Search Results (687)

Background: Cervical osteochondromas invading the vertebral canal are rare but may cause spinal cord compression requiring surgical resection. Conventional open laminectomy may disrupt posterior stabilizing structures and potentially increase the risk of postoperative cervical deformity. This technical note describes a contralateral-structure-preserving endoscopic technique for cervical osteochondroma resection. Methods: A 25-year-old man with multiple hereditary exostosis presented with neck pain, mild numbness, and a positive Lhermitte’s sign. Computed tomography and magnetic resonance imaging revealed a 9 × 6 × 10 mm osteochondroma originating from the base of the C3 spinous process and extending into the vertebral canal with spinal cord compression and cord signal change. Preoperative clinical assessment included a Visual Analog Scale (VAS) for neck pain of 6/10, a modified Japanese Orthopedic Association (mJOA) score of 16/18, a Neck Disability Index (NDI) of 30%, and Nurick grade 1. The lesion was treated using unilateral biportal endoscopic spine surgery through a partial unilateral laminectomy and sublaminar endoscopic corridor, aiming for en bloc resection while preserving the contralateral lamina, posterior ligamentous complex, and posterior tension band. Continuous intraoperative neurophysiological monitoring (SSEP and MEP) was used throughout the procedure. Results: The osteochondroma was completely resected en bloc using a diamond burr and Kerrison rongeur. Histopathological examination confirmed osteochondroma, and negative margins were identified without residual tumor. The patient’s symptoms resolved completely without postoperative complications, and he was discharged on postoperative day 3. At the 18-month clinical and radiological follow-up, the patient remained symptom-free, with VAS improved to 1–2/10, mJOA improved to 18/18, NDI improved to 4%, and Nurick grade improved to 0, with partial regression of the cord signal change and no evidence of tumor recurrence on follow-up imaging. Cervical lordosis was maintained at the immediate postoperative timepoint. Conclusions: Contralateral-structure-preserving endoscopic resection may represent a potential minimally invasive alternative to conventional wide laminectomy or fusion-based approaches in carefully selected cases of benign cervical osteochondroma. Larger comparative studies with long-term follow-up are required to confirm the potential biomechanical and clinical benefits of this approach. Full article

Background: Pathogenic germline BRCA1 and BRCA2 variants cause most hereditary breast and ovarian cancers. Widespread genetic testing has revealed thousands of variants with unknown effects on disease risk, known as variants of uncertain significance (VUS). BRCA VUS, the majority of which are missense, complicate genetic test interpretation and clinical decision-making. This study aimed to evaluate BRCA1 VUS pathogenicity with enhanced accuracy through computational, functional and structural methods. Methods: We characterized the structural distribution of BRCA1 variants. In silico tools scored known consequence variants within a specific region of BRCA1. The Molecular Feature Selection Tool (MolecularFeaST; Renwick Lab at Queen’s University; Kingston, ON, Canada) performed feature selection of the most discriminative tools. MATLAB (MATLAB R2024a; Mathworks; Natick, MA, USA) Classification Learner Application trained supervised machine learning models using combinations of the most accurate tools; the best model assigned pathogenicity prediction scores to VUS. Select VUS were functionally assessed through phosphopeptide binding pull-down assays and structurally analyzed on PyMOL (v2.4.1; Schrödinger Inc.; New York, NY, USA). Results: The RING and BRCT domains were identified as hotspots for missense pathogenic variants and VUS; BRCT was selected as the focus of the computational classifier. Nine in silico tools (CADD hg19, MetaRNN, ClinPred, VEST4, BayesDel AD, EVE, Eigen PC, gMVP and PolyPhen2) defined the BRCT-specific missense variant classifier. Twenty-two VUS (R1699P, F1704S, W1837L, W1712G, F1734S, V1804A, I1674V, V1804L, V1804I, I1807V, T1675S, I1764L, N1774I, E1698K, Q1848K, P1749S, A1669T, N1774H, L1839V, T1658I, L1705I, V1654L) demonstrated varying phosphopeptide binding ability and protein levels relative to the wildtype. Computational structural modeling contextualized VUS phosphopeptide interactions and structural implications. Conclusions: We provide in silico and functional evidence for the classification of BRCA1 BRCT VUS and highlight the utility of domain-specific computational approaches for characterizing missense variants in multi-domain genes. Full article

