Search Results (502)

This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved. Full article

Breast cancer is a heterogeneous disease composed of various biologically distinct subtypes, each characterized by unique molecular features. Its formation and progression involve a complex, multistep process that includes the accumulation of numerous genetic and epigenetic alterations. Although integrating RNA-seq transcriptome data with ATAC-seq epigenetic information provides a more comprehensive understanding of gene regulation and its impact across different conditions, no classification model has yet been developed for breast cancer intrinsic subtypes based on such integrative analyses. In this study, we employed machine learning algorithms to predict intrinsic subtypes through the integrative analysis of ATAC-seq and RNA-seq data. We identified 10 signature genes (CDH3, ERBB2, TYMS, GREB1, OSR1, MYBL2, FAM83D, ESR1, FOXC1, and NAT1) using recursive feature elimination with cross-validation (RFECV) and a support vector machine (SVM) based on SHAP (SHapley Additive exPlanations) feature importance. Furthermore, we found that these genes were primarily associated with immune responses, hormone signaling, cancer progression, and cellular proliferation. Full article

Background: Colorectal cancer, a prevalent gastrointestinal carcinoma, has a high risk for recurrence when locally advanced and remains lethal when in an advanced stage. Prognostic biomarkers may help in better delineating the aggressiveness of this disease in individual patients and help to tailor appropriate therapies. CDX2, a transcription factor of gastrointestinal differentiation, has been proposed as a biomarker for good outcomes and could also be a marker of specific sub-types amenable to targeted therapies. Methods: Colorectal cancers from The Cancer Genome Atlas (TCGA) colorectal cohort and colon cancers from the Sidra-LUMC AC-ICAM cohort were categorized according to their expressions of CDX2 mRNA. Groups with CDX2 suppression were compared with cancers showing no suppression regarding their clinical and genomic characteristics. Results: CDX2-suppressed colorectal cancers showed a high prevalence of Microsatellite Instability (MSI) and a lower prevalence of chromosomal Instability (CIN) compared to non-CDX2-suppressed cancers. In addition, CDX2-suppressed cancers had a higher prevalence of mutations in several receptor tyrosine kinase genes, including EGFR, ERBB3, ERBB4, RET, and ROS1. In contrast, CDX2-suppressed cancers displayed lower mutation frequencies than non-CDX2-suppressed cancers in the genes encoding for the two most frequently mutated tumor suppressors, APC and TP53, and the most frequently mutated colorectal cancer oncogene, KRAS. However, CDX2-suppressed colorectal cancers had a higher prevalence of mutations in alternative genes of the WNT/APC/β-catenin and KRAS/BRAF/MEK pathways. In addition, they showed frequent mutations in DNA damage response (DDR) genes, such as BRCA2 and ATM. Conclusion: CDX2-suppressed colorectal cancers constitute a genomically distinct subset of colon and rectal cancers that have a lower prevalence of KRAS, APC, and TP53 mutations, but a high prevalence of mutations in less commonly mutated colorectal cancer genes. These alterations could serve as targets for personalized therapeutics in this subset. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most diagnosed cancer globally. Radiotherapy is a common treatment strategy for patients but factors such as gene expressions and molecular mechanism effects may affect tumor radioresponse. The aim of this review is to systematically identify genes suggested to have molecular mechanism effects on the radioresponsiveness of CRC patients. Methods: By following the PRISMA guidelines, a comprehensive literature search was conducted on Pubmed, EMBASE and Cochrane Library. After exclusion and inclusion criteria sorting and critical appraisal for study quality, data were extracted from seven studies. A gene set analysis was conducted on reported genes. Results: From the seven studies, 56 genes were found to have an effect on CRC radioresponsiveness. Gene set analysis show that out of these 56 genes, 24 genes have roles in pathways which could affect cancer radioresponse. These are AKT1, APC, ATM, BRAF, CDKN2A, CTNNB1, EGFR, ERBB2, FLT3, KRAS, MET, mTOR, MYC, NFKB1, KRAS, PDGFRA, PIK3CA, PTEN, PTGS1, PTGS2, RAF1, RET, SMAD4 and TP53. The current project was conducted between the period May 2024 to August 2024. Conclusions: The current review systematically presented 56 genes which have been reported to be related to RT or CRT treatment effectiveness in rectal cancer patients. Gene set analysis shows that nearly half of the genes were involved in apoptosis, DNA damage response and repair, inflammation and cancer metabolism molecular pathways that could affect cancer radioresponse. The gene cohort identified in this study may be used as a foundation for future works focusing on the molecular mechanism of specific pathways contributing to the radioresponse of CRC. Full article

