Detection of glioblastoma intratumor heterogeneity in radiosensitivity using patient-derived neurosphere cultures.
PURPOSE
Glioblastoma (GBM) is characterized by extensive clonal diversity suggesting the presence of tumor cells with varying degrees of treatment sensitivity. Radiotherapy is an integral part of glioblastoma treatment. Whether GBMs are comprised of spatially distinct cellular populations with uniform or varying degrees of radiosensitivity has not been established.


METHODS
Spatially distinct regions of three GBMs (J3, J7 and J14) were resected and unique cell lines were derived from each region. DNA from cell lines, corresponding tumor fragments, and patient blood was extracted for whole exome sequencing. Variants, clonal composition, and functional implications were compared and analyzed with superFreq and IPA. Limiting dilution assays were performed on cell lines to measure intrinsic radiosensitivity.


RESULTS
Based on WES, cell lines generated from different regions of the same tumor were more closely correlated with their tumor of origin than the other GBMs. Variant and clonal composition comparisons showed that cell lines from distinct tumors displayed increasing levels of ITH with J3 and J14 having the lowest and highest, respectively. The radiosensitivities of the cell lines generated from the J3 tumor were similar as were those generated from the J7 tumor. However, the radiosensitivities of the 2 cell lines generated from the J14 tumor (J14T3 and J14T6) were significantly different with J14T6 being more sensitive than J14T3.


CONCLUSION
Data suggest a tumor dependent ITH in radiosensitivity. The existence of ITH in radiosensitivity may impact not only the initial therapeutic response but also the effectiveness of retreatment protocols.
['McAbee|Joseph H|JH|', 'Degorre-Kerbaul|Charlotte|C|', 'Valdez|Kristin|K|', 'Wendler|Astrid|A|', 'Shankavaram|Uma T|UT|', 'Watts|Colin|C|', 'Camphausen|Kevin|K|', 'Tofilon|Philip J|PJ|http://orcid.org/0000-0003-0170-1194']
D014408:Biomarkers, Tumor D015972:Gene Expression Regulation, Neoplastic D005909:Glioblastoma D006801:Humans D009154:Mutation D011379:Prognosis D011836:Radiation Tolerance D014407:Tumor Cells, Cultured D000073359:Whole Exome Sequencing
Glioblastoma Intratumor heterogeneity Radiosensitivity