Roberta Losi Guembarovski

Background: Urothelial bladder carcinoma (UBC) is the ninth most common malignancy worldwide and ranks thirteenth in cancer-related mortality. A significant challenge in managing non-muscle-invasive UBC (NMIBC) is the high recurrence rate, compounded by a paucity of robust prognostic biomarkers. Given that evasion of apoptosis is a hallmark of carcinogenesis, the apoptosis regulator BCL-2 oncogene plays a critical role by negatively regulating the intrinsic apoptotic pathway, often leading to protein overexpression and malignant cell immortalization. Methods and Results: This study evaluated the BCL-2 allelic variants rs2279115 (G > T) and rs3943258 (T > C), including their haplotype structures, in association with BCL-2 immunohistochemical expression in UBC patients. Genetic and immunostaining data were analyzed alongside prognostic factors, environmental exposure, and clinical history. Furthermore, we sought to exhibit BCL-2 immunohistochemical staining patterns via immunofluorescence in selected samples. Our findings revealed that the rs2279115 variant is significantly associated with BCL-2 positive expression. Specifically, the TT genotype in the genotypic model ( p = 0.035) and the GT genotype in the overdominant model ( p = 0.045) were linked to protein status. Additionally, the CT haplotype was independently associated with high-grade tumors. Conclusions: The presence of the CT haplotype — in either homozygosity or heterozygosity — exerted a risk effect of high-grade ( p = 0.020). In conclusion, these findings suggest that BCL-2 variants, haplotype structures, and immunohistochemical expression may offer relevant insights into the molecular characteristics of urothelial bladder cancer. Further prospective validation is needed to determine whether BCL-2 profiling can serve as a useful complementary tool for risk assessment in clinical practice.

Prostate cancer (PCa) remains a highly prevalent malignancy and a leading cause of cancer-related mortality, frequently attributed to late-stage diagnosis. Matrix metalloproteinase 14 (MMP14) and Decorin (DCN) are key extracellular matrix (ECM) components essential for tissue remodeling and tumor suppression. This study evaluated the immunohistochemical expression of MMP14 and DCN in relation to clinicopathological parameters in PCa tissue samples ( n = 92), specifically examining the malignant epithelium, adjacent non-tumor tissue, and peritumoral stroma. High MMP14 expression in tumor cells was predominant in metastatic patients and significantly associated with the presence of metastases ( p = 0.012), with overexpression observed in 60% of these cases. Conversely, diminished DCN staining in the peritumoral ECM was linked to metastatic disease (63% low expression). Furthermore, a significant correlation was identified between low stromal DCN expression and ISUP grades 4–5 ( p = 0.047; 66% of high-grade cases). Multivariate analysis confirmed that MMP14 expression profile serves as an independent predictor of metastasis ( p = 0.01). In conclusion, our findings suggest that ECM remodeling, driven by dysregulation of MMP14 and DCN, plays a pivotal role in PCa progression, highlighting their potential as prognostic biomarkers for patient stratification and therapeutic guidance.

Background: Urothelial Bladder Cancer (UBC) remains a significant clinical challenge due to its high morbidity, substantial economic burden, and high recurrence rates. E-cadherin, an important regulator of cell-cell adhesion encoded by the CDH1 gene, is frequently downregulated during malignant progression, serving as a hallmark of invasiveness. This study explored the prognostic significance of CDH1 genetic variants (rs16260 C > A and rs7186053 A > G) and haplotypes, while integrating bioinformatic profiling of repetitive elements. Methods and results: A cohort of 334 UBC patients was genotyped via qPCR, followed by haplotype reconstruction and association with clinical outcomes. This analysis was complemented by immunofluorescence to illustrate the interplay between tissue invasion levels and CDH1 genetic backgrounds in selected samples. Bioinformatic tools characterized the CDH1 genomic repeat elements landscape. The rs16260 heterozygous genotype was significantly associated with a reduced risk of 1-year recurrence ( p < 0.05). Moreover, the CG haplotype emerged as a protective factor against recurrence within two years. Illustrative immunofluorescence analysis confirmed the loss of E-cadherin and epithelial disorganization in muscle-invasive samples compared to non-invasive tumors. Notably, bioinformatic screening revealed a complex architecture of repetitive elements, including novel Alu insertions within Exon 16, indicating potential regulatory hubs. Conclusion: Our findings demonstrate that CDH1 polymorphisms and haplotype structures are potential modulators of UBC recurrence. Furthermore, the identification of repetitive elements in crucial genomic segments highlights a new layer of transcriptional regulation, offering promising approaches for the prognostic stratification and molecular targeting of bladder cancer.