Testicular germ cell tumor (TGCT) is a common tumor type in young men. Family history of TGCT and its presence in twins support the involvement of inherited genetic factors. Germline exome sequencing was performed on monozygotic twins with TGCT and their parents. The twins presented compound heterozygous variants in PDE11A (rs776984134 and rs17400325) inherited from each parent. The rs776984134 variant disrupts the canonical splice acceptor site, leading to aberrant splicing and a frameshift predicted to affect protein structure. The rs17400325 missense variant, located in the catalytic domain, reduces hydrogen bonding capacity and may impair protein stability. Both variants map to a genomic region overlapping the antisense lncRNA PDE11A-AS1. In silico transcript-level analysis predicted multiple energetically favorable RNA–RNA interactions between PDE11A and PDE11A-AS1 transcripts, with rs17400325 located within predicted hybridization regions of several isoforms. These results suggest a potential impact on PDE11A–PDE11A-AS1 pairing and post-transcriptional regulation. Additional variants in MSH6 and CTU2 were also identified and may act as potential modifiers of disease susceptibility, consistent with a multigenic contribution to TGCT risk. These findings support a contributory role for the PDE11A locus in TGCT predisposition and underscore the biological relevance of overlapping sense–antisense genomic regions in hereditary cancer studies. Full article

Understanding germline genetic variation is essential for improving human cancer care. Cancer predisposition genetic testing has become a part of the landscape of healthcare. Clinical guidelines have been established to identify individuals with monogenic risk, support variant classification, and guide enhanced cancer surveillance and prevention strategies. However, genetic mechanisms, cancer syndromes, genetic testing, patient education, and high-risk cancer management are often addressed in separate professional domains leading to limited cross-disciplinary understanding and confusion. A review tailored to a broad spectrum of clinicians is necessary to synthesize information, connect key concepts, and clearly define the principles and reasoning underlying recommended practice. Advanced genetic technology identified numerous genes and countless pathogenic variants contributing to a wide range of cancer predispositions. Rapid and accurate next-generation sequencing has enabled the routine use of multi-gene panel testing to stratify cancer risk. In precision cancer therapies, tumor genomic profiling frequently uncovers not only somatic alterations but also germline mutations, revealing additional cancer risk for the patients and their biological relatives. Beyond monogenic risks, the cumulative effect of numerous common polygenic factors can also significantly influence cancer susceptibility. Despite major advances in integrating germline genetic information into cancer care, substantial challenges remain in variant interpretation, precise risk stratification, and implementing personalized screening and prevention strategies. Using several cancer predisposition syndromes as examples, such as breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome, the review provides a high-level overview of key concepts, the evolution of knowledge and technology, and the rationale underlying the current clinical management strategies. Full article

Background: Women carrying BRCA1 and BRCA2 pathogenic variants face a substantially increased lifetime risk of breast and ovarian cancer. Risk-reducing bilateral mastectomy and salpingo-oophorectomy are well-established strategies to lower this risk. Traditionally, these procedures are performed in separate surgical sessions; however, a simultaneous approach may reduce the overall treatment burden. Evidence regarding the safety and feasibility of combined procedures remains limited. Methods: We conducted a retrospective observational study of BRCA1 and BRCA2 pathogenic variant carriers who underwent risk-reducing or therapeutic breast surgery at the Breast Unit of Policlinico San Martino Hospital (Genova, Italy) between January 2013 and March 2025. Patients were divided into two groups according to surgical strategy: a simultaneous procedure group undergoing risk-reducing mastectomy with immediate breast reconstruction and concurrent salpingo-oophorectomy in a single operative session, and a staged procedure group undergoing the same interventions in separate surgeries. Demographic, surgical, and postoperative variables were collected and analyzed descriptively. Results: A total of 124 BRCA1 and BRCA2 pathogenic variant carriers were included, with 73 patients undergoing the simultaneous approach and 51 undergoing staged procedures. The mean age was similar between the Simultaneous and Staged Procedure Groups Descriptively, similar patterns were observed across the two groups in terms of age distribution, postoperative outcomes, and length of hospital stay (mean 4.56 days). Minor complications such as seroma or delayed wound healing showed similar patterns across both groups, with no apparent increase in major complications in the simultaneous surgery group. Patients undergoing the simultaneous approach required fewer surgical sessions and were exposed to general anesthesia only once. Conclusions: Simultaneous risk-reducing mastectomy with immediate reconstruction and salpingo-oophorectomy appears to be a safe and feasible strategy for selected BRCA1 and BRCA2 pathogenic variant carriers. This integrated surgical approach may reduce the overall surgical burden, with descriptively similar perioperative outcome patterns. Full article

