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

Han-Song Sheng; Fang Shen; Nu Zhang; Li-Sheng Yu; Xiang-Qi Lu; Zhe Zhang; Huang-Yi Fang; Ling-Li Zhou; Jian Lin

doi:10.2147/CMAR.S202394

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

Cancer Manag Res. 2019 May 6:11:4085-4095. doi: 10.2147/CMAR.S202394. eCollection 2019.

Authors

Han-Song Sheng¹, Fang Shen², Nu Zhang¹, Li-Sheng Yu¹, Xiang-Qi Lu¹, Zhe Zhang^{1

3}, Huang-Yi Fang^{1

3}, Ling-Li Zhou⁴, Jian Lin¹

Affiliations

¹ Department of Neurosurgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
² Department of Orthopedic Surgery's Spine Division, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, People's Republic of China.
³ School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
⁴ Department of Pathology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.

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.

Keywords: NF2; TRAF7; fibrous meningioma; multiple meningiomas; secretory meningioma; whole exome sequencing.