Biology subjects

Pinto, J. B. A.

Publications and source records attributed to Pinto, J. B. A..

6 recordsLinked to original sources

bioRxiv2025

Transcriptional Signatures of Field Cancerization in Gastric Cancer

The high rate of local recurrence in gastric adenocarcinoma (GA) suggests that carcinogenesis is not a focal event but a field-wide process. This phenomenon, known as "field cancerization," posits that histologically normal peritumoral tissue is, in fact, a pre-neoplastic field harboring incipient molecular alterations that confound genomic studies using it as a normal control. To overcome this limitation, we performed a three-way comparative transcriptomic analysis of tumor, peritumoral, and true-normal gastric tissues using a deep learning framework. We identified a stable 138-gene signature established within the peritumoral field and conserved in the tumor, which was absent in healthy controls. Within this signature, three key COSMIC-listed driver genes were highlighted: the Hippo pathway component FAT4 and the p53-inhibitor MDM4 were upregulated, while the EMT-suppressor NDRG1 was repressed. Co-expression analysis revealed a dynamic rewiring of these drivers, with a significant positive correlation between FAT4 and MDM4 emerging exclusively in the peritumoral field. In contrast, a negative correlation between FAT4 and NDRG1 was observed specifically in the tumor context. In public cohorts, high expression of FAT4 and MDM4 was significantly associated with poor patient prognosis, whereas NDRG1 showed no prognostic association. Critically, the prognostic power of MDM4 was validated in our local patient cohort. Our findings demonstrate that the peritumoral field is a molecularly distinct state in gastric carcinogenesis, characterized by a metabolic shift, and identify FAT4 and MDM4 as key drivers of this early transition, with significant potential as prognostic biomarkers.

genetics↗

bioRxiv2025

Transcriptomic Mutational Profiling of Gastric Adenocarcinoma in Northern Brazil

Gastric cancer (GC) remains among the neoplasms with the worst prognosis, partly due to its biological heterogeneity and the scarcity of robust biomarkers. The characterization of mutational profiles from transcripts can reveal specific tumor signatures and point to therapeutic targets. This study investigated the landscape of mutations expressed in 102 samples of gastric adenocarcinoma from northern Brazil, which were sequenced using NGS. Readings were aligned to the reference genome using STAR (two-pass mode), and variants were called with GATK and VarDict. Annotations and impact predictions were generated using VEP, SIFT, and PolyPhen. We identified >90,000 variants; among the most frequently mutated genes, FTH1 stood out. The mutational profile was described using maftools, and signatures were inferred with MutationalPatterns. We observed a predominant distribution of SNVs, with C>T transitions as the most common event, in addition to patterns compatible with signatures related to replication damage and DNA repair. To mitigate biases inherent to RNA-seq, we applied filters for coverage, strand bias, and RNA editing hotspots. Together, the data outline a regional landscape of mutations expressed in GC and reinforce the usefulness of the transcriptome for prioritizing biomarkers and functional hypotheses that may guide genomic validations and subsequent clinical studies.

bioinformatics↗

bioRxiv2025

Integrated Expression Analysis of C-MYC Oncogene-Associated Pathways in Gastric Adenocarcinoma and its Correlation with Clinicopathological Factors

BackgroundThe C-MYC oncogene is a well-established driver of gastric carcinogenesis, yet the integrated expression pattern of its complex regulatory network and its clinical implications in gastric adenocarcinoma (GAC) remain to be fully elucidated. This study aimed to perform an integrated bioinformatic analysis of C-MYC and its associated pathways in a cohort of GAC patients to delineate its expression profile, assess its potential as a biomarker, and correlate its patterns with clinicopathological factors such as Lauren classification and neoadjuvant treatment status. MethodsThe study included transcriptome data from 74 GAC tumor samples and 68 normal gastric tissue samples. Following RNA sequencing, a comprehensive bioinformatic analysis was conducted on a curated list of 21 C-MYC-associated genes. The methodology included differential expression analysis (DESeq2), unsupervised hierarchical clustering, Principal Component Analysis (PCA), and Receiver Operating Characteristic (ROC) curve analysis to evaluate diagnostic performance. Gene expression levels were also statistically correlated with Lauren histological subtypes and neoadjuvant therapy status using the Wilcoxon rank-sum test. ResultsThe analysis revealed a profound dysregulation of the C-MYC network in GAC. While MYC itself was significantly upregulated, its transcriptional antagonists, particularly MXD4 and MXD3, were the most significantly downregulated genes. This gene signature robustly separated tumor from normal tissues in both hierarchical clustering and PCA. ROC analysis demonstrated the outstanding diagnostic potential of several genes, with MXD4 achieving a perfect Area Under the Curve (AUC) of 1.00, surpassing the diagnostic value of MYC (AUC=0.86). Stratification by Lauren classification showed that MYC and its stability regulator PTBP1 were significantly more expressed in the intestinal subtype, whereas the repressors MXD3 and MXI1 were higher in the diffuse subtype. No significant expression differences were observed based on neoadjuvant treatment status. ConclusionGastric adenocarcinoma is characterized by a coordinated dysregulation of the C-MYC network, marked by both oncogene activation and a concurrent loss of its key transcriptional repressors. The profound downregulation of antagonists like MXD4 serves as an exceptionally accurate molecular signature for GAC, suggesting its potential as a diagnostic biomarker superior to MYC alone. The divergent expression patterns between Lauren subtypes highlight distinct molecular pathobiology and may have implications for targeted therapies

