Publication
A case study of a long-term glioblastoma survivor with unmethylated MGMT and hypermutated genotype
Publisher:
Cold Spring Harbor Laboratory
Date:
06-2019
DOI:
10.1101/MCS.A003251
Abstract: Effective treatments that extend survival of malignant brain tumor glioblastoma (GBM) have not changed in more than a decade however, there exists a minority patient group ( %) whose survival is longer than 3 yr. We herein present a case report of a long-term surviving 51-yr-old female diagnosed with a MGMT unmethylated GBM. The patient was progression-free for 23 mo. Fresh primary and recurrent tumor s les were collected and processed for patient-derived model development. Whole-genome sequencing (WGS) was performed concurrently with additional standard of care diagnostics. WGS revealed a hypermutated genotype in the germline tissue and in both the primary and recurrent tumor s les. Specific to the matched tumors, an average of 30 cancer driver genes were mutated. Noteworthy was the identification of a nonsynonymous mutation in the POLE gene. As a possible instigator of the hypermutational genotype observed in the tumors, we identified nonsynonymous germline mutations within the mismatch repair genes, MLH1 and PMS2 . Mutations within these genes are often indicative of the pan-cancer phenotype known as Lynch syndrome however, their pathogenicity remains unreported. We performed a drug screen of 165 compounds, which identified one compound, YM155, an experimental survivin inhibitor, that showed effectivity to the patient-derived cell lines of both tumors. Treatment selection based on a patient's genome to in idualize treatment for GBM patients could potentially be useful in the clinic. This is a promising avenue for further translational research, with larger databases and integrated platforms to increase the efficiency of analyzing and interpreting the in idual genomic data of GBM.