Search Results (1,128)

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

The conserved protein SetDB1 has been identified in various vertebrate and invertebrate groups. It plays key roles in vital processes such as germline and nervous system development, immune response, tumorigenesis, cell cycle progression, and others. SetDB1 is initially characterized as an enzyme that methylates lysine 9 on histone H3, leading to gene silencing, which is traditionally considered its primary function. However, SetDB1 also targets about a dozen nuclear, cytoplasmic, and membrane proteins as substrates. Moreover, some functions of SetDB1 do not require methyltransferase activity. Due to its SUMO-interacting motif, Tudor domain, and methyl-binding domains, SetDB1 interacts with a wide range of complexes that regulate protein stability and activity, signal transduction pathways, and chromatin spatial organization. In this review, we aim to expand the classical view of SetDB1 as solely a histone methyltransferase and to highlight the broader diversity of its functions. Full article

Background: Breast cancer susceptibility gene 1 (BRCA1) is a pivotal regulator of DNA repair, and its loss through germline mutations is strongly linked to the development of aggressive breast cancers with characteristic clinical and pathological features. Beyond genetic disruption, epigenetic silencing via promoter hypermethylation has emerged as a non-mutational mechanism of tumour suppressor inactivation and a potential biomarker for guiding therapeutic decisions. Here, we investigate BRCA1 promoter methylation, its impact on gene expression, and its association with clinicopathological features in a cohort of African women with breast cancer. Methods: Matched tumour and adjacent normal tissues from 27 Black African women with breast cancer were analysed for BRCA1 promoter methylation and gene expression using bisulfite pyrosequencing and quantitative real-time PCR. Associations with clinicopathological variables were assessed using Spearman’s correlation analyses. Results: Five CpG sites within the BRCA1 promoter were significantly hypermethylated in breast tumours compared with matched adjacent normal tissues and showed an inverse association with BRCA1 mRNA expression. Elevated promoter methylation was enriched in hormone receptor-negative and triple-negative breast cancer subtypes and was not influenced by neoadjuvant chemotherapy. BRCA1 promoter methylation occurred independently of BRCA1 mutational status. No significant associations were observed between BRCA1 methylation and age, body mass index, smoking status, or alcohol consumption. Conclusions: Our findings provide evidence of BRCA1 epigenetic silencing in breast tumours from African women, particularly within aggressive hormone receptor-negative subtypes. These results suggest that BRCA1 promoter methylation may represent a clinically informative biomarker for patient stratification and highlight the importance of validation in larger, population-representative cohorts before clinical translation. Full article

Background/Objectives: Puerto Rican Hispanic/Latino (PR H/L) men experience a heightened incidence and mortality rate of aggressive forms of prostate cancer. The underlying causes of this increased disease burden likely include a complex interplay of socio-economic and biological factors. This pilot study leveraged the first cancer tissue biobank at a Hispanic-Serving Institution (Puerto Rico BioBank) and aimed to provide an initial description of the genomic features of prostate cancer in 35 PR H/L men. Methods: Whole-exome and RNA sequencing were performed on prostate adenocarcinoma tumor samples to investigate the genomic features associated with prostate cancer. Results: Our analysis suggests that mutation profiles and gene expression pattern differences are observed in this population and may be associated with disease aggressiveness and progression. Notably, mutations in TP53 and TMPRSS2-ERG gene fusions, which are common in broader populations, were less prevalent in the PR H/L cohort. Conclusions: While this study contributes to the understanding of ethnicity-specific genetic factors in prostate cancer, underscoring the need for inclusive genomic studies, continued expansion to larger cohorts of patients under-represented in large genomic studies will be needed to more robustly characterize the full range of genomic features of prostate cancer. A broader understanding of the genomic features of prostate cancer in PR H/L men may lead to future opportunities for delivering more personalized prognoses and treatment options, helping to ensure that treatment advances and better outcomes are available to all patients. Full article

