Introduction: Meningiomas are the most common primary tumor of the central nervous system. Although most are cured by surgery, 20% recur and tend to be minimally responsive to systemic therapy. A major impediment to the treatment is that the somatic genetic events driving meningioma oncogenesis are poorly understood. Although recurrent losses of chromosomes 22q (containing NF2), 6q, and 14q have been detected, no genes other than NF2 have been convincingly linked to meningioma oncogenesis.
Methods: DNA from seventeen grade I meningiomas and paired blood normals was subjected to next-generation sequencing (11 by 60x whole genome and 6 by exome-capture sequencing). Sequences were analyzed by algorithms for detection of somatic mutations, indels, translocation/rearrangements, and copy number alterations. A mutational significance algorithm (MutSig) was then used to determine significant, recurrent events.
Results: As expected, the NF2 gene was identified as the top hit, with over half of tumors harboring nonsense mutations, frame-shift indels, or splice site mutations leading to NF2 disruption. One sample had a translocation affecting the NF2 gene and a nearby region of chr22. All samples with NF2 mutations also showed copy number loss on chr22. In addition, several known cancer driver mutations (some clinically actionable) were seen co-occurring with NF2 mutation. Interestingly, we identified a subset of meningiomas that do not harbor NF2 loss, and seek to explain the development of these tumors by their spectrum of somatic DNA alterations. These may represent novel oncogenes and tumor suppressors driving meningioma tumorigenesis.
Conclusions: While a majority of the grade I meningiomas we studied showed the classic "two-hit" pattern of somatic mutation and loss of heterozygosity in NF2, we identified a subset of tumors that are NF2-wild-type and discuss the genetic events in these samples that may be affecting novel oncogenes or tumor suppressors.
Patient Care: The comprehensive identification of all somatic genetic events in meningiomas has the potential to transform our understanding of this disease.
Learning Objectives: To comprehensively understand the genetic events leading to development of grade I meningiomas.