Abstract
The molecular mechanisms underlying chordoma pathogenesis are unknown. We therefore sought to identify novel mutations to better understand chordoma biology and to potentially identify therapeutic targets. Given the relatively high costs of whole genome sequencing, we performed a focused genetic analysis using matrix-assisted laser desorption/ionization-time of flight mass spectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 oncogenes and selected tumor suppressor genes (OncoMap v. 3.0) of 45 human chordoma tumor samples. Of the analyzed samples, seven were identified with at least one mutation. Six of these were from fresh frozen samples, and one was from a paraffin embedded sample. These observations were validated using an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS (Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This study reports on the largest comprehensive mutational analysis of chordomas performed to date. To focus on mutations that have the greatest chance of clinical relevance, we tested only oncogenes and tumor suppressor genes that have been previously implicated in the tumorigenesis of more common malignancies. We identified rare genetic changes that may have functional significance to the underlying biology and potential therapeutics for chordomas. Mutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When this data is paired with the studies showing 18 of 21 chordoma samples displaying copy loss at the locus for CDKN2A, 17 of 21 chordoma samples displaying copy loss at PTEN, and 3 of 4 chordoma samples displaying deletion at the SMARCB1 locus, we can infer that a loss of heterozygosity at these three loci may play a significant role in chordoma pathogenesis.
Highlights
Chordoma is an aggressive primary malignancy of the axial skeleton that is thought to originate from notochordal tissue[1]
Patient date of surgery (DOS), age, sex, tumor location, recurrence, and metastasis are catalogued in Table 1. 28 specimens were obtained from fresh frozen tissue, and 17 were derived from FFPE blocks
We aimed to broaden our mutational screen while focusing only on those genetic alterations that have been previously implicated as tumorigenisis drivers in other tumor types with the overall goal of identifying new mutations that could direct further research into chordoma therapeutic discovery
Summary
Chordoma is an aggressive primary malignancy of the axial skeleton that is thought to originate from notochordal tissue[1]. The majority of these tumors occur in either the base of the skull (35%) or in the sacrum (50%), and these are typically managed with surgery and/or radiation[2,3,4,5,6,7,8,9,10]. That for a typically chemoresistant tumor such as chordoma where there is no effective systemic therapy, the identification of mutations in genes for which there exist a therapeutic strategy can inform the development of novel drugs. Because of the rarity of PLOS ONE | www.plosone.org
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