Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Adult MeSH
• ErbB Receptors genetics   MeSH
• Papillomavirus Infections MeSH
• Cyclin-Dependent Kinase Inhibitor p16 genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   analysis   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Penile Neoplasms * genetics   mortality   pathology   virology   MeSH
• Prognosis MeSH
• Telomere-Binding Proteins MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Shelterin Complex MeSH
• Carcinoma, Squamous Cell * genetics   mortality   pathology   virology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

• MeSH
• Drug Resistance, Neoplasm * genetics   MeSH
• Adult MeSH
• ErbB Receptors antagonists & inhibitors   MeSH
• PTEN Phosphohydrolase genetics   MeSH
• GTP Phosphohydrolases genetics   MeSH
• Protein Kinase Inhibitors * therapeutic use   MeSH
• Colorectal Neoplasms * genetics   drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Pilot Projects MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Chronic bronchitis is increasingly reported as a healthcare challenge in clinical settings partially due to the disease's bad prognosis and unresponsiveness to therapy, including the ineffectiveness of glucocorticoids. The ineffectiveness could have a link with genetic polymorphism of receptor genes resulting in inappropriate glucocorticoid pharmacodynamics. We sought to identify the role of gene polymorphism in the response of patients with chronic bronchitis to prednisolone therapy. To do so, a total of 60 newly diagnosed chronic bronchitis patients enrolled in the present study. Prednisolone at a dose of 30mg/day for two weeks was given and respiratory parameters [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were measured before and after therapy. Blood samples were withdrawn for genetic profiling of genes involved in glucocorticoids pharmacodynamics, including BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) measured for their homozygous versus heterozygous gene splice variants.Results: Gene splice variants for BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) homozygous (73.3%, 98.7%, and 95%) represented a higher percentage than heterozygous (26.7%, 1.7%, and 5%). The respiratory parameters FEV1, FVC, and FEV1/FVC have shown significantly (p<0.05) better values at baseline in homozygous versus heterozygous, correspondingly, the responsiveness to therapy has shown significantly (p<0.05) better values in homozygous versus heterozygous.Conclusion: The study has provided a good template for genetic behaviour toward individualised medicine in our locality providing that these genes could be a cornerstone for discovering issues related to the pharmacodynamics profiling of drugs in clinical settings.

• MeSH
• Bronchitis, Chronic * diagnosis   genetics   MeSH
• Glucocorticoids pharmacology   MeSH
• Humans MeSH
• Polymerase Chain Reaction methods   MeSH
• Polymorphism, Genetic genetics   MeSH
• Prednisolone pharmacology   therapeutic use   MeSH
• Protein Isoforms genetics   MeSH
• Receptors, Glucocorticoid * genetics   drug effects   MeSH
• Respiratory Function Tests methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Clinical Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.

• MeSH
• Hypoglycemic Agents * pharmacology   MeSH
• Humans MeSH
• Metabolic Reprogramming MeSH
• Mitochondria metabolism   drug effects   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * metabolism   drug therapy   pathology   MeSH
• Pioglitazone * pharmacology   MeSH
• Cell Movement drug effects   MeSH
• PPAR gamma * agonists   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

• MeSH
• DNA-Binding Proteins MeSH
• Epigenesis, Genetic * genetics   MeSH
• Epigenome * genetics   MeSH
• Carcinoma, Renal Cell * genetics   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosome Mapping methods   MeSH
• DNA Methylation * genetics   MeSH
• Von Hippel-Lindau Tumor Suppressor Protein genetics   MeSH
• Kidney Neoplasms * genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Transcription Factors MeSH
• DNA Copy Number Variations * genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

We present here the co-expressed protein-protein interactions algorithm. In addition to minimizing correlation-causality imbalance and contextualizing protein-protein interactions to the investigated systems, it combines protein-protein interactions and protein co-expression networks to identify differentially correlated functional modules. To test the algorithm, we processed a set of proteomic profiles from different brain regions of controls and subjects affected by idiopathic Parkinson's disease or carrying a GBA1 mutation. Its robustness was supported by the extraction of functional modules, related to translation and mitochondria, whose involvement in Parkinson's disease pathogenesis is well documented. Furthermore, the selection of hubs and bottlenecks from the weightedprotein-protein interactions networks provided molecular clues consistent with the Parkinson pathophysiology. Of note, like quantification, the algorithm revealed less variations when comparing disease groups than when comparing diseased and controls. However, correlation and quantification results showed low overlap, suggesting the complementarity of these measures. An observation that opens the way to a new investigation strategy that takes into account not only protein expression, but also the level of coordination among proteins that cooperate to perform a given function.

