P01.126 Frequent Tp53 and ATRX/DAXX gene alterations in giant cell IDH-Wildtype Glioblastomas

The 2016 updated World Health Organization (WHO) classification system recognizes the morphological variant giant cell glioblastoma (GBM) as one rare variant of IDH-wildtype (IDH-wt) GBM. This variant account for <1% of all GBMs, occurs in young adults patients and have a slightly better prognosis that ordinary IDH-wt GBM. Histologically, it is characterized by the presence of bizarre and numerous multinucleated giant cells. The lack of a more precise definition of this morphological variant makes that sometimes the giant cell component is not taken into account, even though some evidences may suggest that it may be clinically relevant. This variant has not been characterized yet by specific genetic biomarkers such as other variants of GBM, e.g. epithelioid GBM with BRAF mutations or secondary GBM with IDH mutations. The purpose of our study is to determine whether there is a molecular genetic base underlying the giant cell morphological variant of GBM. We retrospectively studied 31 cases of giant cell GBMs or GBMs in which a giant cell component was specified in the pathological report. We performed next generation sequencing assays by using a targeted panel of 30 genes involved in gliomas to study mutations and copy number variations. The following histological features were recorded: percentage and size of giant cells, presence of lymphocytes, gemistocytes, epithelioid, necrosis, vascular endothelia proliferation and epithelioid or PNET-like morphology. A review of the clinical records of the patients was also performed. Mean age of the patients was 47 years. The most frequently altered genes were: TP53 (74%), PTEN (32%) and ATRX (29%). Strikingly, 39% of the cases presented mutations in ATRX or DAXX in absence of the previously reported driver IDH or H3.3 gene mutations. Moreover, those cases with high amount of giant cells (> 30%), had frequently (around 75% of the cases) molecular alterations in TP53 accompanied of alterations in the chromatin remodeling genes ATRX or DAXX genes. Our results suggest that giant cell GBMs may have specific molecular characteristics, such as the presence of concurrent TP53 and ATRX/DAXX alterations in the absence of IDH or H3F3A driver mutations. These findings may be relevant for the development of targeted therapies and a personalized medicine.