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

Abstract

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.

Molecular profiling of an osseous metastasis in glioblastoma during checkpoint inhibition: potential mechanisms of immune escape

“…Multiple case reports of GBM metastases have focused on genetic aberrations, potentially involved in tumour cell manifestation outside the brain [11,43,45]. Among others, alterations, such as BRCA1 and ARID1A mutations or overexpression of IGFBP2 have been described in these cases [44,45]. Although we cannot exactly define when the metastatic seeding in our case occurred or if it is directly linked to anti-PD1 treatment, the tumour became symptomatic and most likely progressed during intracranial remission under immune checkpoint inhibition.…”

“…In order to form extracranial metastases, the tumour had to, either gain new genetic drivers to promote peripheral metastatic seeding, or suppress the peripheral immunosurveillance, or develop new mechanisms to evade from immune recognition during its metastatic spread, or both. Multiple case reports of GBM metastases have focused on genetic aberrations, potentially involved in tumour cell manifestation outside the brain [11,43,45]. Among others, alterations, such as BRCA1 and ARID1A mutations or overexpression of IGFBP2 have been described in these cases [44,45].…”

Next-Generation Sequencing in the Diagnosis of Metastatic Lesions: Reclassification of a Glioblastoma as an Endometrial Cancer Metastasis to the Brain

“…Molecular Diagnosis in Endometrial Metastases frequently seen in endometrial carcinomas but are rarely part of the pathogenesis of gliomas [5].…”

“…However, whereas PTEN mutation is also commonly implicated in brain tumors, KRAS is rarely identified in gliomas [4]. ARID1A alterations are also frequently seen in endometrial carcinomas but are rarely part of the pathogenesis of gliomas [5].…”

BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort

“…BRCA1 is a phosphorylation substrate of the kinase ataxia telangiectasia mutated (ATM) and is required for a normal response to ionizing radiation and to alkylating agents [20]. Sporadic cases of glioblastoma have been reported in patients carrying BRCA1 germ line mutations, but the BRCA1 expression status has never been systematically studied in glioblastoma patients [21,22].…”