genetics↗

bioRxiv2025

Viral Landscape of Gastric Adenocarcinoma Reveals Clinically Relevant Viruses

BackgroundGastric cancer (GC) ranks among the most common and lethal cancers worldwide, with poor prognosis mainly due to late diagnosis. Accumulating evidence highlights the role of the gastric microbiome in carcinogenesis through inflammation, genomic instability, and immune modulation. Unlike the bacterial component, the gastric virome remains largely unexplored despite its potential contribution to tumor development. The present study aimed to characterize the virome present in tumor and peritumoral tissues from patients with GC. Materials and Methods105 tumor and 85 peritumoral gastric tissues were analyzed. RNA was extracted, libraries were prepared, and sequencing was performed on the Illumina NextSeq 500. Viral reads were classified with Kraken2. Taxonomic profiles, viral abundance and diversity metrics were computed in R, with group differences assessed by Wilcoxon tests and PERMANOVA (p < 0.05). ResultsIn this study, 38 viral orders and 329 viral genera were identified in gastric tumor and peritumoral tissues. Tumor tissues harbored 210 viral genera, including 109 exclusive to this microenvironment, with bacteriophages comprising the majority, alongside human-infecting and other eukaryotic viruses. Lymphocryptovirus, Cytomegalovirus, and Alphapapillomavirus were enriched in tumors. Alpha and beta diversity analyses revealed no significant differences between tumor and peritumoral tissues, indicating comparable viral richness and composition. ConclusionThese findings underscore the complexity of the gastric virome and provide a foundation for future investigations into the interactions and mechanisms through which the viral community could influence the development of gastric cancer, highlighting its potential role in gastric health and disease.

genetics↗

bioRxiv2025

Characterization of Human Endogenous Retroviruses in Gastric Cancer with Helicobacter pylori: A Study from Northern Brazil

Human endogenous retroviruses (HERVs) are retroelements that have integrated their genetic material into the human genome, accumulating mutations over time and accounting for approximately 8% of the genome. Under abnormal deregulation conditions, these elements can be expressed and contribute to the development of diseases, such as gastric cancer. This malignancy may be associated with infections, including those caused by Helicobacter pylori. However, the scientific literature does not yet provide clear evidence regarding the relationship between HERVs and H. pylori in the context of gastric cancer. Thus, HERVs may represent potential biomarkers for this neoplasm, as well as possible therapeutic targets. This study aimed to characterize HERV expression in gastric cancer using next-generation sequencing (NGS). We analyzed 46 tumor tissue samples and 42 peritumoral tissue samples from patients diagnosed with gastric adenocarcinoma, collected at HUJBB and Ophir Loyola hospitals. Among the tumor samples, 38 tested positive for H. pylori infection. For library preparation, 1 g of total RNA per sample was used, with integrity assessed via TapeStation ([~]260 bp band). cDNA libraries were sequenced using the Illumina NextSeq 500 platform (paired-end), following the ID Output V2 kit protocol. Alignment was performed with STAR software, and HERVs were identified and quantified using Telescope. Differential expression analysis of HERVs was performed on transcript data using DESeq2. A total of 183 HERVs were found to be differentially expressed in tumor tissues compared to adjacent tissues. In tumor samples associated with H. pylori infection, 44 HERVs showed differential expression. Overall, tumor tissues exhibited higher HERV transcription compared to adjacent tissues.

genetics↗

bioRxiv2025

Immune Remodeling and Dysbiosis May Distinguish the Microenvironments of Gastric Adenocarcinoma and Peritumoral Tissue

The gastric tumor microenvironment is dynamically shaped by the interactions between the local microbiota and the host immune system, although the functional integration of these elements remains incompletely understood. In this study, we characterized microbial diversity, immune cell composition, and immune-related gene expression profiles in samples of gastric adenocarcinoma (GAC) and adjacent peritumoral tissue (PTT), aiming to elucidate their functional organization. A total of 106 samples of 75 patients were analyzed using bulk RNA-Seq expression profiling, immune deconvolution, and bacterial taxonomic reconstruction. While alpha diversity remained preserved between GAC and PTT, distinct compositional differences emerged: GAC was enriched with Pseudomonadota, Enterobacteriaceae, and Escherichia, whereas PTT exhibited a predominance of Helicobacteraceae and Helicobacter. Immune deconvolution revealed an expansion of cancer-associated fibroblasts (CAFs) and mast cells in GAC, correlated with higher expression levels of TGFB1 and FOXP3, while neutrophils and B cells predominated in PTT. Integrated analysis demonstrated that GAC formed dense and cohesive networks connecting pro-inflammatory bacteria, activated immune cells, and inflammatory genes such as IL1B, CXCL8, and IFNG. In contrast, PTT exhibited dispersed networks and negative correlations, suggesting a less structured, tolerogenic environment. Our findings indicate that gastric cancer progression involves not only compositional shifts in microbiota and immune cells but also the active construction of functionally integrated inflammatory networks, providing new insights into potential therapeutic targets at the microbiome-immune interface.

genetics↗