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IDH1/2 Mutations in Sinonasal Undifferentiated Carcinomas : Previously Undescribed IDH2 R172K and R140x Variants
Aanchal Kakkar1, Amber Rathor1, Subiyathul Farah Ashraf1
1Departments of Pathology.
Abstract:
Sinonasal undifferentiated carcinoma (SNUC) is a rare, poorly defined sinonasal epithelial neoplasm from which several genetically defined entities are emerging. IDH1/2 mutations were recently identified in a subset of SNUC. However, the ideal method for the detection of these mutations remains to be established. Cases diagnosed as SNUC between 2010 and 2020 were retrieved. Immunohistochemistry was performed using IDH1/2 mutant-specific antibody MsMab-1. Quantitative real-time polymerase chain reaction (qPCR) was performed on genomic DNA extracted from formalin-fixed paraffin-embedded tissue using 2 kits to detect IDH1/2 mutations. Sanger sequencing was performed in a subset of cases. Thirty-eight cases of SNUC were identified, 18 of which showed IDH1/2 mutations by qPCR (47.4%). IDH2 R172K and R140x were most frequent, each seen in 6 cases (33.3%). Sanger sequencing identified IDH1/2 mutations in 4 out of 21 cases (19%) and did not detect mutations identified by qPCR in 7 cases. On immunohistochemistry, strong IDH positivity was present in 2 cases (5.3%), 1 of which had IDH2 mutation, while no mutation was detected in the other. Our results demonstrating IDH2 R172K and IDH2 R140x variants are a novel finding in SNUC. Immunohistochemistry and Sanger sequencing have low sensitivity for detection of IDH1/2 mutations, and qPCR-based assays may be utilized, particularly in resource-limited settings where access to sophisticated sequencing techniques are difficult.
Insights
Quantitative real-time PCR effectively detects IDH1/2 mutations in sinonasal undifferentiated carcinoma (SNUC), outperforming immunohistochemistry and Sanger sequencing, especially in resource-limited settings.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Sinonasal undifferentiated carcinoma (SNUC) is a rare epithelial neoplasm.
- Emerging research identifies specific genetic mutations, including IDH1/2, in a subset of SNUC cases.
- Optimal methods for detecting these IDH1/2 mutations in SNUC require further investigation.
Purpose of the Study:
- To evaluate and compare the sensitivity of different methods for detecting IDH1/2 mutations in SNUC.
- To identify the most frequent IDH1/2 variants in SNUC.
- To assess the utility of qPCR, immunohistochemistry, and Sanger sequencing for IDH1/2 mutation detection in SNUC.
Main Methods:
- Retrospective analysis of 38 SNUC cases diagnosed between 2010 and 2020.
- Detection of IDH1/2 mutations using quantitative real-time polymerase chain reaction (qPCR) on DNA from formalin-fixed paraffin-embedded tissues.
- Comparison with results from immunohistochemistry using a mutant-specific antibody and Sanger sequencing.
Main Results:
- IDH1/2 mutations were detected in 47.4% (18/38) of SNUC cases by qPCR.
- IDH2 R172K and IDH2 R140x variants were the most frequent, each found in 33.3% (6/18) of mutated cases.
- qPCR demonstrated higher sensitivity compared to Sanger sequencing (19%) and immunohistochemistry (5.3%) for IDH1/2 mutation detection.
Conclusions:
- IDH2 R172K and IDH2 R140x variants represent novel findings in SNUC.
- qPCR offers a sensitive and potentially valuable method for IDH1/2 mutation detection in SNUC.
- Immunohistochemistry and Sanger sequencing exhibit limitations in sensitivity for detecting IDH1/2 mutations in SNUC, particularly in resource-limited settings.
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