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Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma.

Abstract

INTRODUCTION

Dedifferentiated chondrosarcoma (DDCHS) is an aggressive type of chondrosarcoma that results from high-grade transformation of a low-grade chondrosarcoma. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations have been recently described in low-grade cartilaginous neoplasms which lead to increased D-2-hydroxyglutarate (2HG) oncometabolite production, promoting tumorigenesis.

AIMS

To examine the prevalence of IDH mutations in a single institution cohort of DDCHS and correlate 2HG levels to mutation status.

METHODS AND RESULTS

We examined a series of 21 primary DDCHS using Sanger sequencing and qPCR genotyping to interrogate for IDH1/2 mutations, and evaluated the level of 2HG in formalin-fixed paraffin-embedded (FFPE) tumor and matched normal tissue samples using a fluorometric assay. 76% of DDCHS (16/21) harbored a heterozygous IDH1 or IDH2 mutation. 6/14 IDH-mutated DDCHS showed elevated 2HG in tumor relative to matched normal tissue. There were no consistent histologic or disease specific survival differences between IDH-mutated tumors and wild-type tumors.

CONCLUSIONS

Our study confirms the frequent presence of a variety of IDH1 and IDH2 mutation variants, indicating that a sequencing-based approach is required for DDCHS if IDH is to be used as a diagnostic marker. Similar to other IDH-mutated tumor types, IDH-mutated DDCHS also show elevated 2HG level, indicating that the oncometabolite activity of 2HG may contribute to DDCHS oncogenesis and progression.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, British Columbia, Canada.Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, British Columbia, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31609487

Citation

Mohammad, Nissreen, et al. "Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma." Histopathology, 2019.
Mohammad N, Wong D, Lum A, et al. Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma. Histopathology. 2019.
Mohammad, N., Wong, D., Lum, A., Lin, J., Ho, J., Lee, C. H., & Yip, S. (2019). Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma. Histopathology, doi:10.1111/his.14018.
Mohammad N, et al. Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma. Histopathology. 2019 Oct 14; PubMed PMID: 31609487.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma. AU - Mohammad,Nissreen, AU - Wong,Derek, AU - Lum,Amy, AU - Lin,Jonah, AU - Ho,Julie, AU - Lee,Cheng-Han, AU - Yip,Stephen, Y1 - 2019/10/14/ PY - 2019/10/15/entrez KW - 2-hydroxyglutarate KW - Dedifferentiated chondrosarcoma KW - IDH mutation KW - IDH1 KW - IDH2 KW - cartilaginous neoplasms KW - sarcoma JF - Histopathology JO - Histopathology N2 - INTRODUCTION: Dedifferentiated chondrosarcoma (DDCHS) is an aggressive type of chondrosarcoma that results from high-grade transformation of a low-grade chondrosarcoma. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations have been recently described in low-grade cartilaginous neoplasms which lead to increased D-2-hydroxyglutarate (2HG) oncometabolite production, promoting tumorigenesis. AIMS: To examine the prevalence of IDH mutations in a single institution cohort of DDCHS and correlate 2HG levels to mutation status. METHODS AND RESULTS: We examined a series of 21 primary DDCHS using Sanger sequencing and qPCR genotyping to interrogate for IDH1/2 mutations, and evaluated the level of 2HG in formalin-fixed paraffin-embedded (FFPE) tumor and matched normal tissue samples using a fluorometric assay. 76% of DDCHS (16/21) harbored a heterozygous IDH1 or IDH2 mutation. 6/14 IDH-mutated DDCHS showed elevated 2HG in tumor relative to matched normal tissue. There were no consistent histologic or disease specific survival differences between IDH-mutated tumors and wild-type tumors. CONCLUSIONS: Our study confirms the frequent presence of a variety of IDH1 and IDH2 mutation variants, indicating that a sequencing-based approach is required for DDCHS if IDH is to be used as a diagnostic marker. Similar to other IDH-mutated tumor types, IDH-mutated DDCHS also show elevated 2HG level, indicating that the oncometabolite activity of 2HG may contribute to DDCHS oncogenesis and progression. SN - 1365-2559 UR - https://www.unboundmedicine.com/medline/citation/31609487/Characterization_of_IDH1/IDH2_Mutation_and_D-2-Hydroxyglutarate_Oncometabolite_Level_in_Dedifferentiated_Chondrosarcoma L2 - https://doi.org/10.1111/his.14018 DB - PRIME DP - Unbound Medicine ER -