P07.04.A THE LOSS OF THE X CHROMOSOME IN THE CONTEXT OF THE MALIGNANCY OF MENINGIOMAS
N Berghaus, D Savran, T Hielscher, D Schrimpf, C Herold-Mende, W Wick, A von Deimling, F SahmAbstract
BACKGROUND
In recent years, molecular markers have become increasingly important in the diagnosis and risk assessment of brain tumours. Besides mutations and methylation, this also includes copy number variations (CNVs). It is well known that CNVs contribute to cancer initiation, progression and therapeutic resistance. Investigating the most common primary intracranial tumours in adults, meningiomas, several studies propose new stratification systems with a more accurate risk prediction than the WHO grading. Several of these approaches combine morphology, methylation, or both, with CNV status to derive a more precise risk assessment. However, a common shortcoming is the absence of separate analyses based on the sex of the patients or the inclusion of the X chromosome.
MATERIAL AND METHODS
A cohort of over 6000 meningiomas was stratified and analysed regarding the loss of the X chromosome. Further, a differential methylation analysis was conducted based on EPIC v1 data.
RESULTS
In general, meningiomas from females displayed a loss of chromosome X more than three times more often than tumours from males (p = <0.001) and were significantly associated with a more malignant classification, affecting both the WHO classes and the methylation classification. Calculating oncogenetic trees, females and males share the loss of chr22q as first node followed by a loss of chr1p but only in females, the loss of chromosome X directly follows the high-risk CNV event “loss of chr14q”. However, not only CNVs, but also DNA methylation is a decisive factor. Therefore, a differential methylation analysis was conducted between meningiomas from females with and without a loss of the X chromosome, stratified for methylation classes. Within the methylation class (MC) ben-1, almost no difference between the two cohorts could be detected for the autosomes. In contrast, within the MC mal, the highest and significant difference was noted for a region overlapping with the RUNX3 gene (p = <0.001) - indicating a higher methylation in the “noloss” subgroup. This is of special interest as RUNX3, a transcription factor, regulates gene expression, impacts the cell cycle, cell differentiation, apoptosis, tumor suppression, and cancer cell metastasis. Analyzing the MC mal regarding the X chromosome, for example, a significant difference was detected for a region overlapping COX7 (p = <0.001). The mitochondrial protein COX7b has previously been linked to driving metastasis of human breast cancer cells in mice.
CONCLUSION
The findings indicate that the loss of the X chromosome in females is linked to tumor malignancy and can also be correlated with different methylation patterns.