• MeSH
• Algorithms * MeSH
• Glucosylceramidase genetics   metabolism   MeSH
• Humans MeSH
• Protein Interaction Mapping * methods   MeSH
• Protein Interaction Maps MeSH
• Brain metabolism   MeSH
• Parkinson Disease * metabolism   genetics   physiopathology   MeSH
• Proteomics methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. METHODS: In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. RESULTS: Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR. CONCLUSIONS: These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.

• Publication type
• Journal Article MeSH

The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts correlated with both transcripts and protein levels of inflammatory and HIF-regulated genes, including hemoglobin. While overexpression of the AS-NFKB1 variant led to increased expression of inflammatory and HIF-targeted genes; under inflammatory stress, NF-kB protein translocation to the nucleus was attenuated, resulting in reduced expression of these genes. Our study reveals AS-NFKB1 splicing events correlating with increased hemoglobin in Aymara and their possible protective mechanisms against excessive inflammation.

• MeSH
• Alternative Splicing * genetics   MeSH
• Adult MeSH
• Exons genetics   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Granulocytes metabolism   MeSH
• Hemoglobins * metabolism   genetics   MeSH
• Humans MeSH
• Quantitative Trait Loci MeSH
• NF-kappa B p50 Subunit * metabolism   genetics   MeSH
• Gene Expression Regulation MeSH
• Transcriptome MeSH
• Inflammation * genetics   metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Bolivia MeSH

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.

• MeSH
• Carcinoma, Adenoid Cystic * genetics   pathology   MeSH
• Adult MeSH
• Phenotype MeSH
• Gene Fusion MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Genetic Predisposition to Disease MeSH
• In Situ Hybridization, Fluorescence * MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Biomarkers, Tumor * genetics   MeSH
• Paranasal Sinus Neoplasms * genetics   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• NFI Transcription Factors genetics   MeSH
• High-Throughput Nucleotide Sequencing * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Gliomas are the most common and lethal forms of malignant brain tumors. We attempted to identify the role of the aging-suppressor Klotho gene and Klotho protein in the immunopathogenesis of gliomas. We examined Klotho genetic variants by PCR-RFLP and measured serum Klotho levels using the ELISA method. We found a statistically significantly increased frequency of rs1207568A allele and rs1207568 GA genotypes in co-dominant, dominant and over-dominant models in grade IV as compared to grade II and III glioma patients. The levels of soluble α Klotho (sαKL) were significantly lower in grade III and IV glioma patients than in healthy controls (p = 0.034; 0.0083). Patients with sαKL levels above 2500 pg/mL survived significantly longer than patients with sαKL below 2500 pg/mL (p = 0.038). We also found a positive correlation of the serum levels of sαKL with seven biomarkers, like angiogenic vascular endothelial growth factor (p = 0.0008), chemokine fractalkine (p = 0.0009), interferon γ (p = 0.003), glial derived neurotrophic factor (p = 0.0268), pro-inflammatory and pro-Th1 cytokine IL-6 (p = 0.0347), anti-inflammatory, pro-Th2 cytokines IL-4 (p = 0.0037) and IL-13 (p = 0.0004). Our results suggest the impact of Klotho genetic variants and Klotho levels on advanced-grade glioma.

• MeSH
• Cytokines * blood   genetics   MeSH
• Adult MeSH
• Genotype MeSH
• Glioma * genetics   blood   mortality   pathology   MeSH
• Glucuronidase * blood   genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor blood   genetics   MeSH
• Brain Neoplasms * genetics   blood   mortality   pathology   MeSH
• Klotho Proteins * MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Neoplasm Grading * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH