Mismatch repair proteins PMS2 and MLH1 can further refine molecular stratification of IDH-mutant lower grade astrocytomas.

Abstract

The diagnostic role of Isocitrate Dehydrogenase (IDH) mutation status in adult lower grade astrocytomas was first formally presented within the WHO Classification of Tumours of the Central Nervous System (2016). IDH-mutant astrocytomas are not as common as IDH-wildtype astrocytomas but are of better prognosis. Our previous study provided an evident that IDH-mutant lower grade astrocytomas is not a homogeneous group and could be further stratified by PDGFRA amplification, CDK4 amplification and CDKN2A deletion. In this study, we detected the expressions of DNA mismatch repair (MMR) proteins (PMS2, MLH1, MSH2, MSH6) and PD-L1 by immunohistochemistry in 147 IDH-mutant lower grade astrocytomas and explored their clinical relevance. The loss of was identified in 28.6%, 1.4%, 8.8% and 13.6%, respectively. PD-L1 expression was detected in 1.4% of this cohort. Survival analysis revealed that loss of PMS2 was correlated with shorter OS (p < 0.001) and PFS (p = 0.005). Loss of PMS2 or MLH1 was associated with shorter OS (p < 0.001) and PFS (p = 0.008). In IDH-mutant lower grade astrocytomas without CDKN2A deletion, loss of PMS2 was associated with poorer OS (p < 0.001) and PFS (p = 0.001). Furthermore, among IDH-mutant lower grade astrocytomas lacking the three biomarkers (PDGFRA, CDK4 and CDKN2A), loss of PMS2 was also associated with a poorer OS (p < 0.001) and PFS (p = 0.003). Our data illustrated the potential application of MMR genes in stratification of IDH-mutant lower grade astrocytomas without PDGFRA, CDK4 and CDKN2A copy number alterations.

• Authors: Rui Ryan Yang, Kay Ka-Wai Li, Zhen-Yu Zhang, Aden Ka-Yin Chan, Wei-Wei Wang, Danny Tat-Ming Chan, Wen-Cai Li, Xian-Zhi Liu, Fang-Cheng Li, Hong Chen, Ho-Keung Ng, Ying Mao, Zhi-Feng Shi
• Journal: Clinical neurology and neurosurgery (Clin Neurol Neurosurg) Vol. 208 Pg. 106882 (Sep 2021) ISSN: 1872-6968 [Electronic] Netherlands
• PMID: 34428613 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Isocitrate Dehydrogenase
• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1

Topics

• Adult
• Astrocytoma (genetics, metabolism, mortality, pathology)
• Biomarkers, Tumor
• Brain Neoplasms (genetics, metabolism, mortality, pathology)
• Female
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Male
• Middle Aged
• Mismatch Repair Endonuclease PMS2 (genetics, metabolism)
• MutL Protein Homolog 1 (genetics, metabolism)
• Mutation
• Prognosis
• Survival Rate