Cellular responses to DNA damage play a crucial role in carcinogenesis, particularly in environmentally related cancers such as bladder cancer (BC). This is the ninth most frequently occurring cancer globally and most frequent in the urinary system. Polymorphic variants in genes encoding DNA repair proteins may interfere with their expression and/or activity. Consequently, modulation in an individual's gene response to exposure might occur resulting in greater susceptibility and lower survival rates in BC. Taking this into account, the study evaluated associations of single-nucleotide polymorphisms (SNPs) in base excision repair genes (XRCC1 rs25487 and OGG1 rs1052133) with BC susceptibility and prognosis. A total of 274 cases and 274 controls, matched on gender, age, and smoking status, were genotyped using DNA from peripheral blood. In susceptibility analyses, individuals with a family history of cancer who carried at least one reference allele (rs1052133, CC + CG) exhibited an increased risk of BC occurrence. For XRCC1, the TT + CC genotypes were associated with elevated risk for BC among pesticide-exposed individuals. Regarding prognosis, the rs1052133 CC genotype was associated with an enhanced risk of recurrence among smokers and female patients. Bioinformatic analyses indicated significantly higher expression of XRCC1 and OGG1 in bladder tissue and marked elevation in expression in tumors. These results suggest that gene-environment interaction might modulate risk of BC occurrence and subsequent prognosis.

COVID-19 continues to spread six years after its discovery. Cancer patients are at an increased risk of severe outcomes, likely due to immunosuppression and tumor-related dysregulation. Programmed cell death protein 1 (PD-1), encoded by the PDCD1 gene, is a critical immune checkpoint involved in T-cell regulation. Since genetic polymorphisms can influence immune responses and individual susceptibility to SARS-CoV-2 infection, this case–control study aimed to investigate the association between the PDCD1 rs41386349 polymorphism and COVID-19 severity in individuals with and without cancer. This study included 279 COVID-19-positive and 160 negative individuals, genotyped by qPCR. COVID-19- positive cancer patients were significantly more likely to develop moderate (OR = 13.6) and severe (OR > 200) disease compared to cancer-negative individuals. No association was observed between the PDCD1 polymorphism and SARS-CoV-2 infection or disease severity, even after adjusting for cancer status, age and sex. However, age and sex were independently associated with severe outcomes: each additional year of age increased the odds of severe disease by 5.3%, and male patients had a three times higher risk of severe COVID-19. These findings confirm that cancer, male sex and older age are major predictors of worse prognosis in COVID-19, while the rs41386349 polymorphism alone does not appear to influence susceptibility or disease progression.

High-risk Human Papillomavirus (HPV) infection is the main etiological factor for cervical carcinogenesis, although genetic cofactors also play a role. Single-nucleotide variants (SNVs) in the CTLA4 gene can alter the gene expression and immune response against HPV, influencing cervical malignancy progression. This study analyzed the association of the alleles, genotypes, and haplotypes of the CTLA4 SNVs rs5742909 (−318 C>T), rs231775 (+49 A>G), and rs3087243 (+6230 G>A) with HPV infection, the development of low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and cervical cancer in 445 women treated by the public health service of Paraná, Brazil. Peripheral blood and cervical secretion samples were collected for genomic DNA extraction, CTLA4 SNV genotyping, and HPV detection via PCR. Statistical analyses used p < 0.05. The HPV-negative control group included 181 women, while the HPV-positive group included 264 women. The HPV-positive group was divided into no lesion (n = 84), LSILs (n = 19), HSILs (n = 56), and cervical cancer (n = 105). The T allele of −318 C>T and the TAG haplotype were associated with increased susceptibility to HPV infection, HSILs, and cervical cancer. These findings suggest that the T allele of −318 C>T and the TAG haplotype may serve as potential molecular biomarkers for HPV susceptibility and worse prognosis.

The programmed cell death protein 1 (PD-1), expressed mainly by T lymphocytes, is an important checkpoint of the immune response and may contribute to tumorigenesis when associated with its ligands, PD-L1 or PD-L2, expressed by tumor cells. In this context, this study aimed to analyze the allelic variants rs11568821 G > A and rs41386349 C > T of the PDCD1 gene in breast cancer (BC) patients and cancer-free women and correlate them with clinical-pathological parameters. DNA extraction was performed from peripheral blood samples, and the PDCD1 genotyping was carried out by the polymerase chain reaction technique followed by enzymatic restriction. The fragments were separated by acrylamide gel electrophoresis for genotyping. In this case–control association study, it was found that carriers of the A allele of the PDCD1 rs11568821 G > A genetic polymorphism have a higher risk of developing BC (OR = 2.42; CI 95% = 1.59–3.69; P < 0.001). This polymorphism was also correlated with positivity for estrogen (τ = 0.25; P < 0.001) and progesterone receptors (τ = 0.17; P = 0.021). The haplotypic analysis also indicated that AC allele carriers have a higher risk of BC development (OR = 2.41; CI 95% = 1.58–3.69; P < 0.001), specifically luminal A subtype (OR = 3.59; CI 95% = 2.15–5.97; P < 0.001). These results indicate that the PDCD1 rs11568821 G > A polymorphism may contribute as a potential susceptibility and prognosis marker for BC, especially for ER+/PR+ subtypes, considering the importance of PD-1 inhibitor effect over antitumor response.