Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas

Author:

Pemov, Alexander

Dewan, Ramita

Hansen, Nancy F

Chandrasekharappa, Settara C

Ray-Chaudhury, Abhik

Jones,Kristine

Luo,Wen

Heiss, John D

Mullikin, James C

Chittiboina, Prashant

Stewart, Douglas R

Asthagiri, Ashok R
Author Address

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Neuromuscular Disease Research Section, National Institute On Aging, NIH, Bethesda, MD, USA., Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Frederick National Laboratory for Cancer Research, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Rockville, MD, USA., Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA. drstewart@mail.nih.gov., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. ara5x@hscmail.mcc.virginia.edu., Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA. ara5x@hscmail.mcc.virginia.edu.,

Abstract:

Neurofibromatosis type 2 (NF2) is an autosomal dominant Mendelian tumor predisposition disorder caused by germline pathogenic variants in the tumor suppressor NF2. Meningiomas are the second most common neoplasm in NF2, often occurring in multiple intracranial and spinal locations within the same patient. In this prospective longitudinal study, we assessed volumes and growth rates of ten spinal and ten cranial benign meningiomas in seven NF2 patients that concluded with surgical resection and performed whole-exome sequencing and copy-number variant (CNV) analysis of the tumors. Our comparison of the volume and the growth rate of NF2-associated spinal and cranial meningiomas point to the differences in timing of tumor initiation and/or to the differences in tumor progression (e.g., non-linear, saltatory growth) at these two anatomical locations. Genomic investigation of these tumors revealed that somatic inactivation of NF2 is the principal and perhaps the only driver of tumor initiation; and that tumor progression likely occurs via accumulation of CNVs, rather than point mutations. Results of this study contribute to a better understanding of NF2-associated meningiomas clinical behavior and their genetic underpinnings.

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