A case study of a long-term glioblastoma survivor with unmethylated MGMT and hypermutated genotype

被引:3
作者
Jue, Toni Rose [1 ]
Olafson, Lauren R. [1 ]
Siddell, Anna H. [1 ]
Rapkins, Robert W. [1 ]
Ng, Benedict [1 ]
Yin, Julia X. M. [1 ]
Lu, Victor M. [1 ]
Chung, Sylvia A. [1 ]
Whittaker, Shane P. [1 ]
Davies, Matthew [1 ]
Fairhall, Jacob M. [2 ,3 ]
Hovey, Elizabeth J. [3 ,4 ]
McDonald, Kerrie L. [1 ]
机构
[1] Univ New South Wales, Cure Brain Canc Biomarkers & Translat Res Grp, Prince Wales Clin Sch, Sydney, NSW 2052, Australia
[2] Prince Wales Hosp, Neurospine Clin, Randwick, NSW 2031, Australia
[3] Univ New South Wales, Sydney, NSW 2031, Australia
[4] Prince Wales Hosp, Nelune Comprehens Canc Ctr, Dept Med Oncol, Sydney, NSW 2031, Australia
来源
COLD SPRING HARBOR MOLECULAR CASE STUDIES | 2019年 / 5卷 / 03期
关键词
MISMATCH-REPAIR; MUTATIONAL PROCESSES; TUMORS; EXPRESSION; CARCINOMA; GENOME; EVOLUTION; VARIANTS; GERMLINE; BLOCKADE;
D O I
10.1101/mcs.a003251
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 (<5%) 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 samples 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 samples. 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 individualize 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 individual genomic data of GBM.
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页数:15
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