Background and Objectives: Hereditary hearing loss is the most common auditory disability among various disabilities. Consanguineous populations have been found to have autosomal recessive disorders twice as often as in the general population. This study aimed to highlight the phenotypic and genetic complexity of non-syndromic hearing loss (NSHL) in South Indian consanguineous families. Materials and Methods: Whole-exome sequencing (WES) was performed on individuals with NSHL who were negative for common deafness-causing genes (GJB2, GJB6, SLC26A4, and MTRNR1). The candidate variants identified were correlated with ROH regions identified using the Automap tool. Sanger sequencing was performed for validation, followed by segregation analysis for the available family members. The effects of the candidate variants were analyzed using an in silico structural approach and the ACMG guidelines. Results: WES identified variants, including a stop-gain, an indel, and a missense mutation, in the genes SIX1, MYO7A, MYO3A, and MYO15A. Three variants were classified as likely pathogenic, one variant as a variant of uncertain significance (VUS), and one variant as likely benign. Homozygous variants in MYO15A and MYO7A were identified within ROH regions, indicating autosomal recessive inheritance. Additionally, two heterozygous variants in the SIX1 and MYO3A genes were identified. This study indicates a high degree of genotypic and phenotypic heterogeneity of hearing loss among affected individuals. Conclusions: This integrated approach, which combines homozygosity mapping with WES, could be effective for diagnosing NSHL in affected individuals. Further genetic screening and characterization of NSHL in consanguineous families is also warranted. Genetic testing in high-risk populations could be a valuable method for diagnosing genetic hearing loss in children. Full article

Background: Metabolic syndrome (MetS) is a cluster of risk factors increasing the likelihood of cardiovascular and metabolic diseases. Objectives: This study investigated the relative mRNA expression of key hepatic and intestinal phase II drug-metabolising enzymes, specifically UDP-glycosyltransferases (UGTs) and sulfotransferases (SULTs), in four non-obese rat models of MetS characterised by different dominant traits: the hereditary hypertriglyceridaemic (HHTg) rat, spontaneously hypertensive rat (SHR), SHR-expressing transgenic human C-reactive protein (SHR-CRP) rat, and bilaterally ovariectomised female Wistar (W-OVX) rat, compared to Wistar controls. Methods: Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method. Results: Measurements showed significant model-specific differences, especially in the liver. HHTg rats exhibited significant hepatic suppression of Ugt1a9 (−90%) and undetectable Ugt2b transcripts, alongside compensatory upregulation of Sult1a1 (196%) and Sult1b1 (277%). The SHR model showed significant hepatic upregulation of Ugt1a1 (330%), Sult1a1 (266%), and Sult1b1 (328%). Chronic inflammation in SHR-CRP rats caused a significant decrease in hepatic Ugt1a1, whereas a significant induction occurred in the intestine. Oestrogen deprivation (W-OVX) led to significant downregulation of hepatic Ugt1a6 and Ugt1a9. Conclusions: These findings highlight that the alterations in phase II metabolism strongly depend on the pathophysiological context, potentially affecting drug disposition in preclinical models. Full article

