<p>Whole exome sequencing of multiple meningiomas with varying histopathological presentation in one patient revealed distinctive somatic mutation burden and independent clonal origins</p>

Abstract

Background: Although meningiomas are common intracranial tumors, multiple meningiomas (MMs) are rare entities in patients without neurofibromatosis type 2. Previous studies suggest most sporadic MMs are of monoclone in origin. Objective: To elucidate the clonal relationship between two sporadic meningiomas from the same patient by using the next-generation sequencing (NGS) platform. Methods: Two MMs, located frontally and parietally on the right side, were surgically removed from a 52-year-old male. Pathological examinations and whole exome sequencing were performed on tumor samples, followed by Sanger sequencing validation. Results: MMs were diagnosed as secretory and fibrous subtypes, respectively, on histology (WHO grade I) and tumor DNA exhibited distinctive somatic mutation patterns. Specifically, the secretory subtype carried more single nucleotide variant while the fibrous subtype had much higher copy number variation. Besides, the two tumors demonstrated different mutation profiles in predisposing genes and known driver mutations. For example, the secretory subtype had missense mutations in TRAF7 and KLF4 , while the fibrous subtype had frameshift deletion of NF2 gene in addition to copy number loss of NF2 and SMARCB1 , genetic events that have already been associated with the development of meningiomas. Significantly mutated gene analysis revealed novel mutations of LOC729159 in the secretory subtype and RPGRIP1L and DPP6 in the fibrous subtype. Sanger sequencing validated important point mutations in TRAF7 (c.1678G>A, p .G560S), KLF4 (c.1225A>C, p .K409Q) and CDH11 (c.169T>G, p .W57G). Conclusion: Our data suggest the two meningiomas might develop independently in this patient and molecular subtyping by NGS is a valuable supplement to conventional pathology. Further study is needed to ascertain whether these novel genetic events are tumorigenic or simply passenger mutations, as well as their clinical implications

Genomic profiling of sporadic multiple meningiomas

“…The genomics of familial MMs is also well understood with known inherited driver germline mutations in NF2, SUFU , or SWI/SNF complex ( SMARCE1, SMARCB1 ) genes [ 8 – 10 ]. While the molecular basis for the formation and development of sporadic MMs has been suggested to be through either mono- or multi-clonal (i.e., independent from one another) formation [ 11 , 12 ], the genomic studies to test these hypotheses have been limited [ 13 – 17 ].…”

Whole Exome Sequencing of Multiple Atypical Meningiomas in a Patient without History of Neurofibromatosis Type II: A Case Report

“…Although meningioma is the most common primary tumor of the central nervous system, the mechanism of progression from benign to atypical or anaplastic grade remains elusive [5]. It has been suggested that the atypical tumor may have progressed from the benign tumor.…”

“…It can occur sporadically or as part of a familial syndrome of either neurofibromatosis type II or familial multiple meningiomas [4]. The incidence of sporadic multiple meningiomas without history of neurofibromatosis type II was low [5]. Multiple meningiomas usually show a uniform histology, but the synchronous meningiomas of different grades have been reported and may be formed independently due to separate genetic mutation and aberrant pathway expressions [6].…”

Case Report: Whole-Exome Sequencing of Hypothalamic Hamartoma From an Infant With Pallister-Hall Syndrome Revealed Novel de novo Mutation in the GLI3

“…DNA was isolated from tumor tissues, the patient's peripheral lymphocytes, and his parents' peripheral lymphocytes as described before ( 11 ). The quality of isolated DNA was assessed by using 1% agarose gel electrophoresis and Qubit ® DNA Assay Kit in Qubit ® 2.0 Fluorometer (Life Technologies, CA, USA).…”

“…The WES protocol was similar to the one we used previously ( 11 ). Briefly, DNA libraries were prepared using the Agilent SureSelect Human All Exon kit (Agilent Technologies, Santa Clara, CA, USA) following the manufacturer's recommendations, and index codes were applied to each sample.…”