Background: Urothelial carcinoma presents as non-muscle-invasive bladder cancer (NMIBC) in ~75% of primary cases. Addressing the limitations of the TNM and WHO04/16 classification systems, this study investigates genetic alterations, the mitotic activity index (MAI), and immunohistochemistry (IHC) markers CK20, p53, and CD25 as better prognostic biomarkers in NMIBC. Methods: Using the Oncomine™ Focus Assay for targeted next-generation sequencing (NGS), 409 single-nucleotide variations (SNVs) and 193 copy number variations (CNVs) were identified across 287 patients with TaT1 tumors. Results: FGFR3 and PIK3CA alterations were significantly more prevalent in Ta tumors, while T1 tumors had significant ERBB2 alterations. Low-grade (LG) tumors were enriched with FGFR3 alterations, while high-grade (HG) tumors were significantly associated with ERBB2 alterations, as well as FGFR1 and CCND1 amplifications. FGFR3 alterations were linked to shorter recurrence-free survival (RFS; p = 0.033) but improved progression-free survival (PFS; p < 0.001). Conversely, ERBB2 alterations (p < 0.001), ERBB3 mutations (p = 0.044), and both MYC (p < 0.001) and MYCN (p = 0.011) amplifications were associated with shorter PFS. Survival analysis of gene sets revealed inverse associations between PIK3CA and ERBB2 (p = 0.003), as well as PIK3CA and MYC (p = 0.005), with PFS. Conclusions: In multivariate Cox regression, MAI was the strongest predictor for PFS. Integrating genetic alterations and histopathological features may improve risk stratification in NMIBC. Full article

Background: Patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (mBC) generally receive hormonal therapy (HT) combined with CDK4/6 inhibitors (CDK4/6i). Despite this treatment, resistance mechanisms to CDK4/6i emerge and the majority of these patients experience disease progression (PD). This highlight the necessity to uncover the resistance mechanism to CDK4/6i through the identification of specific biomarkers. The primary objective is to assess the accuracy and feasibility of a novel multi-gene target panel NGS assay on circulating tumor DNA (ctDNA) to detect molecular alterations of AKT1, ERBB2, ESR1, KRAS, PIK3CA, and TP53 genes in women with BC undergoing HT plus CDK4/6i treatment. Secondarily, the study aims to explore the relationship between genomic profiling and clinical outcomes. Materials and Methods: Plasma samples were collected from 16 patients diagnosed with advanced/locally advanced HR+/HER2- BC at 2 time points: T0 (baseline) and at T1 (3 months after CDK4/6i treatment). Starting from 2 mL of plasma, ctDNA was isolated and libraries were set up using the Plasma-SeqSensei (PQS)^® Breast Cancer IVD Kit, sequenced on Nextseq 550 and analyzed using the Plasma-SeqSensei™ IVD Software^®. Results: Among the five patients who presented PD, three had PIK3CA mutations and, of these, two showed a higher mutant allele frequency (MAF) at T1. In three patients with stable disease and in eight patients with partial response, the MAF of the detected alterations decreased dramatically or disappeared during CDK4/6i treatment. Conclusions: Based on our findings, the liquid biopsy analysis using the PQS panel seems to be both feasible and accurate, demonstrating a strong sensitivity in detecting mutations. This exploratory analysis of the clinical outcome associated to the mutational status of patients highlights the potential of molecular analysis on liquid biopsy for disease monitoring, although further validation with a larger patient cohort is necessary to confirm these preliminary observations. Full article

Background: In pigs, a hair whorl refers to hairs that form a ring of growth around the direction of the hair follicle at the dorsal hip. In China, a hair whorl is considered a negative trait that affects marketing, and no studies have been conducted to demonstrate whether hair whorl affects pig performance and provide an explanation for its genetic basis. Methods: Performance-measured traits and slaughter-measured traits of hair whorl and non-hair whorl pigs were differentially analyzed, followed by genome-wide association analysis (GWAS) and copy number variation (CNV) methods to investigate the genetic basis of hair whorl in pigs. Results: Differential analysis of 2625 pigs (171 hair whorl and 2454 non-hair whorl) for performance measures showed that hair whorl and non-hair whorl pigs differed significantly (p < 0.05) in traits such as live births, total litter size, and healthy litter size (p < 0.05), while differential analysis of carcass and meat quality traits showed a significant difference only in the 45 min pH (p = 0.0265). GWAS identified 4 SNP loci significantly associated with the hair whorl trait, 2 of which reached genome-significant levels, and 23 candidate genes were obtained by annotation with the Ensembl database. KEGG and GO enrichment analyses showed that these genes were mainly enriched in the ErbB signaling, endothelial apoptosis regulation, and cell proliferation pathways. In addition, CNV analysis identified 652 differential genes between hair whorl and non-hair whorl pigs, which were mainly involved in the signal transduction, transcription factor activity, and nuclear and cytoplasmic-related pathways. Conclusions: The candidate genes and copy number variation differences identified in this study provide a new theoretical basis for pig breeding efforts. Full article

Human epidermal growth factor receptor 2 (HER2) is a major driver of disease progression, treatment resistance, and worse survival for patients with various types of cancers, including prostate cancer. However, key bench studies and clinical trials have failed to evaluate the role of HER2 in prostate cancer using racially diverse experimental designs and protocols. This lack of diversity represents what has been the status quo of cancer research in the United States for decades. In the case of prostate cancer, homogenic study designs are problematic as Black men are much more likely to be diagnosed and die from aggressive and incurable forms of the disease. Therefore, the strategic inclusion of biospecimens collected from Black patients as well as the recruitment and enrollment of Black men into prostate cancer clinical trials is necessary to comprehensively evaluate genetic and molecular factors that contribute to variable outcomes in this high-risk population. Additionally, a higher prevalence of HER2 expression in Black men was recently reported in a small cohort of prostate cancer patients and may contribute to worsened prognosis. In this review, we carefully consider the role of HER2 in prostate cancer while, for the first time, taking into account the influences of race and genetic ancestry. Full article

