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

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.

Identification of Mechanisms of Resistance to ALK Inhibitors. Next-generation sequencing-based liquid biopsy profiling: A step towards personalized treatment.

“…The R149Q mutation in IDH2 is frequent in angioimmunoblastic T-cell lymphoma (27). In NSCLC, IDH1/2 mutations are rarely detected in primary tumors but it has been suggested that they could be branching drivers leading to subclonal evolution, based on the MAFs at which these mutations are detected (28). It is therefore not surprising that we found them upon treatment failure.…”

Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients

“…Simultaneous genomic changes may impact biological behaviors, such as treatment response; thus, the investigation of co-occurring genomic alterations could help to stratify KRAS-mutant lung cancer patients into distinct subgroups with distinctive therapeutic responses [24]. While driver mutations (e.g., mutations in KRAS, EGFR, BRAF) are known to initiate tumor development in lung cancer, secondary mutations may promote subclonal evolution such as mutations in TP53 and PIK3CA, which were previously described in KRAS-, BRAF-, and EGFR-mutant lung tumors [25,26]. Scheffeler and colleagues conducted a study on 4507 NSCLC patients using a NGS panel containing 14 genes, and 53.5% of the mutant KRAS patients had at least one additional mutation, a percentage higher than ours, since KRAS concomitant mutations were observed in eight of 24 mutant samples (33.3%) [27].…”

NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

“…This mutation is also frequent in angioimmunoblastic T-cell lymphoma (32). In NSCLC, IDH1/2 mutations are rarely detected in primary tumors but it has been suggested that they could be branching drivers leading to subclonal evolution, based on the MAFs at which these mutations are detected (33). In this way, Zhao et al described a case of an ALK-positive tumor in which an IDH1 variant was detected upon disease progression (34).…”