Integrated Radiographic And Phylogenetic Case Study Of A Primary And Contralateral Recurrent Glioma

Extensive neuropil invasion is a hallmark of glioma growth and a subset of tumors demonstrate recurrence in the contralateral hemisphere without a path of tumor spread detected by MR imaging. We used an integrated genomic and radiographic approach to study a patient with a right nonenhancing insular mass histologically diagnosed as IDH1/2 wild-type anaplastic astrocytoma (AA) and a punctate nonenhancing T2 hyperintense focus within the left middle frontal gyrus subcortical white matter. Follow-up MR imaging, six months after initiation of Temozolomide based chemoradiotherapy, demonstrated focal enhancement within the left middle frontal gyrus lesion. Six months later a rim enhancing centrally necrotic mass involving left frontal lobe white matter was observed and diagnosed as glioblastoma. Whole exome sequencing of both tumors and targeted Sanger sequencing of 7-9 samplings from each tumor identified a novel five amino acid in-frame insertion in the PTEN C2 domain in both tumors that potentially disrupts cell membrane interaction and activates phosphotidylinositol 3-kinase (PI3K) signaling. As wild-type PTEN inhibits cellular migration, this early PTEN mutation might also promote invasion and the seeding of metastatic foci remote from the initial tumor mass. The right insular AA harbored amplifications of EGFR, MDM4 and PDGFRA (amplified and mutated) that were not detected within the contralateral glioblastoma. Conversely, the glioblastoma acquired CDKN2A homozygous deletion, probable NF1 biallelic inactivation (mutation and heterozygous loss), and a second hit to PTEN (heterozygous loss). Thirty-six shared mutations (including PTEN) and two shared copy number alterations unequivocally indicate a common origin for these spatially and temporally separated tumors. Taken together, these integrated radiographic and genomic data strongly suggest that the cells seeding the left frontal lobe tumor migrated from the evolving right insular tumor at an early time point and then followed an independent evolutionary trajectory.