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Case Reports
. 2024 Oct;41(3-4):132-138.
doi: 10.1007/s10014-024-00486-9. Epub 2024 Jul 27.

Comprehensive genomic analysis reveals clonal origin and subtype-specific evolution in a case of sporadic multiple meningiomas

Maki Sakaguchi  1 , Masafumi Horie  2 , Yukinobu Ito  1 , Shingo Tanaka  3 , Keishi Mizuguchi  4 , Hiroko Ikeda  4 , Etsuko Kiyokawa  5 , Mitsutoshi Nakada  3 , Daichi Maeda  1
Affiliations
Case Reports

Comprehensive genomic analysis reveals clonal origin and subtype-specific evolution in a case of sporadic multiple meningiomas

Maki Sakaguchi et al. Brain Tumor Pathol. 2024 Oct.

Abstract

Meningioma is the most common primary intracranial tumor in adults, with up to 10% manifesting as multiple tumors. Data on the genomic and molecular changes in sporadic multiple meningiomas are scarce, leading to ongoing debates regarding their evolutionary processes. A comprehensive genetic analysis of a large number of lesions, including precursor lesions, is necessary to explore these two possible origins: clonal and independent. In the present study, we performed whole-exome sequencing and analyzed somatic single-nucleotide variants (SNVs), insertions/deletions (INDELs), and copy number alterations (CNAs) in a patient with sporadic multiple meningiomas. These meningiomas included two mass-forming lesions of different histological subtypes (transitional and chordoid) and two small meningothelial nests. Genetic analysis revealed CNAs on chromosomes 22q and Y as common abnormalities in the two largest tumors. Furthermore, we identified SNV/INDELs unique to each focus, with NF2 mutation prevalent in the transitional meningioma and CREBBP mutation in the chordoid meningioma. Loss of chromosome 22 was detected in two small meningothelial nests. Overall, we elucidated the clonal origin and subtype-specific evolution of multiple meningiomas in this case. CNAs may serve as the initial driving event in meningioma development.

Keywords: Copy number alteration; Multiple meningiomas; Occult meningioma; Whole-exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
a Gadolinium enhanced T1-weighted magnetic resonance image and b–i histological images of the patient in the present case. a–c Mass-forming tumors and d–i non-mass forming precursor lesions. In addition to the multiple lesions in the bilateral convexities, a a large tumor with strong homogenous gadolinium enhancement was present in the left sphenoidal ridge. The two large tumors located in the left convexity (M1) and on the left sphenoidal ridge (M2) were resected. Arrowhead: non-resected multiple lesions in the convexity; arrow: resected tumors. Histologically, b M1 was composed of proliferative meningothelial cells arranged in bundles or whorls, whereas c M2 exhibited cord-like arrays of epithelioid tumor cells within an abundant basophilic myxoid matrix. d Low magnification of the two microdissected areas of the dura surrounding the left convexity tumor. e, f Microscopically, the small meningothelial nests (S1, S2) composed of more than 10 layers of oval or spindle-shaped meningothelial cells with or without psammoma bodies were identified. S1 and S2 were 2.7 mm apart. In immunohistochemistry, the small meningothelial nests are positive for EMA (g), PgR (h), and SSTR2a (i)
Fig. 2
Fig. 2
a Copy number alterations and b deletion mutations of M1 and M2 detected by whole-exome sequencing. a M1 showed loss of chromosomes 22q and Y, whereas M2 exhibited loss of chromosomes 1p, 10q, 22q, and Y. Homozygous deletions of CDKN2A and CDKN2B were not detected in either M1 or M2. b Information and coordinates of genetic mutations observed in M1 and M2. The NF2 frameshift mutation (c.503delC:p.K170Rfs*43) in M1 and CREBBP frameshift mutation (c.3923delT:p.L1308Cfs*30) in M2 were considered significant
Fig. 3
Fig. 3
Mutation and copy number analyses of small meningothelial nests by Sanger sequencing and fluorescence in situ hybridization of chromosome 22. a The NF2 frameshift mutation in M1 and CREBBP frameshift mutation in M2 were confirmed by Sanger sequencing. These mutations were not found in S1 and S2. b Two small meningothelial nests (S1, S2) contained scattered cells exhibiting monosomy of chromosome 22q with one red and one green signal (arrowhead: heterozygous deletion; arrow: non-deleted). c Summary of CNA of chromosome 22 and mutations of NF2 and CREBBP in two small meningothelial nests and two tumors. d Phylogeny inferred from the somatic CNA and SNV/INDEL
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