balanced structural rearrangements to conventional osteoblastomas. Three of the tumors recurred multiple and complex changes. No recurrent, tumor-associated and in the remaining patients there was no evidence of disease aberration has been described. 25-253 months after diagnosis. Detailed patient information can In the present study, we have applied cytogenetic and single be found in Table 1. nucleotide polymorphism (SNP) array analyses on osteoblastomas in order to identify recurrent genomic Cytogenetic analyses aberrations of importance for tumor development. We have Chromosome banding and COBRA fluorescence in situ also re-analyzed previously published global gene expression hybridization analyses were performed at the Departments of data on osteoblastoma [6], in order to evaluate the possible Clinical Genetics, Lund and Molecular Cell Biology, Leiden, impact of genomic alterations. and karyotypes were described according to the recommendations in ISCN 2009 [7]. Chromosome preparations Materials and Methods were prepared as described [8]. Ethics statement Genomic copy number and loss of heterozygosity All samples were obtained after informed written consent analyses from patients or from patient’s parents. The study was SNP array analysis was used for combined DNA copy approved by the Regional Ethics Committee of Lund University. number and loss of heterozygosity investigation. In eight of the cases (cases 1, 2 and 6-11), fresh frozen tumor biopsies were Patient information and tumor material available. DNA was extracted according to standard Tumor material was available from 11 osteoblastoma procedures [9], and hybridized onto Illumina Human Omni- patients, treated at the Leiden University Medical Center, Quad BeadChips, containing more than 1 million reporters, PLOS ONE | www.plosone.org 2 November 2013 | Volume 8 | Issue 11 | e80725 Recurrent Chromosome 22 Deletions in Osteoblastoma following protocols supplied by the manufacturer (Illumina, San hemizygous deletion affecting major parts of chromosome 22 Diego, CA). Data analysis was performed using the was found by SNP arrays (Figure 1, Table 2). This deletion was GenomeStudio software (Illumina), detecting imbalances by overlapping with hemi- and homozygous
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