Dados do Trabalho

Título

Neoadjuvant Therapy Induces Similarity of Transcriptional Profiles between Gastric Adenocarcinoma and Non-cancerous Tissues

Introdução

Gastric Adenocarcinoma (GAC) ranks prominently in cancer-related mortality, displaying diverse geographic incidence. FLOT regimen as standard for locally advanced GAC treatment. However, molecular effects remain unclear and chemoresistance hampers clinical gains. A comprehensive analysis of therapy-related molecular effects is pivotal for improved GC management and survival outcomes. Surpassing messenger RNAs (mRNAs), a distinct class—long non-coding RNAs (lncRNAs)—ascends as master regulators intricate GAC developmental pathways.

Objetivo

We aim to investigate transcriptional changes linked to the FLOT regimen and advance our understanding of lncRNAs' role in GAC biology.

Métodos

Total RNA was extracted from fresh tumor tissues of 24 patients who underwent neoadjuvant FLOT treatment (treated group) and 20 patients who did not receive neoadjuvant therapy (untreated group) - CAAE 47580121.9.0000.5634. For library construction, the TruSeq Stranded Total RNA kit (Illumina®, US) was used and sequenced in pair-end on the NextSeq 500® platform (Illumina®, US). Differential expression analyses were performed using the DESeq2 package. Criteria for differentially expressed (DE) RNAs were|Log2(Fold-Change)|> 1; and adjusted p-value<0.05. Gene ontology (GO) analysis was performed to elucidate mRNA biological roles. Survival analysis was also carried out to investigate the effect of gene expression on overall survival using the Survminer package.

Resultados

In the untreated cohort, we detected 1608 lncRNAs and 5648 mRNAs DE between the tumor and adjacent tissues (ADJ). Among them, 173 lncRNAs and 241 mRNAs exhibited area under the curve (AUC) values >0.8 and >0.85, indicating a tumor-specific expression signature. Interestingly, the treated group showed a more modest number of DE lncRNAs (n=11) and mRNAs (n=344) when comparing tumor and ADJ samples, with only 21 mRNAs showing AUC values >0.85. In addition, it was possible to distinguish the tumor tissues of the treated patients into responder and non-responder groups from the lncRNA and mRNA profiles. Among the three patients who responded to FLOT, 36 DE mRNAs were identified, 26 of which accurately determined the responders (AUC>0.75). The enriched GO terms encompassed processes crucial to tumor progression, including cell death and angiogenesis regulation. In addition, higher expressions of TEX261 and NEURL1 were related to the best overall survival rates (p-value 0.05). Interestingly, patients who responded to FLOT displayed high expressions of these genes. Discriminant Principal Component Analysis also showed that the treated group was closely aligned with the ADJ samples, most notably in the responding patients.

Conclusões

The study highlights the implication of lncRNAs in tumor biology, but further research is needed to comprehensively understand their role. Moreover, it elucidates FLOT neoadjuvant therapy's influence on GAC's transcriptional landscape, yielding a convergence of tumor and non-tumor tissue profiles. This is prominent in patients exhibiting complete or partial pathological responses, offering pivotal insights for unraveling molecular signatures with clinical utility.

Palavras-chave

Neoadjuvant Therapy; Gastric Adenocarcinoma; Transcriptional profiles

Financiador do resumo

Fundação Amazônia de Amparo a Estudos e Pesquisas (convênio
004/2021) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

Área

Estudo Clínico - Tumores do Aparelho Digestivo Alto