Paired genomic analysis of squamous cell carcinoma transformed from EGFR-mutated lung adenocarcinoma

Autor: Youjin Kim, Boram Lee, Sehhoon Park, Jong-Mu Sun, Keunchil Park, Joon Ho Shim, Jin Seok Ahn, Woong-Yang Park, Se-Hoon Lee, Inju Cho, Yoon-La Choi, Myung-Ju Ahn, Joungho Han
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Biopsy
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Gene Frequency
Epidermal growth factor
Positron Emission Tomography Computed Tomography
Osimertinib
Epidermal growth factor receptor
biology
TOR Serine-Threonine Kinases
Genomics
Middle Aged
Immunohistochemistry
Cell Transformation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Adenocarcinoma
Female
Signal Transduction
Pulmonary and Respiratory Medicine
Adult
Nonsense mutation
Adenocarcinoma of Lung
Clonal Evolution
03 medical and health sciences
medicine
PTEN
Humans
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Alleles
Germ-Line Mutation
Aged
business.industry
PTEN Phosphohydrolase
Genetic Variation
Genes
erbB-1
medicine.disease
030104 developmental biology
Mutation
Cancer research
biology.protein
business
Tomography
X-Ray Computed
Proto-Oncogene Proteins c-akt
Zdroj: Lung cancer (Amsterdam, Netherlands). 134
ISSN: 1872-8332
Popis: Objectives Adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transformation (AST) is reported in epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer after tyrosine kinase inhibitor (TKI) failure. However, little is known about the underlying genomic changes during the AST process. Materials and methods We retrospectively reviewed our tissue database collected after first- or second- generation EGFR TKI resistance (n = 263) and identified 3 cases of AST. The additional case was acquired from the osimertinib resistance sample. Deep target sequencing (381 genes) using paired samples from 4 patients with AST after EGFR TKI treatment was performed. The histology of each sample was confirmed by TTF-1 and p63 immunohistochemistry. The patients received first- or second-generation EGFR TKI as an initial treatment. Results Overall incidence of AST was 1.1% (3/263). Transformed SCC acquired genomic alterations related to the PI3K/AKT/mTOR pathway, in addition to the initial EGFR mutation. In a representative case, two separate sub-clones, with a PTEN nonsense mutation and EGFR p.T790 M mutation, were observed without histologic transformation at the time of gefitinib resistance. After subsequent treatment with osimertinib, SCC transformation was observed with the disappearance of the EGFR p.T790 M mutation and acquired copy number loss in PTEN. Adopting the sub-clonal fraction model elucidates the sub-clonal evolution process of the PTEN mutant sub-clone toward AST under the background of EGFR mutation. The rest of the transformed samples also had acquired genomic alterations in PTEN, LKB1, PIK3CA, or RICTOR, which are related to the PI3K/AKT/mTOR pathway. Conclusions Paired genomic analysis from our sample provides early clinical evidence of the ADC to SCC lineage transition that might be provoked by an alteration in the PI3K/AKT/mTOR pathway during EGFR TKI treatment. This finding could potentially broaden the known spectrum of EGFR TKI resistance mechanisms.
Databáze: OpenAIRE
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