Search Results (1,862)

Background/Objectives: Several trials have highlighted the importance of PARP inhibitors (PARPi) in the treatment of BRCA-associated breast cancers (BC), initiating changes in practice. However, data on the real-life outcomes of PARPi therapy is limited. In this study, we characterized the clinical characteristics and outcomes of patients with advanced BC and germline BRCA pathogenic variants (PVs) who received PARPi therapy. Methods: We conducted a retrospective single-institution cohort study of patients with advanced BC and germline BRCA1/2 PVs treated with PARPi. Outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Survival was estimated using Kaplan–Meier methods, and prognostic factors were evaluated using Cox regression analysis. Results: Of the 107 patients treated with PARPi, 48 (44.9%) and 59 (55.1%) had BRCA1 and BRCA2 PVs, respectively. Ninety-seven patients (90.7%) had invasive ductal carcinoma and 42 (39.3%) had triple-negative BC. Nineteen (17.8%) patients had de novo metastatic BC. Sixty-two (57.9%) patients received at least one line of systemic therapy before PARPi; 24 (22.4%) patients received prior platinum. ORR was 62.6%, and the median duration of response (DoR) was 7 months (range, 2.1–96.2). The median PFS was 9 months (95% CI, 6.9–10.5) and median OS was 25.8 months (95% CI, 18.7–31.5). In multivariable models for PFS, bone metastases (HR = 2.25; 95% CI, 1.40–3.61; p = 0.0008) and lung metastases (HR = 2.40; 95% CI, 1.45–3.98; p = 0.0007) were independently associated with increased risk of progression or death. In multivariable models for OS, brain metastases (HR = 3.54; 95% CI, 1.59–7.90; p = 0.0020), bone metastases (HR = 2.22; 95% CI, 1.27–3.88; p = 0.0050), and lung metastases (HR = 2.38; 95% CI, 1.38–4.11; p = 0.0018), were independently associated with increased risk of death. Conclusions: The clinical outcomes of our real-world patients are similar to those reported in previous clinical trials. In addition, metastatic site distribution was independently prognostic for survival outcomes and may support baseline risk stratification at the time of PARPi initiation. Further studies of predictive markers of response and resistance, as well as sequencing with platinums and combinations with other targeted agents, are needed to optimize the benefits of PARPi in this patient population. Full article

Endometrial cancer (EC) is the sixth most common cancer in women. Its overall incidence has increased by 132% over the past 30 years, reflecting an increase in the prevalence of risk factors. The mortality rate decreased by 15% in the last 30 years, despite the high number of endometrial cancer-related deaths occurring world-wide. An inverse relationship has been observed between the incidence of EC, mortality and socio-economic status: more patients living in low-income countries die from EC because they do not have access to timely and effective treatment. About 80% of EC cases are diagnosed in an early stage and have a good prognosis. However, about 20% of cases present in advanced stages and are characterized by a poor prognosis. The molecular classification proposed by The Cancer Genome Atlas (TGCA) and its surrogate for clinical use allowed the adoption of personalized treatments. The assessment of the status of the MMR has revolutionized the treatment of advanced ECs, leading to significant results both in terms of PFS and OS. In this review we will focus on MMR deficiency (dMMR)/microsatellite instability-hypermutated (MSI-H) tumors, which globally account for 20–30% of ECs. The dMMR group encompasses multiple etiologies, including sporadic defects in MMR genes, germline mutations, and hypermethylation of the MLH1 promoter. Currently, the combination of immunotherapy (I-O) with standard chemotherapy has become the new standard first-line treatment for dMMR advanced or recurrent ECs. Although the main clinical trials involving patients with MMRd/MSI-H ECs treated with I-O and chemotherapy have demonstrated efficacy and long-term control of the disease, a significant number of patients do not respond to treatment (intrinsic or primary resistance) and others develop progression during treatment (acquired or secondary resistance). In this narrative approach the biological and molecular bases of these tumors have been integrated with recent advances involving diagnostic techniques, therapeutic opportunities and the genomic and phenotypical alterations underpinning the mechanisms of resistance. Special attention was given to the need for robust, clinically affordable biomarkers to promptly identify responders and non-responders to the current treatment regimens. Full article

