DNA Methylation Subgroup and CNV Predict Response to Radiotherapy

Background: Chordomas are rare aggressive primary bone cancers affecting the skull-base and spine. Standard of care treatment includes radical surgical resection and radiotherapy. Despite this, the overall survival at 10 years is only 40%, with most patients experiencing disease recurrence. Radiotherapy is a cornerstone in the treatment of chordomas, however the impact of radiotherapy remains incompletely described: not all patients appear to benefit, and many studies fail to replicate the finding of improvement in overall survival. Herein, we utilized our previously described DNA Methylation subgroups to examine sensitivity to radiation.

Methods: We utilized a well annotated dataset of 68 patients from a multi-institutional 20-year series who had undergone whole genome DNA methylation profiling on the Illumina EPIC array. Copy number variance (CNVs) were extracted from the raw methylation data after normalization, with median intensity values calculated and converted to amplification and deletions defined as a log2 copy number ratio of over .3. Multivariable cox analysis and Kaplan Meyer analysis were then completed.

Results: Within our cohort we found that patients with a cellular molecular subtype who had received radiation had a significantly improved overall survival on cox multivariate analysis (median survival 17.3 years, p = 0.0208) when compared to patients with a immune-infiltrative (median survival 6.0 years). The favorable nature of the cellular molecular subtype appeared to diminish if radiation was not given (median survival 1 year). This improvement in survival did not appear to be fully explained by simply delayed progression, as progression-free survival between irradiated immune-infiltrative and cellular subtypes did not differ significantly (p = 0.65). A panel of 30 target genes were investigated through CNV analysis for association with this phenomenon, for which 3 were identified: FGFR-1 heterozygous deletion (p = 1.74e-6), GLI2 heterozygous deletion (p = 0.0103) and KRAS homozygous amplification (p = 0.0134).

Conclusion: Overall, molecular subtype predicted through DNA methylation influenced the response to radiotherapy: patients with a cellular subtype have improved survival overall, which appears to be partially mediated through response to and enhanced response to radiotherapy which does not appear to be shared with their immune-infiltrative counterparts. Moreover, three target genes have been identified as potential targets that may be exploited to improve potentiate radiosensitivity in chordoma.

Publikationsverlauf

Artikel online veröffentlicht:
05. Februar 2024