Purpose: Hearing loss (HL) is a prevalent condition significantly impairing quality of life, with genetic mutations accounting for a substantial proportion of congenital cases, notably those involving the GJB2 gene encoding connexin 26. This study aims to analyze the current knowledge, feasibility, and challenges of gene therapy targeting GJB2-related HL, emphasizing both embryonic and postnatal interventions. Methods: A comprehensive scoping review was conducted across electronic databases up to October 2025, including studies focusing on GJB2-associated HL, gene therapy approaches, and the timing of interventions. Data extraction encompassed mutation types, animal models, delivery strategies, outcomes, and ethical considerations. Results: The results indicated over 467 GJB2 variants which could impair cochlear ion homeostasis and development. Animal models, mainly murine, demonstrated early-onset degeneration with limited recovery following delayed gene therapy, while early postnatal intervention showed greater efficacy. Viral vectors like AAV have been employed for targeted gene delivery via cochlear injections, achieving partial restoration of connexin expression and cochlear function, yet they have faced limitations including transduction efficiency, immune responses, and long-term stability. Challenges in translating these findings to humans have been compounded by anatomical, immunological, ethical, and safety issues, particularly regarding embryonic gene therapy and germline modifications. Ethical frameworks can vary internationally, highlighting the necessity for careful regulation. Conclusions: While promising advances in gene therapy for GJB2-related HL have been achieved in preclinical studies, significant scientific, technical, and ethical barriers must be addressed before clinical application, especially during embryogenesis. A multidisciplinary, cautious approach is essential to realize the potential of gene therapy in restoring natural hearing while safeguarding individual and societal interests. Full article

Background: Clinical outcomes for multiple myeloma are highly variable. Inherited genetic variants of immune regulatory genes can modulate disease susceptibility and clinical outcomes. The germline variant CTLA4 rs231775 polymorphism may alter T-cell function and affect clinical outcomes. Methods: We conducted a retrospective single-center study including 156 consecutive myeloma patients who underwent first-line ASCT. The patients were stratified according to the CTLA4 rs231775 genotype and disease stage (ISS I–III). Results: The CTLA4 rs231775 AA genotype was associated with inferior PFS in ISS I–II and superior PFS in ISS III. In the multivariate analysis, the CTLA4 rs231775 AA genotype emerged as a potential risk factor in ISS I-II and a potential protective factor in ISS III. Conclusions: This germline CTLA4 polymorphism may serve as biomarker to refine post-transplant risk stratification and enable personalized treatment management. Full article

PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs initially identified in germline cells as genome guardians that silence transposable elements. Recent studies have expanded this view, revealing that piRNAs and PIWI proteins are broadly expressed in somatic tissues and participate in epigenetic and post-transcriptional gene regulation. This review systematically summarizes piRNA biogenesis and molecular mechanisms, with a focus on their functional diversification from germline to somatic cells. We detail piRNA dysregulation and its association with various human diseases, including cancer, cardiovascular disorders, neurodegenerative diseases, immune dysfunction, and reproductive disorders. By integrating recent findings, this review provides a comprehensive overview of piRNA-mediated regulatory networks and highlights their potential as novel biomarkers and therapeutic targets. Full article

Background: The integration of multi-omics data, such as genomics and transcriptomics, into artificial intelligence models has advanced precision medicine. However, their clinical applicability remains limited due to model complexity. We integrated DNA mutation, RNA expression, and A>I(G) RNA editing data to develop a predictive model for drug response in breast cancer. Methods: We analyzed 104 patients from the Breast Cancer Genome-Guided Therapy Study (ClinicalTrials.gov: NCT02022202). Clinical variables, gene expression, tumor and germline DNA variants, and RNA editing features were integrated into machine learning models to predict therapy response. Generalized linear models (GLM), random forest (RF), and support vector machines (SVM) were trained and evaluated across multiple random 70/30 train-test splits. Feature selection was performed exclusively within the training set using LASSO regularization. Model performance was assessed using the F1-score on independent test sets. The additive effect of RNA editing was evaluated using paired comparisons across identical train/test splits. Results: We characterized the cohort using clinical, mutational, transcriptomic, and RNA editing profiles in 69 non-responders and 35 responders. Across repeated splits, adding RNA editing frequently maintained or modestly improved predictive performance, particularly in expression-based models, with paired analyses showing a statistically significant increase in F1-score. Conclusions: RNA editing represents a complementary molecular layer that can enhance multi-omic models for therapy response prediction in breast cancer, supporting further investigation of epitranscriptomic features in precision oncology. Full article

