Clinical Validation of Coexisting Activating Mutations Within EGFR, Mitogen-Activated Protein Kinase, and Phosphatidylinositol 3-Kinase Pathways in Lung Cancers

Marchi, Federico De; Haley, Lisa; Fryer, Henderson; Ibrahim, Junaid; Beierl, Katie; Zheng, Gang; Gocke, Christopher D.; Eshleman, James R.; Belchis, Deborah A.; Illei, Peter B.; Lin, Ming Tseh

doi:10.5858/arpa.2017-0495-oa

Cited by 15 publications

(10 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…26 These trunk drivers are usually mutually exclusive, although rare cases with coexisting EGFR and KRAS mutations have been reported. 27 In contrast, TP53 and PIK3CA mutations are branching drivers and can be seen in BRAF-, EFGR-, or KRAS-mutated lung adenocarcinomas. In a total of 25 IDH1/2-mutated lung adenocarcinomas reported by Toth et al, TCGA, MSK-IMPACT, and this study, known trunk F I G U R E 4 Correlation of variant allele frequency (VAF).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Akt1 mutation is rare in lung cancer with a total reported frequency of 0.6–5.5%, and studies to date have found that the E17K mutation is mainly expressed in the lung epithelium and that the mutation may be present only in squamous cell carcinoma in non-small cell lung cancer (Bleeker et al, 2008 ; Do et al, 2008 ; Kim et al, 2008 ; Malanga et al, 2008 ; Rekhtman et al, 2012 ; De Marco et al, 2015 ; De Marchi et al, 2019 ). The AKT1(E17K) mutation promotes migration and invasion of human lung epithelial cells, enhancing their oncogenic and metastatic potential (De Marco et al, 2015 ).…”

Section: The Effects Of Akt E17k Mutation Across Various Tumorsmentioning

confidence: 99%

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

Chen

Huang

Dong

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The substitution of the seventeenth amino acid glutamate by lysine in the homologous structural domain of the Akt1 gene pleckstrin is a somatic cellular mutation found in breast, colorectal, and ovarian cancers, named p. Glu17Lys or E17K. In recent years, a growing number of studies have suggested that this mutation may play a unique role in the development of tumors. In this review article, we describe how AKT1(E17K) mutations stimulate downstream signals that cause cells to emerge transformed; we explore the differential regulation and function of E17K in different physiological and pathological settings; and we also describe the phenomenon that E17K impedes tumor growth by interfering with growth-promoting and chemotherapy-resistant AKT1 low QCC generation, an intriguing finding that mutants may prolong tumor patient survival by activating feedback mechanisms and disrupting transcription. This review is intended to provide a better understanding of the role of AKT1(E17K) in cancer and to inform the development of AKT1(E17K)-based antitumor strategies.

show abstract

“…Unexpectedly, ALK patients had a low OS, perhaps due to the unavailability of TKIs as first-line treatment at the beginning of the study and to the coexistence of KRAS mutation in three of the nine ALK patients. This occurrence is rare, but it has already been reported as being associated with primary resistance to TKIs [32,33]. The expected co-occurrence of TP53 mutations with KRAS, EGFR, BRAF , PIK3CA , and STK11 were also identified.…”

Section: Discussionmentioning

confidence: 78%

Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation

Fernandes

Jacob

Martins

et al. 2019

Cancers

View full text Add to dashboard Cite

Identification of targetable molecular changes is essential for selecting appropriate treatment in patients with advanced lung adenocarcinoma. Methods: In this study, a Sanger sequencing plus Fluorescence In Situ Hybridization (FISH) sequential approach was compared with a Next-Generation Sequencing (NGS)-based approach for the detection of actionable genomic mutations in an experimental cohort (EC) of 117 patients with advanced lung adenocarcinoma. Its applicability was assessed in small biopsies and cytology specimens previously tested for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status, comparing the molecular changes identified and the impact on clinical outcomes. Subsequently, an NGS-based approach was applied and tested in an implementation cohort (IC) in clinical practice. Using Sanger and FISH, patients were classified as EGFR-mutated (n = 22, 18.8%), ALK-mutated (n = 9, 7.7%), and unclassifiable (UC) (n = 86, 73.5%). Retesting the EC with NGS led to the identification of at least one gene variant in 56 (47.9%) patients, totaling 68 variants among all samples. Still, in the EC, combining NGS plus FISH for ALK, patients were classified as 23 (19.7%) EGFR; 20 (17.1%) KRAS; five (4.3%) B-Raf proto-oncogene (BRAF); one (0.9%) Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2); one (0.9%) STK11; one (0.9%) TP53, and nine (7.7%) ALK mutated. Only 57 (48.7%) remained genomically UC, reducing the UC rate by 24.8%. Fourteen (12.0%) patients presented synchronous alterations. Concordance between NGS and Sanger for EGFR status was very high (κ = 0.972; 99.1%). In the IC, a combined DNA and RNA NGS panel was used in 123 patients. Genomic variants were found in 79 (64.2%). In addition, eight (6.3%) EML4-ALK, four (3.1%), KIF5B-RET, four (3.1%) CD74-ROS1, one (0.8%) TPM3-NTRK translocations and three (2.4%) exon 14 skipping MET Proto-Oncogene (MET) mutations were detected, and 36% were treatable alterations. Conclusions: This study supports the use of NGS as the first-line test for genomic profiling of patients with advanced lung adenocarcinoma.

show abstract

Clinical Validation of Coexisting Activating Mutations Within EGFR, Mitogen-Activated Protein Kinase, and Phosphatidylinositol 3-Kinase Pathways in Lung Cancers

Cited by 15 publications

References 50 publications

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

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

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation

Contact Info

Product

Resources

About