Genetic and histologic spatiotemporal evolution of recurrent, multifocal, multicentric and metastatic glioblastoma

Abstract

Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by extensive brain invasion and rarely, systemic metastases. The pathogenesis of metastatic glioblastoma is largely unknown. We present the first integrated clinical/histologic/genetic analysis of 5 distinct brain and lung foci from a unique case of recurrent, multifocal, multicentric and metastatic glioblastoma. The initial right frontotemporal gliosarcoma received standard surgical/chemoradiation therapy and recurred 1.5 years later, co-occurring with three additional masses localized to the ipsilateral temporal lobe, cerebellum and lung. Synchronous metastatic lung carcinoma was suspected in this long-term smoker patient with family history of cancer. However, glioblastoma was confirmed in all tumors, although with different morphologic patterns, including ependymomatous and epithelioid. Genomic profiling revealed a germline FANCD2 variant of unknown significance, and a 4-gene somatic mutation signature shared by all tumors, consisting of TERT promoter and PTEN, RB1 and TP53 tumor suppressor mutations. Additional GRIN2A and ATM heterozygous mutations were selected in the cerebellar and lung foci, but were variably present in the supratentorial foci, indicating reduced post-therapeutic genetic evolution in brain foci despite morphologic variability. Significant genetic drift characterized the lung metastasis, likely explaining the known resistance of circulating glioblastoma cells to systemic seeding. MET overexpression was detected in the initial gliosarcoma and lung metastasis, possibly contributing to invasiveness. This comprehensive analysis sheds light on the temporospatial evolution of glioblastoma and underscores the importance of genetic testing for diagnosis and personalized therapy.

Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma

“…Focal somatic pathogenic alterations occurred in B2M and GRIN2A genes encoding transmembrane proteins (Fig. 3 a), the latter gene being mutated in metastatic glioblastoma [ 24 ] and frequently, in melanoma [ 44 ]. Other VUS were detected in F12: EGFR p.A613T at low VAF in frontal focus, and STAT4 p.E194* at heterozygous VAF in pontine and frontal foci (Suppl.…”

“…The two F10 biopsies were additionally sequenced at University of California/San Francisco. Variant analysis and interpretation were performed as described [ 22 – 24 ]. Copy number variation (CNV) analysis was performed at Tempus Labs [ 25 ].…”

“…All samples were sequenced by using a customized 295-gene DNA library (SureSelect XT-HS, Agilent, Santa Clara, CA), as described [22,23]. For all F5 and F12 samples, and for F10 ganglion-like cells (GCs), NGS was also performed at Tempus Labs (Chicago, IL), by using the xT 596-gene panel, as described [22,24]. The two F10 biopsies were additionally sequenced at University of California/San Francisco.…”

“…The genomic/proteomic analysis of infratentorial and supratentorial foci confirmed and expanded these histologic invasion patterns. We have previously shown that the tumor mutation signature shows little spatiotemporal variability, being reliable for tracking the origin of invasive populations, whereas the CNV composition shows high variability in distinct tumor foci [24]. A common mutation set characterized all tumor foci in each DIPG case, and additional genetic alterations allowed tracking the spatiotemporal selection and migration of neoplastic populations.…”

Characterizing the Genomic Landscape of Brain Glioma With Circulating Tumor DNA From Tumor In Situ Fluid

“…Glioma is a tumor with high molecular heterogeneity, its constantly evolving genetic landscape can be a huge obstacle to the clinical management of patients (1). Studies about sequential glioma biopsies have unearthed enormous divergence of the cancer genome between the initial and recurrent tumor from the same patient (2,3). The need for precision medicine is to characterize the real-time molecular status of the tumor, which is believed to have therapeutic significance for glioma patients (4).…”