Papillary thyroid cancer (PTC) is the most common endocrine malignancy with especially high incidence in Middle Eastern populations. While classical hereditary syndromes explain a minority of cases, the broader germline landscape of non-syndromic PTC remains unclear. Whole-exome sequencing was performed on 245 unselected Saudi PTC patients to identify germline pathogenic or likely pathogenic variants (PVs/LPVs) in cancer predisposition genes. Clinical and molecular characteristics, and family history were integrated to assess phenotypic correlations. Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1. Four patients (36.4%) carried PVs/LPVs in canonical FA pathway genes; this increased to five patients (45.5%) when RAD50 was included. Two unrelated patients harbored the same STK11 variant (p.R304Q) without classical Peutz–Jeghers syndrome features. A TP53 hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li–Fraumeni syndrome. Notably, the BRCA1 PV detected matches a known Saudi founder mutation in hereditary breast cancer, now observed in PTC. Most germline positive cases lacked syndromic manifestations, underscoring limitations of phenotype or family history-driven genetic testing strategies. These findings suggest that a small subset of non-syndromic PTC cases may carry germline PVs/LPVs in cancer predisposition genes, highlighting the need for broader genetic screening frameworks. Unbiased whole-exome analysis in unselected cohorts can uncover under-recognized genetic risk and guide screening strategies to address the unique hereditary landscape of thyroid cancer in underrepresented populations. Full article

Background: Glofitamab is a bispecific antibody engaging CD3 on T-cells and CD20 on B-cells. Glofitamab is approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (R/R DLBCL). Lymphocyte-activation gene 3 (LAG3) and T-lymphocyte-associated protein 4 (CTLA4) are immune checkpoint receptors with inhibitory effects on T-cell activity. There are several common germline variants of both receptor genes. Methods: Here, we evaluate clinical outcomes in R/R DLBCL patients treated with glofitamab according to the single-nucleotide polymorphisms LAG3 rs870849 and CTLA4 rs231775. Results: While there was no apparent association of CTLA4 genotype with glofitamab treatment outcomes, significant differences emerged in LAG3 rs870849 carriers with extended progression-free and overall survival in homozygous LAG3 T455, intermediate PFS and OS in heterozygous LAG3 I455T, and short PFS and OS in homozygous LAG3 I455 carriers. Conclusions: LAG3 rs870849 may be a prognostic response marker in R/R DLBCL treated with glofitamab. Full article

Background/Objectives: Acute radiotherapy-induced skin toxicity is a common complication in breast cancer treatment, with marked interindividual variability not fully explained by clinical factors. This study investigated the contribution of germline mutations in DNA repair and tumor suppressor genes to acute radiodermatitis in a homogeneous cohort treated with hypofractionated intensity-modulated radiotherapy with inverse planning, with adjustment for potential lifestyle confounders. Methods: Mutations were grouped into four functional categories: homologous recombination repair (HRR), Fanconi anemia (FA), DNA damage response (DDR), and tumor suppressor (TS) genes. Ordinal logistic regression models adjusted for clinical covariates evaluated pooled and functional category-specific mutation effects. Results: Overall, any mutation significantly increased the risk of higher-grade acute radiodermatitis (OR = 2.24, p = 0.003), an effect driven primarily by HRR and FA mutations, as exclusion of these mutations rendered the association non-significant (OR = 1.785, p = 0.064). Functional category-based analyses showed that HRR (OR = 2.60, p = 0.002) and FA (OR = 2.62, p = 0.002) mutations were the strongest predictors, reflecting overlapping roles in double-strand break and interstrand crosslink repair. DDR and TS mutations showed no significant effect. Conclusions: These results highlight the key role of high-fidelity DNA repair in normal tissue radiosensitivity and demonstrate that functional genetic stratification has diagnostic value as a pre-treatment predictive biomarker framework, enabling identification of patients at increased risk of acute skin toxicity and supporting personalized radiotherapy planning. Full article