Infiltrative cardiomyopathies comprise a heterogeneous spectrum of hereditary and acquired diseases characterised by the accumulation of pathological substrates within the myocardium, ultimately resulting in progressive impairment of cardiac function and the development of heart failure. Across these conditions, atrial fibrillation is a frequent and clinically relevant complication, contributing to symptom burden, heart failure progression, and thromboembolic risk. Structural, functional, and electrical atrial remodelling, collectively referred to as atrial cardiomyopathy, emerges as a common pathophysiological substrate linking myocardial infiltration to atrial fibrillation and adverse cardiovascular outcomes. Multi-modality cardiac imaging enables comprehensive assessment of atrial cardiomyopathy, offering mechanistic insights into the atrial substrate of atrial fibrillation, with potential impact on the clinical management of this group of diseases. This review summarises contemporary evidence on atrial fibrillation in infiltrative cardiomyopathies, with a particular focus on the role of non-invasive multimodal imaging in the evaluation of atrial cardiomyopathy. Full article

Pediatric gastrointestinal polyps are frequently associated with an underlying hereditary syndrome associated with multisystem manifestations and increased risk of early-onset cancer. Thus, the identification of polyps in a child should prompt evaluation with genetic testing to (1) characterize the syndrome to determine next clinical steps including surveillance recommendations, and (2) conduct cascade testing to identify affected family members. Given the considerations for pediatric genetic testing, including autonomy and psychosocial stressors associated with the early detection of a cancer risk syndrome, it is important to conduct targeted testing. Herein, we propose a stepwise approach to genetic testing in the pediatric patient with gastrointestinal polyps. Full article

Cryptorchidism is one of the most frequently diagnosed developmental disorders of the male canine reproductive system, defined as the failure of one or both testes to descend into the scrotum. Physiologically, testicular descent is typically completed by six to eight weeks of age, although some authors extend this period to sixteen weeks. Failure of testicular descent beyond this timeframe is considered pathological. The condition has multiple causes and affects between 1% and 10% of the canine population. Genetics is the most significant factor, indicating the hereditary basis of cryptorchidism. In addition, increasing attention has been directed toward the potential impact of environmental and epigenetic factors on the incidence of cryptorchidism, suggesting that the condition may result from complex interactions between genetic predisposition and external influences. The effect of hormones (such as INSL3 and testosterone), mechanical factors (including narrowing of the inguinal canal, abnormalities of the gubernaculum, and shortening of the spermatic cord), and environmental factors (for example, exposure to external estrogens and maternal stress during pregnancy) all contribute to the development of this disorder. Recent results have emphasized the role of the orexin system, particularly the OX2R receptor, in regulating endocrine and reproductive functions in cryptorchid testes. Computed tomography is increasingly utilized in complex cases due to its high precision in localizing retained testes. Clinically, cryptorchidism may present unilaterally or bilaterally. Unilateral cryptorchidism may preserve partial fertility, whereas bilateral cryptorchidism results in complete infertility. Undescended testes may be located in the abdominal cavity or inguinal canal. Major complications include an increased risk of testicular cancer (Sertoli cell tumors and seminomas) and endocrine disorders leading to feminization. Diagnosis is based on clinical examination and imaging modalities such as ultrasound. Orchiectomy, involving the removal of both the retained and normally descended testicles, is thought to be the gold standard for treatment. This method helps avoid complications and the transmission of the defect to offspring. According to Fédération Cynologique Internationale (FCI) standards, affected individuals should not be used for breeding or shows. Early detection, surgical intervention, and consistent exclusion from breeding programs are the primary strategies for reducing the incidence of this disorder in the canine population. Full article

