Temozolomide-associated hypermutation in gliomas

Choi, Serah; Yu, Yao; Grimmer, Matthew; Wahl, Michael; Chang, Susan M.; Costello, J

doi:10.1093/neuonc/noy016

Cited by 145 publications

(115 citation statements)

References 96 publications

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“…Possible mechanisms include acquired inactivating mutations or epigenetic silencing of the MMR genes MSH6, MSH2, MLH1, and PMS2. Recent studies show that treatment with TMZ of MGMT unmethylated tumors, such as in our case, introduces a strong selective pressure to lose mismatch repair pathway function [26]. Although immunostaining demonstrated intact MMR protein expression in the recurrent and metastatic specimens of our case, mutational hotspot analysis of the PDX derived from the temporal recurrence revealed inactivation of ARID1A, which has recently been shown to promote MMR by interacting with MSH2 [27].…”

Section: Resultsmentioning

confidence: 50%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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Background: Glioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations. Case presentation: A 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMTunmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre-and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor. Conclusion: This case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.

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Section: Resultsmentioning

confidence: 50%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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“…Preliminary results have failed to show an advantage of nivolumab for GBM 114 . One explanation could be the relatively low mutational burden in GBM as compared to many other malignancies 115 . In an interesting paper by Costello et al, they discuss the effects of TMZ to cause a "hypermutated phenotype" in tumor recurrences.…”

Section: Resultsmentioning

confidence: 99%

“…In an interesting paper by Costello et al, they discuss the effects of TMZ to cause a "hypermutated phenotype" in tumor recurrences. This occurs when the tumor is MGMT methylated and lacks intact MMR genes 104,115 . They hypothesize that this hypermutated tumor cell might be a functional target for immune therapy, as the mutational burden has been correlated to efficacy 115 .…”

Section: Resultsmentioning

confidence: 99%

“…This occurs when the tumor is MGMT methylated and lacks intact MMR genes 104,115 . They hypothesize that this hypermutated tumor cell might be a functional target for immune therapy, as the mutational burden has been correlated to efficacy 115 . Another monoclonal antibody against PD-1, pembrolizumab, is currently being investigated for recurrent gliomas with hypermutator phenotype (NCT02658279) 115 .…”

Section: Resultsmentioning

confidence: 99%

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Studies for Better Treatment of Patients with Glioma

Malmström

2019

Linköping University Medical Dissertations

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Previously published papers I and II and additional material included in this thesis have been reprinted with permission of the copyright holder. Paper III is included as Accepted Manuscript. This is a pre-copyedited, author-produced version of an article accepted for publication in Neuro-Oncology Practice following peer review. The version of record: Annika Malmström et al. Do we really know who has an MGMT methylated glioma? Results of an international survey regarding use of MGMT analyses for glioma. Neuro-Oncology Practice (2019)

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“…However, no tumor responses were observed in four other patients with hypermutated recurrent glioblastomas treated with ICIs [13]. TMZ treatment can also result in tumors with a high mutational load due to acquired mutations in the DNA repair genes MSH2, MSH6, PMS2, and MLH2 [14][15][16][17], and these tumors are likely more immunogenic compared to other glioblastomas. Hypermutation at glioblastoma diagnosis or at recurrence is associated with enhanced numbers of CD8 T cells [18].…”

Section: Pd-1 Inhibitor Trialsmentioning

confidence: 95%

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

Weenink

French

Smitt

et al. 2020

Cancers

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Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells.

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Temozolomide-associated hypermutation in gliomas

Cited by 145 publications

References 96 publications

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Studies for Better Treatment of Patients with Glioma

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

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