Genomic aberrations frequently alter chromatin regulatory genes in chordoma

Abstract

Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ~8 Mb segment at 3p21.1–p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (~23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (~40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes.

Benign notochordal cell tumour: clinicopathology and molecular profiling of 13 cases

“…The most common chromosomal changes in chordoma are the gain of 1q, 5, 6 and 7 and the loss of 1p, 3, 4, 9, 10, 13, 14 and 18 8 40–45. Furthermore, the chromosomal copy number loss was significantly more than the gain,38 40 and thus most studies suggest that the development of chordoma may lie in molecular mechanisms mediating copy number loss 38. Interestingly, the aberration analysed using the OncoScan array detection of BNCT/EPs showed that copy number gain in large fragments was very common, which is different from chordoma.…”

First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies

“…At first sight, chordoma is not a promising candidate for immunotherapy, considering the abundance of extracellular matrix and the low mutational burden, 12 a commonly accepted criterion suggesting limited tumor immunogenicity. 9 However, as extensively described in the context of melanoma, 13 the rapid onset of vitiligo after chemotherapy for patient 1 was suggestive of a cross-reactive immune reaction to both melanocytes and tumor cells.…”

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

“…This research has resulted in the opening of a recent phase II clinical trial using Afatinib, a third generation EGFR inhibitor. Finally, cancer driver events have also been identified in chromatin remodeling genes including SETD2 , ARID1A , and PBRM1 raising the possibility that chordoma may be susceptible to epigenetic inhibitors …”

“…Finally, cancer driver events have also been identified in chromatin remodeling genes including SETD2, ARID1A, and PBRM1 raising the possibility that chordoma may be susceptible to epigenetic inhibitors. 49,59,60 Poorly differentiated chordoma was first described by Mobley et al as tumors with cohesive epithelioid morphology, marked pleomorphism, and mitotic activity. They express TBXT and cytokeratins but unlike conventional chordoma additionally reveal loss of SMARCB1 expression on immunohistochemistry.…”