Abstract 1275P
Background
Factors involved in non-small cell lung cancer (NSCLC) recurrence remain to be elucidated. Previous studies have revealed that the premalignant process in the small bronchi distant from the tumor is associated with NSCLC progression: patients with basal cell hyperplasia (BCH) more often have distant metastases, whereas patients with BCH combined with squamous metaplasia (SM) predominantly show locoregional relapses. The molecular mechanisms of this association are still not understood. Here, we aimed to assess the mutational landscape of NSCLC in patients with different premalignant bronchial lesions.
Methods
The study included 38 (58.8±8.6 years old) patients with NSCLC (T1-4N0-3M0): 22 cases with isolated BCH and 16 cases with the presence of BCH and SM (BCH+SM). Premalignant lesions were identified in hematoxylin and eosin-stained sections of formalin-fixed paraffin-embedded samples of small bronchi distant (3-5 cm) from the tumor. Tumor samples were sequenced on a NextSeq 500 (Illumina) using SureSelect XT Human All Exon v7 kit (Agilent). Data were analyzed using the GATK pipeline, and genetic variants were annotated using the ANNOVAR tool.
Results
Functional mutations were 1.3 times higher in NSCLC patients with BCH and SM than in cases with BCH. Among patients with BCH, mutations were 1.3 times more frequent in metastatic tumors than in non-metastatic tumors. The most frequently mutated gene in both patient groups was TP53; however, stop-gain mutations of exon 10 that affect protein folding were detected only in BCH+SM cases. Also, all patients harbored mutations in common drivers of carcinogenesis (LRP1B, KEAP1, FAT3, KMT2D, etc.). Nevertheless, ARID1A and NF1 genes were mutated only in BCH cases, whereas RET, STK11, and PBRM1 mutations were detected in BCH+SM patients. Moreover, BCH patients more often harbored mutations in cell movement and adhesion genes (DNAH9, NRXN1, FREM3, and RELN), while BCH+SM cases frequently had mutated genes involved in cell polarity, proliferation, and apoptosis (FMN2, PKHD1, and PRKCB1).
Conclusions
Thus, the mutational landscape of NSCLC is different between patients with BCH and BCH+SM. This study was funded by the Russian Science Foundation (grant #20-75-10060).
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Cancer Research Institute, Tomsk National Research Medical Center.
Funding
Russian Science Foundation (grant #20-75-10060).
Disclosure
All authors have declared no conflicts of interest.