Background: Breast cancer and gynecological malignancies, including cervical, ovarian, and endometrial cancers, remain leading causes of cancer incidence and mortality among women worldwide. This study investigated hereditary predisposition rates in women diagnosed with breast or gynecological cancer, focusing on the effect of age on germline pathogenic/likely pathogenic (P/LP) variant detection. We sought to determine whether younger age at diagnosis should be used as a criterion for patient selection for genetic testing. Methods: A total of 9084 consecutive females with breast cancer or gynecological tumors underwent germline NGS-based genetic testing (52 cancer-relevant genes) at Genekor laboratory from 2020–2026. Multivariable logistic regression evaluated factors associated with P/LP variant detection, adjusting for tumor type and family history. Results: Overall P/LP prevalence was approximately 20% (one in five patients), with tumor-specific rates of 19.24% in breast cancer, 27.59% in ovarian cancer, and 26.67% in endometrial cancer. P/LP prevalence declined significantly with age from 24.37% in patients <40 years to 15.90% in those ≥70 years, while Variants of Uncertain Significance (VUS) remained stable (40–43%). P/LP patients had earlier diagnosis (median 45 vs. 46 years, p < 0.001), driven predominantly by high-risk genes (13.87% in <40 y vs. 7.11% in ≥70 y). BRCA1 showed stronger age enrichment than BRCA2 (8.14% vs. 3.16% in <40 y; median diagnosis 43 vs. 45 years). Age remained independently associated with P/LP detection in multivariable analysis, with an 18% reduction in odds per 10-year increase for any P/LP (OR 0.82, 95% CI 0.78–0.86) and a stronger 28% reduction for high-risk variants (OR 0.72, 95% CI 0.67–0.78). Family history also independently predicted P/LP detection (OR 1.40, 95% CI 1.19–1.66). Conclusions: Although derived from a referral-based (and thus selected) population, these findings show that while younger patients have a higher prevalence of high-risk P/LP variants, clinically actionable findings are present across all age groups, including those ≥70 years. These results suggest that reliance on age alone to determine eligibility for genetic testing may be insufficient. Broadening access to testing beyond strict age-based criteria could improve the identification of hereditary cancer risk and inform patient management, although further evaluation in less selected populations is warranted. Full article

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising globally, yet its underlying risk factors remain incompletely understood, particularly in cases without recognised hereditary syndromes. Objectives: To update and synthesise the current body of evidence on modifiable and non-modifiable risk factors for sporadic early-onset colorectal cancer. Methods: A systematic review of peer-reviewed articles published in English reporting original observational research examining risk factors for sporadic early-onset colorectal cancer (<50 years old) was conducted. PubMed and EMBASE databases were searched from inception to March 2025. Across studies, effect measures varied; therefore, the synthesis focused on the consistency of associations rather than the direct comparison of effect sizes. Results: The initial search identified 2575 papers; 34 studies were included after screening. Several consistent associations were identified, with dietary and lifestyle factors along with metabolic conditions emerging as key risk factors. EOCRC risk was higher in males (adjusted odds ratio (aOR) 1.36–2.21 across studies), individuals of Caucasian ethnicity (aORs 1.48–2.56), and in individuals whose age was approaching 50 years (per year, aORs 1.05–1.11). Putatively sporadic EOCRC was associated with a family history of CRC or other cancers (aORs up to 8.61). Other key factors linked to higher risk included obesity (aORs 1.92–2.88; adjusted Hazard Ratios (aHRs) 1.04–1.82), metabolic syndrome (aORs 1.25–2.48; aHRs 1.2–1.26), diabetes (aORs 1.24–3.42), Western dietary patterns (aORs 1.84–2.99), and sedentary behaviours (adjusted relative risks (aRR) 1.69–2.44). Moderate-to-vigorous exercise appeared protective (aORs 0.34–0.58), as did higher vitamin D levels (aHRs 0.41–0.61). Evidence for smoking, alcohol, medications and early/in utero environmental exposures was inconsistent. Conclusions: Lifestyle and metabolic factors, including Western dietary patterns, obesity and sedentary behaviours, were associated with sporadic EOCRC. Family history also emerged as a significant contributor to putatively sporadic disease, suggesting heritable influences beyond recognised syndromes and interplay between environmental factors and genetic predisposition. Future research should focus on integrated tumour and germline profiling, including broader genomic analyses in well-characterised cohorts, to better understand potential pathogenic mechanisms and support the development of risk stratification approaches. Full article

