BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology


Winner of the Brian D Silber Award, Ganesh Mani Shankar, presented his research, BRAF Alteration Status and the Histone H3F3A Gene K27M Mutation Segregate Spinal Cord Astrocytoma Histology, during the 2016 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting.

Intramedullary spinal cord neoplasms represent two percent to 4% of central nervous system tumours, of which astrocytic gliomas represent 80%. Histologic grading can be challenging in spinal cord astrocytomas because of the relatively small samples often obtained during surgery. To address the hypothesis that genomic alterations could segregate spinal cord astrocytoma histologic grades, the authors sequenced cancer-related genes in a cohort of 17 tumours.

Spinal cord astrocytomas from children and adults were obtained as formalin-fixed, paraffin-embedded (FFPE) specimens from Massachusetts General Hospital, the University of Toronto and New York University. Targeted sequencing of 560 cancer-related genes and 39 translocation events was performed on DNA extracted from these specimens. Data was analysed for somatic nucleotide variants, copy number changes and rearrangement analysis.

The most recurrent findings in grade I spinal cord astrocytomas were a BRAF-KIAA1549 translocation and BRAF copy number gain. World Health Organisation grade II astrocytomas were similarly characterised by alterations involved in the MAPKERK or PI3K pathways, including BRAF amplification. In addition, the authors observed that all four Grade III and IV astrocytomas in the discovery cohort shared the H3F3A K27M mutation. Further, targeted Sanger sequencing of H3F3A was performed in five additional specimens and revealed the K27M mutation in 2/3 spinal grade IV astrocytomas and 0/2 Grade I astrocytomas.

The findings described here represent the first genomic characterisation of spinal cord astrocytomas. In summary, study observations indicate that BRAF alterations and histone H3F3A K27M mutations are grade-related features of spinal cord astrocytomas that should enter routine initial evaluation of spinal cord gliomas and provide a potential foundation for adjuvant therapeutic strategies.