Work

The dominant TP53 hotspot mutation in IDH -mutant astrocytoma, R273C, has distinctive pathologic features and sex-specific prognostic implications

Year: 2021

Type: article

Abstract: Background Infiltrative astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation frequently contain mutations in the TP53 tumor suppressor gene. Disruption of normal p53 protein activity confers neoplastic cells with a number of oncogenic properties and is a common feature of aggressive malignancies. However, the high prevalence of TP53 mutation and its pathogenic role in IDH-mutant (IDHmut) astrocytoma is not well understood. Methods We performed a retrospective analysis of molecular and clinical data from patients with IDHmut astrocytoma at the University of Pittsburgh Medical Center between 2015 and 2019 as our initial cohort. We validated and expanded our findings using molecular and clinical data from The Cancer Genome Atlas. Results We show that the TP53 mutational spectrum in IDHmut astrocytomas is dominated by a single hotspot mutation that codes for the R273C amino acid change. This mutation is not enriched in IDH-wildtype astrocytomas. The high prevalence of TP53R273C mutation is not readily explained by known mutagenic mechanisms, and TP53R273C mutant tumors have lower transcriptional levels of proliferation-related genes compared to IDHmut astrocytomas harboring other forms of mutant p53. Despite lower proliferation, TP53R273C mutant tumors tend to progress more quickly and have a shorter overall survival than those with other TP53 mutations, particularly in male patients. Conclusions Our findings suggest that compared to other TP53 mutations, IDHmut astrocytomas may select for TP53R273C mutations during tumorigenesis. The genotype, sex, and mutation-specific findings are clinically relevant and should prompt further investigation of TP53R273C.

Source: Neuro-Oncology Advances

DOI: 10.1093/noajnl/vdab182

Authors: Daniel F Marker, Sameer Agnihotri, Nduka Amankulor, Geoffrey H Murdoch, Thomas M Pearce

Institutions: University of Pittsburgh, Abramson Cancer Center, University of Pennsylvania

Language: English

Topic: Glioma Diagnosis and Treatment

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,142