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Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

ABSTRACT: A significant proportion of low-grade WHO grade I and higher-grade WHO grade II or III meningiomas are at risk to develop post-resection recurrence. Though recent studies investigated genomic alterations within histological subtypes of meningiomas, few have compared genomic profiles of primary meningiomas matched to their recurrences. The present study aimed to identify oncogenic driver mutations that may indicate risk of meningioma recurrence and aggressive clinical course. Seventeen patients treated for low-grade (n = 8) or high-grade (n = 9) meningioma and underwent both primary and recurrent resection between 2007-2017 were reviewed. Tumor specimens (n = 38) underwent genomic sequencing of known oncogenic driver mutations. Primary and recurrent tumors were compared using matched-pair analyses for mutational associations with clinical outcomes including functional status, progression-free survival (PFS) and overall survival (OS). Most common driver mutations included POLE and NF2. There was no enrichment for any driver mutation from primary to recurrent tumor specimen. NF2 mutant meningiomas were associated with larger tumor size (8-fold increase), presence of vasogenic edema, and higher mitotic proliferation on univariate and independently on multivariate regression (p's < 0.05) after controlling for preoperative and tumor features. Tumors with POLE driver mutations were associated with decreased functional status at last postoperative follow-up (p = 0.022) relative to presentation. Mutation status was not associated with PFS or OS on multivariate Cox regression, but rather with grade of resection (p = 0.046) for PFS. While primary and recurrent tumors exhibited similar driver mutations within patients, the identification of driver mutations associated with clinical outcomes is crucial for guiding potential targeted treatments in recurrent meningiomas.

SUBMITTER: Loewenstern J

PROVIDER: S-EPMC6544407 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

Loewenstern Joshua J Rutland John J Gill Corey C Arib Hanane H Pain Margaret M Umphlett Melissa M Kinoshita Yayoi Y McBride Russell R Donovan Michael M Sebra Robert R Bederson Joshua J Fowkes Mary M Shrivastava Raj R

Oncotarget 20190528 37

A significant proportion of low-grade WHO grade I and higher-grade WHO grade II or III meningiomas are at risk to develop post-resection recurrence. Though recent studies investigated genomic alterations within histological subtypes of meningiomas, few have compared genomic profiles of primary meningiomas matched to their recurrences. The present study aimed to identify oncogenic driver mutations that may indicate risk of meningioma recurrence and aggressive clinical course. Seventeen patients t ...[more]

PMID: 31191822

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Project description:BACKGROUND:Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE:To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS:Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS:Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS:Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY:In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Dataset Information

Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

Publications

Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

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