Disruption of Type I Collagen Through Genetic Rearrangements or Mutations Is Implicated in the Tumorigenesis of Bizarre Parosteal Osteochondromatous Proliferation (Nora’s Lesion)

Abstract Bizarre parosteal osteochondromatous proliferation (BPOP, or Nora’s lesion) is a benign bone surface lesion which most commonly occurs in the digits of young patients and has a high recurrence rate. 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 7 BPOP cases affecting the fingers, toe, ulna, and radius of 4 female and 3 male patients, aged 5 to 68 years. RNA sequencing on 5 cases identified genetic fusions between COL1A2 and LINC-PINT, a long non-coding RNA, in 3 cases, and COL1A1::MIR29B2CHG fusion in 1, both validated with fluorescence in situ hybridization (FISH) and reverse transcription-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole exome sequencing and confirmed with 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 2 BPOPs by FISH identified one additional case with COL1A1 rearrangement. Our findings are consistent with reported chromosomal abnormalities, and implicate the disruption of type I collagen through COL1A1/2 rearrangements or COL1A1 mutations in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.