Background: Many studies evaluating central nervous system (CNS) metastases in breast cancer (BC) combine germline BRCA1 and BRCA2 pathogenic variant carriers, limiting gene-specific interpretation. We evaluated gene-specific overall survival (OS) after CNS metastasis and time to CNS involvement. Methods: We retrospectively identified BC patients with confirmed CNS metastases (1995–2022) from the Medical University of Vienna and the kConFab consortium. Germline status was classified as gBRCA1 PV, gBRCA2 PV, or non-carrier. Primary endpoint was OS from CNS metastasis diagnosis; secondary endpoint was CNS metastasis-free interval from primary BC diagnosis. Kaplan–Meier/log-rank tests were used for group comparisons. Multivariable Cox models assessed OS in complete cases, stratified by molecular subtype and adjusted for prognostic factors. Sensitivity analyses included subtype-adjusted and time-period models. Results: Among 115 patients (gBRCA1 n = 32, gBRCA2 n = 18, and non-carriers n = 65), median OS differed by germline status (p = 0.019): 20.0 months (95% CI 6.7–60.0) for gBRCA2 versus 7.1 months (95% CI 3.7–10.0) for gBRCA1 and 7.6 months (95% CI 3.4–12.0) for non-carriers. In subtype-stratified analyses, gBRCA1 showed similar mortality to non-carriers (HR 0.90, 95% CI 0.49–1.64, p = 0.730), while gBRCA2 showed a lower but non-significant hazard (HR 0.48, 95% CI 0.18–1.25, p = 0.131). Median CNS metastasis-free interval was longer for gBRCA2 (8.4 years) versus gBRCA1 (3.0 years) and non-carriers (3.1 years; p = 0.020). Sensitivity analyses were consistent. Conclusions: gBRCA2 carriers demonstrated longer unadjusted OS after CNS metastasis and a longer CNS metastasis-free interval compared with gBRCA1 carriers and non-carriers. However, these associations were attenuated and not statistically significant after adjustment, and should therefore be interpreted as hypothesis-generating. These findings supports further investigation of gene-specific CNS disease trajectories in larger cohorts. Full article

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

Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal central nervous system malignancy occurring predominately in infants and toddlers. Spinal AT/RT (spAT/RT) cases are even more limited, and as a result, little is known regarding prognostic factors and optimal treatment regimens. Molecularly, AT/RT is divided into three groups: AT/RT-SHH, AT/RT-TYR and AT/RT-MYC. spAT/RT is predominantly of the MYC subtype. Additionally, a third of patients with AT/RT have a germline Rhabdoid Tumor Predisposition Syndrome (RTPS) that increases the likelihood of developing additional rhabdoid tumors, including renal rhabdoid tumors. Due to the rarity of these tumors, there is a lack of consensus on treatment strategies to be employed. This review paper details the published literature on spAT/RT, with particular emphasis on the recent advances in understanding the biology of these aggressive tumors and currently available therapeutic options, and highlights the challenges associated with the management of this extremely rare condition. Full article

Early-onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50 years, is increasing globally and is frequently characterized by aggressive biology and a disproportionate burden of liver metastases. This review synthesizes emerging evidence on the distinct molecular, immunologic and clinical features that differentiate EOCRC liver metastases from those arising in older adults. Genomic studies revealed increased chromosomal instability, increased copy number variation burden and unique amplification patterns involving MYC, RAD21, GNAS and MAPK1, alongside altered frequencies of classical driver mutations and increased germline predisposition. EOCRC liver metastases also exhibit a progenitor-like transcriptional state and an immune-cold microenvironment marked by reduced myeloid infiltration, impaired antigen presentation and profound resistance to immunotherapy, particularly in microsatellite-stable disease. Mechanistic insights into ferroptosis highlight therapeutic vulnerabilities, especially in PIK3CA-mutant tumors, where aspirin and ferroptosis inducers show synergistic potential. Clinically, high-risk EOCRC patients often present with left-sided primary tumors, synchronous metastases, adverse histology, elevated CEA levels and a hereditary predisposition, with prognostic models incorporating these variables outperforming traditional staging. Collectively, accumulating evidence suggests that EOCRC liver metastases may represent a biologically and clinically distinct entity, although ongoing debates regarding the extent of this distinction underscore the need for age-specific molecular profiling and prospectively validated therapeutic strategies. Full article

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D₁-like receptor family (D₁R and D₅R) and the D₂-like receptor family (D₂R, D₃R, and D₄R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension. 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: Contralateral breast cancer (CBC) is a significant concern among breast cancer survivors, particularly in those with moderator-high penetrance germline mutations such as BRCA1, BRCA2, CHEK2, and ATM. While radiotherapy (RT) is a crucial component of breast cancer (BC) treatment, its potential role in increasing CBC risk remains unclear. This systematic review and meta-analysis aim to evaluate the incidence of radiation-induced CBC in germline mutation carriers. Methods: Following PRISMA guidelines, we conducted a comprehensive search in six electronic databases (PubMed, Scopus, Cochrane Library, ProQuest, EBSCO, and Epistemonikos) for studies published fifteen years prior, up to August 2025. We included cohort and case–control studies assessing the association between RT and CBC incidence in germline mutation carriers. A meta-analysis was performed using a random-effects model to estimate cumulative risk (CR) and rate ratios (RR). Results: Seven studies were included. The 5-year cumulative risk (CR) of contralateral breast cancer (CBC) was 0.55 for BRCA1/2, 0.89 for ATM, and 0.80 for CHEK2 carriers. At 10 years, overall CR increased to 0.65, with ATM and CHEK2 remaining high. Rate ratio (RR) analysis showed a significant risk for ATM (2.98), while overall RR indicated more than a two-fold increased CBC risk with radiotherapy (RR = 2.70 common-effect; 2.53 random-effects). Conclusions: Radiotherapy significantly increases contralateral breast cancer risk, particularly in ATM and CHEK2 carriers, emphasizing the importance of personalized genetic risk stratification in treatment decisions. 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

