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Identification of COL1A1/2 Mutations and Fusions With Noncoding RNA Genes in Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion)

Kao, Yu Chien ; Yoshida, Akihiko ; Hsieh, Tsung Han ; Nord, Karolin H. LU ; Saba, Karim H. LU orcid ; Ichikawa, Hitoshi ; Tsai, Jen Wei ; Huang, Hsuan Ying ; Chih-Hsueh Chen, Paul and Fletcher, Christopher D.M. , et al. (2023) In Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 36(2).
Abstract

Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5... (More)

Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
bizarre parosteal osteochondromatous proliferation, gene fusions, Nora lesion
in
Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
volume
36
issue
2
article number
100011
publisher
Nature Publishing Group
external identifiers
  • scopus:85149154480
  • pmid:36853784
ISSN
1530-0285
DOI
10.1016/j.modpat.2022.100011
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.
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29914e45-2f96-4041-9225-bf29f1fe0aad
date added to LUP
2023-03-20 11:08:45
date last changed
2024-06-14 00:36:15
@article{29914e45-2f96-4041-9225-bf29f1fe0aad,
  abstract     = {{<p>Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.</p>}},
  author       = {{Kao, Yu Chien and Yoshida, Akihiko and Hsieh, Tsung Han and Nord, Karolin H. and Saba, Karim H. and Ichikawa, Hitoshi and Tsai, Jen Wei and Huang, Hsuan Ying and Chih-Hsueh Chen, Paul and Fletcher, Christopher D.M. and Lee, Jen Chieh}},
  issn         = {{1530-0285}},
  keywords     = {{bizarre parosteal osteochondromatous proliferation; gene fusions; Nora lesion}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}},
  title        = {{Identification of COL1A1/2 Mutations and Fusions With Noncoding RNA Genes in Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion)}},
  url          = {{http://dx.doi.org/10.1016/j.modpat.2022.100011}},
  doi          = {{10.1016/j.modpat.2022.100011}},
  volume       = {{36}},
  year         = {{2023}},
}