FLOT neoadjuvant therapy turns the expression patterns of cancer cells similar to those of non-cancer cells in gastric cancer patients.

Abstract

e16056 Background: FLOT perioperative have emerged as a new standard for locally advanced gastric cancer (LAGC). Nevertheless, the molecular consequences of such therapy remain obscure. Aiming to investigate changes in the tumor transcriptional landscape in LAGC patients treated with FLOT, a comprehensive analysis of messenger RNA (mRNAs) and long noncoding RNA (lncRNAs) expression was developed using next-generation sequencing (NGS). Methods: Paired tumor and non-tumor fresh samples, including 17 patients with intestinal-type LAGC submitted to neoadjuvant FLOT treatment (treated group) and 13 who did not receive neoadjuvant therapy (untreated group), were sequenced and compared. Differential expression analyses were performed using the DESeq2 package. Criteria for differentially expressed (DE) lncRNAs and mRNAs were|Log2(Fold-Change)| > 2; and adjusted p-value < 0.05. In silico analyses were adopted to identify DE lncRNAs with transcription factors (TFs) and RNA-binding proteins (RPBs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene ontology (GO) was also performed to elucidate these target proteins’ and mRNAs biological’s roles. Results: In tumor samples from the untreated group, 4443 mRNAs and 961 lncRNAs DE were found, in which 293 mRNAs and 148 lncRNAs accurately discriminated (the area under the curve ROC > 0.9) tumor and non-tumor tissues. Only 265 mRNAs and 29 lncRNAs DE were detected in treated patients, indicating that neoadjuvant therapy led to changes in expression patterns, making tumor tissues similar to non-tumor tissues. Subsequent analyzes identified that non-tumor tissues (treated vs. untreated) showed similar expression profiles. Among tumor samples, 34 mRNAs and 54 lncRNAs DE were found, in which 7 mRNAs and 16 lncRNAs can discriminate between treated and untreated tumors, indicating the effect of neoadjuvant treatment is predominant in the tumor. GO evaluation of genes was significant for 83 terms for biological process. The most annotated terms were the regulation of catalytic activity. We also observed that DE lncRNAs interact with TFs and RBPs were enriched in related cancer development and progression pathways, including transcriptional dysregulation and cellular senescence. Conclusions: Despite the need for further validation to better understand the transcriptional landscape related to neoadjuvant treatment, the present study highlights the functional relevance of lncRNAs in tumor biology and, mainly, shed light on the molecular effects of FLOT neoadjuvant treatment, that might help to guide future investigations aiming to establish personalized management of GC.