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Anastasia A. Schegoleva
MA04 - Models and Biomarkers (ID 122)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Montse Sanchez-Cespedes, Kwok-kin Wong
- Coordinates: 9/08/2019, 13:30 - 15:00, Interlaken (1988)
MA04.05 - Deciphering the Molecular Mechanisms Underlying the Progression of Bronchial Premalignant Lesions (Now Available) (ID 2108)
13:30 - 15:00 | Author(s): Anastasia A. Schegoleva
The mechanisms underlying the progression of bronchial lesions to squamous cell lung cancer remain undefined. Previously, we hypothesized that bronchial lesions presented individually or combined with each other in the bronchi of non-small cell lung cancer (NSCLC) patients mirror the different scenarios of the premalignant process: individual basal cell hyperplasia (iBCH) – the stoppage at hyperplasia, BCH plus squamous metaplasia (SM) – the progression of hyperplasia to metaplasia, and SM plus dysplasia – the progression of metaplasia to dysplasia. In this study, we aimed to assess the molecular profile of BCH, SM, and dysplasia depending on their co-occurrence in the bronchi of NSCLC patients and to identify mechanisms that are involved in the different scenarios of the premalignant process.Method
The samples of lung tissue were obtained at a distance of 4-5 cm from the tumor during surgery of 21 NSCLC patients. Normal bronchial epithelium, BCH, and SM, as well as dysplasia, were isolated from tissue sections using laser microdissection PALM (Carl Zeiss). The microdissected samples underwent whole genome (One Step WGA, Bioron) and transcriptome (Ovation PicoSL WTA System V2, Nugen) amplification and sequenced using the SeqCap EZ Human Oncology Panel (Roche) and profiled using SurePrint G3 Human GE v2 8x60K microarrays (Agilent). Additionally, the samples were sequenced using the Pico Methyl-Seq Library Prep Kit (Zymo Research). Changes in gene expression were confirmed using immunohistochemical staining.Result
Genetic alterations were observed already at the early stages of the premalignant process in the bronchial epithelium; however, their number varied from sample to sample. For example, one case of BCH showed more than 10 deleterious mutations in the GRM5, MAML2, SP1, ETV4, and other genes, whereas other BCHs carried single alterations. No significant differences were found in the mutational landscape between the iBCH and BCH combined with SM. Bisulfite sequencing demonstrated significant changes in the methylation status of the SAPCD2 and ST14 genes in BCH. Importantly, these changes differed between various forms of BCH. Sequencing of SM and dysplasia is in progress and results will be presented later. Gene expression profiling showed differences in the activity of immune response genes between the iBCH and BCH combined with SM and the cell cycle and cilium assembly genes between SMs co-presented with BCH and dysplasia. Overall, the transcription profile of SM co-presented with BCH was closer to BCHs, whereas SM co-detected with dysplasia was similar to dysplasia. Several genes were identified to be expressed specifically in different forms of BCH and SM, among which CCDC114, MAP7D2, and LIFR were confirmed by immunohistochemistry. The loss of CCDC114 and MAP7D2 in SM may serve as an indicator of its progression to dysplasia.Conclusion
Taken together, this study demonstrates the significant differences between various types of BCH and SM. These differences support the hypothesis that the isolated and combined forms of the bronchial lesions mirror the different scenarios of the premalignant process as well as explore the mechanisms underlying the progression of hyperplasia and metaplasia to dysplasia.
The study was supported by RFBR (#17-29-06002) and the Russian President Fellowship (#SP-1549.2018.4).
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