Abstract
BackgroundTo investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas.Methodology/Principal FindingsTo address intertumoral heterogeneity we investigated non- microdissected tumor tissue of 106 gliomas representing 51 recurrent tumors. To address intratumoral heterogeneity a set of 16 gliomas representing 7 tumor pairs with at least one recurrence, and 4 single mixed gliomas were investigated by microdissection of distinct oligodendroglial and astrocytic tumor components. All tumors and tumor components were analyzed for allelic loss of 1p/19q (LOH 1p/19q), for TP53- mutations and for R132 mutations in the IDH1 gene. The investigation of non- microdissected tumor tissue revealed clonality in 75% (38/51). Aberrant molecular alterations upon recurrence were detected in 25% (13/51). 64% (9/14) of these were novel and associated with tumor progression. Loss of previously detected alterations was observed in 36% (5/14). One tumor pair (1/14; 7%) was significant for both. Intratumoral clonality was detected in 57% (4/7) of the microdissected tumor pairs and in 75% (3/4) of single microdissected tumors. 43% (3/7) of tumor pairs and one single tumor (25%) revealed intratumoral heterogeneity. While intratumoral heterogeneity affected both the TP53- mutational status and the LOH1p/19q status, all tumors with intratumoral heterogeneity shared the R132 IDH1- mutation as a common feature in both their microdissected components.Conclusions/SignificanceThe majority of recurrent gliomas are of monoclonal origin. However, the detection of divertive tumor cell clones in morphological distinct tumor components sharing IDH1- mutations as early event may provide insight into the tumorigenesis of true mixed gliomas.
Highlights
Glioma therapy experiences a gradual paradigm shift replacing former ‘‘one-fit-all’’ strategies towards the development of more individual, patient- and tumor- tailored therapeutic approaches.Astrocytomas, oligodendrogliomas and oligoastrocytomas account for the majority of glial tumors
While astrocytomas frequently feature fibrillary neoplastic astrocytes, oligodendrogliomas are composed of monomorphic cells with uniform round nuclei and perinuclear proofed to be the decisive alteration predicting better tumor prognosis and therapy response in oligodendroglial tumors
To elucidate clonal diversity within single and recurrent gliomas we investigated oligodendroglial and astrocytic tumor components of a total 16 tumors representing 7 tumor pairs with at least on recurrence and 4 single tumors by microdissection
Summary
Glioma therapy experiences a gradual paradigm shift replacing former ‘‘one-fit-all’’ strategies towards the development of more individual, patient- and tumor- tailored therapeutic approaches. Astrocytomas, oligodendrogliomas and oligoastrocytomas account for the majority of glial tumors. While astrocytomas frequently feature fibrillary neoplastic astrocytes, oligodendrogliomas are composed of monomorphic cells with uniform round nuclei and perinuclear proofed to be the decisive alteration predicting better tumor prognosis and therapy response in oligodendroglial tumors [1,2,3,4], there is evidence that the methylation status of the MGMT- promoter may be of similar importance for the therapy and long term prognosis of malignant astrocytic tumors [5,6,7]. For the majority of patients, molecular testing is confined to the initial tumor, only. To investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas
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