Hereditary breast cancer (BC) remains unexplained in a substantial proportion of families who test negative for BRCA1/2 and other known susceptibility genes. To contribute to the genomic characterization of these unresolved cases, we generated a whole-genome sequencing (WGS) dataset from six women belonging to two unrelated high-risk families, each comprising three sisters diagnosed with BC. All participants had previously received negative results in conventional multigene panel testing. WGS was performed on peripheral blood DNA using the Illumina NovaSeq platform, followed by variant calling against GRCh38 and the comprehensive annotation of single-nucleotide variants, indels, and structural variants. For each family, we identified shared ClinVar-annotated variants, rare exonic or splice-site alterations, and intronic variants located within a curated set of 286 cancer-related genes. The dataset includes per-patient VCF files, copy number variation annotations, and family-level variant summaries. Raw and processed data are publicly available through the Sequence Read Archive and Zenodo. This resource supports variant reinterpretation, exploration of regulatory and intronic regions, and methodological benchmarking in the study of familial BC beyond established susceptibility genes. Full article

Background/Objectives: Genetic testing in Human Epidermal Growth Factor Receptor 2-negative (HER2−) metastatic breast cancer (mBC) is necessary to enable optimal treatment choices including poly(ADP-ribose)polymerase inhibitors (PARPis). The present study evaluated the implementation of genetic testing in a real-world setting to reveal and subsequently allow targeting of potential inadequacies and risk factors for low testing frequency. Methods: We performed a retrospective analysis including HER2− mBC patients treated at a single academic center starting from 10 April 2019 (date of European Medicines Agency (EMA) approval of Olaparib for germline breast cancer gene mutant (gBRCAm) HER2− mBC) to 7 September 2021. The primary objective of the study was to evaluate the rate of HER2− mBC patients that were recommended to undergo genetic testing by the multidisciplinary tumor board (MTB). The secondary objective was to identify factors that were associated with a higher likelihood of having undergone genetic testing. Results: In total, 47.6% (109 of 229) of HER2− mBC patients had been recommended to undergo genetic testing by the MTB. Of these informed patients, 89.0% (97 of 109) underwent genetic testing, of which 11.6% (11 of 95) had a germline BRCA mutation (gBRCAmut) and were eligible for PARPi treatment. In multivariate analysis, younger age (p-value: 0.0007), hormone receptor positive (HR+)/HER2− subtype (p-value < 0.0001) and positive family history for breast and ovarian cancer (p-value: 0.0001) were significantly associated with the performance of genetic counseling. Conclusions: The present study demonstrated low genetic counseling rates of HER2− mBC patients, especially in individuals without specific risk factors for hereditary breast cancer. Informed patients showed a high willingness to undergo genetic testing. Genetic testing revealed targetable mutations in over 10% of tested patients. Full article

Background: Germline CDKN2A variants are associated with Familial Atypical Mole-Malignant Melanoma (FAMMM) syndrome. This syndrome involves an increased risk of melanoma, pancreatic cancer, and, in specific populations, duodenal cancer, breast cancer, and astrocytoma. The CDKN2A (c.146T>C) variant has been found in hereditary cancer patients within the Mexican population. Furthermore, the phenotype linked to this variant in Mexico differs from that observed in other groups. This study aims to evaluate the founder effect of the CDKN2A (c.146T>C) variant through epidemiological analysis and to describe the phenotype within our population. Patients and Methods: We examined 72 Mexican patients (14 probands from distinct families, 48 relatives, and 10 nonrelated probands) carrying the CDKN2A (c.146T>C) form three hereditary cancer centers between September 2023 and September 2025. Results: Of the 72 individuals analyzed, 52 (72.22%) tested positive. A cancer diagnosis was established in 27 (37.50%) of the individuals analyzed. Breast cancer was the most common neoplasia, accounting for 19 cases (70.37%), followed by melanoma with 4 cases (14.81%) and ovarian cancer with 2 cases (7.40%). Three patients (11.11%) had two distinct primary neoplasms. Conclusions: Based on our findings and the fact that this variant has been reported nearly exclusively in the Mexican population, we conclude that it has a founder effect in this population. Additionally, the phenotype associated with this variant can vary among populations, with breast cancer being the most common carcinoma rather than melanoma among Mexican carriers, highlighting the importance of updating screening guidelines. Full article