The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

Autor: Kwok Ling Kam, Alicia Steffens, Craig Horbinski, Matthew McCord, Kathleen McCortney, Rodrigo Javier
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
DNA Mismatch Repair
lcsh:RC346-429
0302 clinical medicine
PMS2
Hypermutator
Early Detection of Cancer
Mismatch Repair Endonuclease PMS2
Aged
80 and over
0303 health sciences
Pilocytic astrocytoma
Brain Neoplasms
Glioma
Middle Aged
Immunohistochemistry
3. Good health
DNA-Binding Proteins
MutS Homolog 2 Protein
030220 oncology & carcinogenesis
DNA mismatch repair
Female
IDH1
MutL Protein Homolog 1
MGMT
Adult
Sensitivity and Specificity
Pathology and Forensic Medicine
Mismatch repair
03 medical and health sciences
Cellular and Molecular Neuroscience
Young Adult
medicine
Temozolomide
Humans
neoplasms
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
Aged
business.industry
Research
medicine.disease
digestive system diseases
nervous system diseases
MSH6
MSH2
Cancer research
Neurology (clinical)
Neoplasm Grading
business
Anaplastic astrocytoma
Zdroj: Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-8 (2020)
Acta Neuropathologica Communications
ISSN: 2051-5960
Popis: A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.
Databáze: OpenAIRE
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