Recurrent loss of chromosome 22 and SMARCB1 deletion in extra‐axial chordoma: A clinicopathological and molecular analysis

Abstract

Extra-axial chordoma is a rare neoplasm of extra-axial skeleton and soft tissue that shares identical histomorphologic and immunophenotypic features with midline chordoma. While genetic changes in conventional chordoma have been well-studied, the genomic alterations of extra-axial chordoma have not been reported. It is well known that conventional chordoma is a tumor with predominantly non-random copy number alterations and low mutational burden. Herein we describe the clinicopathologic and genomic characteristics of six cases of extra-axial chordoma, with genomewide high-resolution single nucleotide polymorphism array, fluorescence in situ hybridization and targeted next-generation sequencing (NGS) analysis. The patients presented at a mean age of 33 years (range: 21-54) with a female to male ratio of 5:1. Four cases were histologically conventional type, presented with bone lesions and three of them had local recurrence. Two cases were poorly differentiated chordomas, presented with intra-articular soft tissue masses and both developed distant metastases. All cases showed brachyury positivity and the two poorly differentiated chordomas showed in addition loss of INI-1 expression by immunohistochemical analysis. Three of four extra-axial conventional chordomas showed simple genome with loss of chromosome 22 or a heterozygous deletion of SMARCB1. Both poorly differentiated chordomas demonstrated a complex hyperdiploid genomic profile with gain of multiple chromosomes and homozygous deletion of SMARCB1. Our findings show that heterozygous deletion of SMARCB1 or the loss of chromosome 22 is a consistent abnormality in extra-axial chordoma and transformation to poorly differentiated chordoma is characterized by homozygous loss of SMARCB1 associated with genomic complexity and instability such as hyperdiploidy. K E Y W O R D Sextra-axial chordoma, extra-axial poorly differentiated chordoma, INI1, SMARCB1

Molecular and immunohistochemical testing of bone tumours: review and update

“…147 Of note, heterozygous deletion of SMARCB1 has been described in some conventional chordomas, including extra-axial tumours. 148,149 Loss of INI1 expression, while necessary for the diagnosis of poorlydifferentiated chordoma, is not entirely specific and has been reported in rare conventional and dedifferentiated chordomas. 144 The diagnosis of poorlydifferentiated chordoma thus requires both the appropriate histologic and immunophenotypic features.…”

“…EWSR1 can be codeleted due to its proximity to SMARCB1 , leading to complex FISH patterns that may be mistaken for EWSR1 rearrangement 147 . Of note, heterozygous deletion of SMARCB1 has been described in some conventional chordomas, including extra‐axial tumours 148,149 . Loss of INI1 expression, while necessary for the diagnosis of poorly‐differentiated chordoma, is not entirely specific and has been reported in rare conventional and dedifferentiated chordomas 144 .…”

A chronicle review of new techniques that facilitate the understanding and development of optimal individualized therapeutic strategies for chordoma

“…Poorly differentiated chordomas are characterized by the loss of INI1 / SMARCB1 and may also represent a discrete entity with a more aggressive phenotype, which is more similar to rhabdoid tumors. However, driver gene alterations are critical in tumor initiation and progression, but may not be involved in tumor dedifferentiation and high-grade transformation ( 82 ).…”

SMARCB1/INI1 loss in skull base conventional chordomas: a clinicopathological and molecular analysis

“…Recent studies have described the immunohistochemical loss of SMARCB1/INI1 protein in poorly differentiated chordoma associated with SMARCB1 gene deletions at fluorescence in situ hybridization (FISH) examination, mainly deriving from large, homozygous deletions at 22q11 locus (4,(6)(7)(8). The loss of SMARCB1/INI1 protein could potentially serve as theoretical basis for evaluating the efficacy of new targeted therapies, i.e., Enhancer of Zeste homologue 2 (EZH2) inhibitors (Tazemetostat), histone deacetylase inhibitors, and CDK4 inhibitors (4,7,(9)(10)(11).…”

“…Genetic studies have demonstrated that conventional chordomas are characterized by very low to modest mutation burden, and are mainly characterized by large copy number loss, typically involving chromosomes 1p, 3, 9q, 10, 13, and 14, and a small number of copy number gains on chromosome 7 and 1q (4,9). Loss of chromosome 22 and/or heterozygous deletion of SMARCB1 seems to be a rare event in conventional chordomas, although data are referred to small series (4,(17)(18)(19).…”