Background: Feline mammary carcinoma (FMC) is a prevalent and fatal carcinoma that predominantly affects unspayed female cats. FMC is the third most common carcinoma in cats but is still underrepresented in research. Current diagnosis methods include physical examinations, imaging tests, and fine-needle aspiration. The diagnosis through these methods is sometimes delayed and unreliable, leading to increased chances of mortality. Objectives: The objective of this study was to identify the biomarkers, including blood metabolites and genes, related to feline mammary carcinoma, study their relationships, and develop a machine learning (ML) model for the early diagnosis of the disease. Methods: We analyzed the blood metabolites of felines with mammary carcinoma using the pathway analysis feature in MetaboAnalyst software, v. 5.0. We utilized machine-learning (ML) methods to recognize FMC using the blood metabolites of sick patients. Results: The metabolic pathways that were elucidated to be associated with this disease include alanine, aspartate and glutamate metabolism, Glutamine and glutamate metabolism, Arginine biosynthesis, and Glycerophospholipid metabolism. Furthermore, we also elucidated several genes that play a significant role in the development of FMC, such as ERBB2, PDGFA, EGFR, FLT4, ERBB3, FIGF, PDGFC, PDGFB through STRINGdb, a database of known and predicted protein-protein interactions, and MetaboAnalyst 5.0. The best-performing ML model was able to predict metabolite class with an accuracy of 85.11%. Conclusion: Our findings demonstrate that the identification of the biomarkers associated with FMC and the affected metabolic pathways can aid in the early diagnosis of feline mammary carcinoma. Full article

The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody–drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs. Full article

HER2-low tumors have shown promise in response to antibody–drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group’s clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes (ERBB2, GRB7 and MIEN1), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer. Full article

Breast cancer is one of the most common forms of neoplasia worldwide. The purpose of our observational study was to evaluate the status of HER2 overexpression among new cases of breast neoplasia with an impact on the natural history of breast cancer disease and therapeutic personalization according to staging. This study included 45 breast cancer patients which have an overexpression of HER2 through the mutation of the EGFR-ERBB2 receptor. Immunohistochemical staining was performed on sections of formalin-fixed paraffin-embedded breast tissue. The patients were evaluated demographically and therapeutically in all stages. The post-surgical histopathological examination revealed complete pathological responses in 19 patients and pathological responses with residual disease either at the tumor level or lymphatic or both variants in a percentage of 44% (15 cases). The disease-free interval (DFI) under anti-HER2 therapy was recorded in 41 patients, representing 91% of the study group. Anti-HER2 therapy in any therapeutic stage has shown increased efficiency in blocking these tyrosine kinase receptors, evidenced by the high percentage of complete pathological responses, as well as the considerable percentage (47%) of complete remissions and stationary disease, in relation to the HER2-positive patient group. Full article

Causal networks are important for understanding disease signaling alterations. To reveal the network pathways affected in the epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to the poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) were analyzed. The network pathways in GC were analyzed using Ingenuity Pathway Analysis (IPA). The analysis of the probe sets in which the gene expression had significant differences between diffuse- and intestinal-type GC in RNA sequencing of the publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of EMT regulation via the growth factors pathway, the coronavirus pathogenesis pathway, and vorinostat. The network had RNA–RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-223, mir-25, mir-27, mir-29, and mir-34. The molecular networks revealed in the study may lead to identifying drug targets for GC. Full article

Hirschsprung’s disease (HSCR, incidence 1/5000 live births) is caused by the failure of neural crest-derived precursors to migrate, survive, proliferate, or differentiate during the embryonic development of the Enteric Nervous System (ENS), which could be disrupted by many factors, including inflammatory processes. The NF-κB family controls several biological processes, including inflammation, neurogenesis, and cell migration. With the aim of studying the potential role of NF-κB in HSCR, we have analyzed the expression of the NF-κB main subunits and other NF-κB-related genes by RT-qPCR in HSCR tissue samples (sub-divided into ganglionic and aganglionic segments). We found decreased gene expression of the NF-κB main subunit RELA but also of NFKBIA, TNFA, TFGBR2, and ERBB3 in the pathologic distal aganglionic segments compared to the proximal ganglionic segments. Moreover, we could also confirm the lower protein expression of RelA/p65 in the aganglionic distal segments by immunofluorescence staining. Further, we show that the expression of RelA/p65 protein in the proximal segments concurs with lymphocyte infiltration in the bowel tissue, indicating a pro-inflammatory activation of p65 in the proximal ganglionic HSCR tissue in the patients analyzed. All in all, our findings suggest that the modulation of NF-κB signaling in the neuro-enteric system does obviously contribute to the pathological effects of HSCR. Full article

Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials. Full article