Molecular epidemiology of IDH2 hotspot mutations in cancer and immunohistochemical detection of R172K, R172G, and R172M variants Journal Article


Authors: Dogan, S.; Frosina, D.; Geronimo, J. A.; Hernandez, E.; Mohanty, A.; Bale, T.; Hechtman, J. F.; Arcila, M. E.; Hameed, M. R.; Jungbluth, A. A.
Article Title: Molecular epidemiology of IDH2 hotspot mutations in cancer and immunohistochemical detection of R172K, R172G, and R172M variants
Abstract: IDH1/2 hotspot mutations occur in glioma, cholangiocarcinoma, chondrosarcoma, sinonasal carcinoma, and T-cell lymphoma and have diagnostic, prognostic, and/or therapeutic value. Availability of immunohistochemistry (IHC) protocols for specific IDH2 mutation detection is limited. A targeted exome sequencing assay MSK-IMPACT cohort comprising >38,000 cancer cases was explored for the presence of IDH1/2 mutations in solid malignancies and select T-cell lymphomas. Seventy-four formalin-fixed paraffin-embedded IDH1/2-mutated (n = 62) and wild-type (n = 12) samples were used for testing and optimization of anti–IDH2 monoclonal antibodies (mAbs) 14H7, 3C11, and MMab1 targeting R172K, R172G, and R172M mutant proteins, respectively. IDH1/2 mutations were common in glioma (26.8% and 1.6%), intrahepatic cholangiocarcinoma (23.1% and 5.7%), chondrosarcoma (19.4% and 10.7%), sinonasal undifferentiated/large-cell neuroendocrine carcinoma (0% and 84.2%), angioimmunoblastic T-cell lymphoma (0% and 22%), and peripheral T-cell lymphoma (0 and 5.1%). In other cancers, IDH2 mutations were rare. IDH2 R172 variants included R172K (39%), R172S (29%), R172W (12%), R172G (10%), R172M (5%), and R172T (4%). 14H7, 3C11, and MMab1 detected all IDH2 R172K, R172G, and R172M, respectively, and produced a crisp, granular cytoplasmic staining pattern. 3C11 was also positive in 5 of 6 IDH1 R132G mutants showing a homogeneous, smooth cytoplasmic staining. All 3 mAbs were negative in other IDH1/2 mutant or wild-type cases. IHC using mAbs 14H7, 3C11, and MMab1 can facilitate molecular diagnosis as a reliable, fast, and inexpensive alternative for specific IDH2 variant detection. Given the distinct distribution of IDH2 R172 mutations in cancers, these mAbs could also serve as useful pathologic diagnostic markers. © 2020 Elsevier Inc.
Keywords: glioma; chondrosarcoma; sinonasal undifferentiated carcinoma; 14h7; 3c11; idh2 immunohistochemistry; mmab1
Journal Title: Human Pathology
Volume: 106
ISSN: 0046-8177
Publisher: Elsevier Inc.  
Date Published: 2020-12-01
Start Page: 45
End Page: 53
Language: English
DOI: 10.1016/j.humpath.2020.09.013
PUBMED: 33017591
PROVIDER: scopus
PMCID: PMC7721993
DOI/URL:
Notes: Article -- Export Date: 1 December 2020 -- Source: Scopus
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MSK Authors
  1. Meera Hameed
    282 Hameed
  2. Snjezana Dogan
    189 Dogan
  3. Achim Jungbluth
    456 Jungbluth
  4. Maria Eugenia Arcila
    666 Arcila
  5. Denise Frosina
    123 Frosina
  6. Jaclyn Frances Hechtman
    212 Hechtman
  7. Abhinita Subhadarshin Mohanty
    39 Mohanty
  8. Tejus Bale
    122 Bale