This essay offers a philosophical and bioethical upholding of Dignitas Personae §27, which cautions against the use of human gene editing (HGE) for non-therapeutic purposes. After situating the debate within the historical development of gene-editing technologies, the essay classifies enhancement-oriented interventions—physical, behavioral, and cognitive—and argues that such practices risk violating human dignity, diminishing authentic freedom, and promoting a deterministic anthropology. Drawing on a personalist framework, the analysis incorporates insights from neuroscience, genetics, and natural law. In the second part, the essay examines Aristotelian–Thomistic metaphysics, integrating Ernest Mayr’s notion of teleonomy to explain how the rational soul actualizes its perfect operations. It is argued that non-therapeutic HGE, especially germline modifications, may disrupt the ontological structure of the human person by impairing the soul’s expression through properly disposed prime matter. Ultimately, Dignitas Personae stands as a coherent and prescient response to emerging biotechnologies, defending the human person against technocratic reductionism and the ideological drive to transcend our embodied finitude. Full article

Background/Objective: Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. Methods: We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. Results: MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell–matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (ANO4) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in ANO4 was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced ANO4 expression levels in prostate cancer tissues and improved survival in patients with high ANO4 expression levels. Pathway analyses linked low ANO4 expression levels with enhanced cell cycle activity and compromised cell adhesion. Conclusions: Our findings suggest that ANO4 may act as a mediator of MEHP-associated prostate cancer progression and support a gene–environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease. Full article

Objectives: This study aimed to fill the data gap regarding the prevalence of germline (g) BRCA1/2 mutations in patients with metastatic breast cancer (mBC) in France. Methods: A prospective gBRCA1/BRCA2 mutation analysis was proposed to all patients with mBC treated in seven French centers between 19 February and 30 November 2015. The BRCA TrueTM test (Pathway Genomics^®, San Diego, CA, USA) analyzed the coding and flanking regions of BRCA1 and BRCA2 genes using next-generation sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification. Results: Among 407 included mBC patients, 11 (2.7%) carried pathogenic gBRCA1/2 mutations. Of these, five (45%) would not have met standard criteria for genetic screening. Compared with non-carriers, gBRCA1/2 carriers were significantly younger at mBC diagnosis (47.5 vs. 60.7 years, p = 0.0006), had higher-grade tumor histology (p = 0.044), and had a higher rate of contralateral recurrence (36.4% vs. 11.6%, p = 0.035), with comparable adjusted survival (median overall survival 74.9 vs. 100.1 months, p = 0.97). Variants of uncertain significance were identified in 17 (4.2%) patients. Conclusions: The 2.7% prevalence of gBRCA1/2 mutations in this prospective French mBC cohort was relatively low. Nearly half of the mutation carriers would not have been routinely referred for oncogenetic counseling, underscoring the potential value of broader genetic screening in this population. Full article

Paired box (PAX) genes encode a family of nine transcription factors that function as master regulators of embryogenesis, organogenesis, and lineage specification. Their tightly regulated spatial and temporal expression is essential for the development of multiple organ systems, including the central nervous system, eyes, kidneys, immune system, musculoskeletal system, and endocrine organs. Germline mutations of PAX genes result in a broad and often pleiotropic spectrum of human disease, reflecting the developmental programs governed by each family member. Pathogenic variants in PAX genes underlie diverse congenital disorders such as aniridia (PAX6), renal coloboma syndrome (PAX2), otofaciocervical syndrome with immunodeficiency (PAX1), Waardenburg syndrome (PAX3), maturity-onset diabetes of the young (PAX4), and tooth agenesis (PAX9). These conditions frequently demonstrate variable expressivity, incomplete penetrance, and overlapping phenotypes, which make it challenging to be clinically recognized. Beyond embryogenesis and embryologic development, emerging evidence indicates that several PAX proteins remain active in postnatal tissue maintenance, adult stem cell regulation, immune function, and regenerative responses (particularly PAX7 in skeletal muscle satellite cells and PAX5 in B-cell homeostasis), further expanding their clinical relevance. This review provides a synopsis of the major, clinically relevant, germline PAX gene mutations, emphasizing genotype–phenotype correlations, developmental mechanisms, and disease classification across the organ systems. By integrating molecular genetics with human pathology, we highlight the diagnostic implications of PAX genes as central determinants of congenital disease and provide a framework for understanding how alterations in the developmental transcriptional networks translate into human pathology. Full article