In:
Cancer Medicine, Wiley, Vol. 9, No. 12 ( 2020-06), p. 4386-4394
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2045-7634
,
2045-7634
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2659751-2
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