IDH1 and IDH2 mutations in lung adenocarcinomas: Evidences of subclonal evolution

Research output: Contribution to journalArticle

Abstract

Background: Selective IDH1 and IDH2 inhibitors have been approved for targeted therapy of acute myeloid leukemia. Clinical trials for solid tumors with IDH1 and IDH2 (IDH1/2) mutations are ongoing. Reports of IDH1/2-mutated non–small cell lung cancers (NSCLCs), however, are limited. Methods: We evaluated IDH1/2 mutations in 1,924 NSCLC specimens (92% adenocarcinoma) using a next-generation sequencing assay. Results: Retrospective quality assessments identified false detection of IDH1 c.395G>A (p.R132H) resulting from cytosine deamination (C:G→T:A) artifact in one specimen. IDH1/2 mutations were detected in 9 (0.5%) adenocarcinomas taken by fine-needle aspiration (n = 3), thoracentesis (n = 2) or core biopsy (n = 4). All nine adenocarcinomas showed high-grade features. Extensive clear cell change, however, was not observed. High expression (50% or greater) of PD-L1 was observed in two of five specimens examined. IDH1/2 mutations were associated with old age, smoking history, and coexisting KRAS mutation. Lower than expected variant allele frequency of IDH1/2 mutants and coexistence of IDH1/2 mutations with known trunk drivers in the BRAF, EGFR, and KRAS genes suggest they could be branching drivers leading to subclonal evolution in lung adenocarcinomas. Multiregional analysis of an adenocarcinoma harboring two IDH2 mutations revealed parallel evolution originating from a KRAS-mutated lineage, further supporting subclonal evolution promoted by IDH1/2 mutations. Conclusions: IDH1/2 mutations in NSCLCs are uncommon. They occur in adenocarcinomas with high-grade features and may be branching drivers leading to subclonal evolution. Accumulation of more IDH1/2-mutated NSCLCs is needed to clarify their clinicopathological characteristics and implications for targeted therapy.

Original languageEnglish (US)
Pages (from-to)4386-4394
Number of pages9
JournalCancer medicine
Volume9
Issue number12
DOIs
StatePublished - Jun 1 2020

Keywords

  • IDH1
  • IDH2
  • cytosine deamination
  • lung cancers
  • parallel evolution

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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