Human endogenous retroviruses (HERVs), remnants of ancient germline infections, constitute ~8% of the human genome. Although mostly silenced, these elements can be expressed and play physiological or pathological roles. We investigated HERV expression dynamics, proviral load, and systemic inflammatory status in young and older adults, as well as the impact of regular physical exercise. PBMC and serum samples were collected from 30 young controls (YC), 30 inactive older adults (INAC) and 30 regularly exercising older adults (REG). Expression of HERV-W, -K, -H, Syncytin-1 and -2 was assessed by qPCR using the −2ΔΔCt method, and proviral load (HERV-W, -K, -H) was estimated by relative copy number. Serum cytokines (IL-1β, IL-6, IL-17, TNF-α, IFN-γ, IL-10) were quantified by ELISA. Statistical significance was set at p < 0.05. INAC participants showed higher proviral load of HERV-K, -W and -H compared to YC (p = 0.025), but overall lower HERV expression, except for HERV-K. REG presented increased expression of HERV-W (~1.5-fold, p < 0.0001), HERV-H (~1.8-fold, p < 0.0001; higher than YC p = 0.01), HERV-K (vs. YC p = 0.02) and Syncytin-1 (~1.4-fold vs. INAC and YC, p < 0.01). HERV-K was the most upregulated element in INAC. HERV-W and HERV-H expression were strongly correlated in all groups. INAC showed a pro-inflammatory profile, with elevated IL-6/IL-10, IL-1β/IL-10, and IFN-γ/IL-10 ratios. Older adults exhibit higher HERV proviral load, suggesting possible age-related insertions. Regular physical exercise modulates HERV expression, whereas inactivity is associated with reduced expression and increased inflammation. HERV-W and HERV-H maintain coordinated expression across ages, indicating interplay between inflammatory balance, aging, and retroviral activity. 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: Precision oncology has traditionally relied on genomic biomarkers to guide therapy selection; however, static molecular profiling often fails to predict real-world responses to cytotoxic chemotherapy. Increasing evidence suggests that treatment outcomes are determined by the interaction between tumor-intrinsic biology and host-specific pharmacology. Functional ex vivo platforms, including patient-derived organoids and tumor slice cultures, provide a complementary phenotypic readout of drug sensitivity that reflects tumor architecture and microenvironmental interactions. Methods: This narrative review integrates recent experimental, translational, and clinical evidence on molecular oncodiagnostics combining tumor transcriptomics, germline pharmacogenetics, and ex vivo drug sensitivity testing. Relevant literature was identified through targeted searches of major biomedical databases, focusing on studies describing multi-omic predictive models, functional precision oncology platforms, and patient-derived tumor models. Results: Converging data indicate that integrated oncodiagnostic strategies can improve prediction of chemotherapy response beyond genomics-only approaches. Transcriptomic profiling captures dynamic pathway activity and resistance programs, pharmacogenetic testing informs host-specific toxicity and dosing constraints, and ex vivo assays enable direct phenotypic validation of drug efficacy. Together, these complementary approaches provide a biologically grounded framework for individualized therapy selection. Conclusions: The convergence of molecular profiling and functional phenotyping represents an emerging paradigm in precision oncology. Integrating multi-omic and functional data may enhance treatment prediction and reduce ineffective therapy, although prospective validation and standardization remain necessary for routine clinical implementation. Full article

Background/Objectives: Thoracic aortic aneurysms have long been associated with germline mutations such as FBN1, TGFBR2, and COL3A1, which predispose to Marfan, Loeys–Dietz, and Ehlers–Danlos syndromes, respectively. However, recent research has identified a correlation between the JAK2 V617F somatic mutation and thoracic aortic aneurysm formation. This review aims to synthesize the current evidence on the relationship between JAK2 V617F and TAA development. Methods: A literature review was conducted using PubMed reviewed articles up to June 2025. Search terms included “thoracic aortic aneurysm”, “somatic mutations” and “JAK2 V617F”. Relevant clinical datasets and population-based cohort studies were identified and evaluated. Results: The available studies demonstrated a consistent association between JAK2 V617F and thoracic aortic aneurysm formation, with JAK2 V617F variant allele frequency (VAF) being a valuable biomarker of aneurysm risk. The mutation is accompanied by the onset of increased cytokine production, pro-inflammatory leukocytes, and elevated expression levels of MMPs—all of which drive elastin degradation and are classically associated with thoracic aortic aneurysm development. Conclusions: Compelling emerging evidence supports an association between the JAK2 V617F somatic mutation and the formation of thoracic aortic aneurysms, with VAF acting as a valuable biomarker for aneurysm risk. However, no studies have evaluated whether increasing VAF influences aneurysm growth rate, highlighting the need for future clinical research. Full article