Overcome intraoperative difficulties of ALPPS procedure: a single-center outcomes and technical experience.

Backgrounds/aims: Recently, the ALPPS (Associating liver partition and portal vein ligation for staged hepatectomy) has become widely known to achieve hepatic resection by rapid future liver remnant hypertrophy, but it comes with intraoperative difficulties, followed by increased complications. This study aimed to report the outcomes of an oncology center in a low-income and middle-income country with ALPPS in patients with liver tumors and its technical variants, which were invented to overcome intraoperative difficulties of the ALPPS procedure. Patients and methods: A retrospective analysis of patients undergoing ALPPS from September 2022 to December 2023 was performed. Results: A total of 25 patients underwent the ALPPS procedure: 21 procedures for hepatocellular carcinoma (HCC), 3 combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and 1 for small cell neuroendocrine carcinoma (SNEC). The mean postoperative stay was 29.6 ± 9.3 days (range 16-58 days). After stage 1, we counted 8 complications, all of grade II; after stage 2, the number of complications was decreased to 3:2 were of grade I and 1 were of grade IIIB. 3 (12%) patients failed to proceed to ALPPS stage 2. After a median follow-up of 9 months (range 2-25), disease recurrence has been recorded in 3 patients (12%), while 1 patient (4%) died, affected by HCC. The entire group's 2-year overall survival (OS) and disease-free survival (DFS) were 83.3% and 82.5%, respectively. Conclusion: The ALPPS procedure is an approach for large liver tumors with small future liver remnant with acceptable OS and DFS in a low-income and middle-income country.

Population-scale variability of the human UDP-glycosyltransferase gene family.

Human UDP-glycosyltransferases (UGTs) are responsible for the glucuronidation of a wide variety of endogenous substrates and multiple commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed. We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across seven major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family. Overall, 9666 exonic variants were observed of which 98.9% were rare. To interpret the functional impact of UGT missense variants, we developed a gene family-specific variant effect predictor. This algorithm identified a total of 1208 deleterious variants, most of which were found in African and South Asian populations. Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites. Combined, our analyses provide a systematic overview of UGT variability, which can yield insights into inter-individual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: a narrative review.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare pancreatic tumor that accounts for less than 1% of all pancreatic malignancies. The characteristic pathological manifestation of UCOGCP is the presence of osteoclast-like giant cells (OGCs) distributed among pleomorphic undifferentiated tumor cells. UCOGCP can occur either alone or in association with other types of pancreatic tumors. At present, there is no unified consensus or guideline for the diagnosis and treatment of UCOGCP, and most of the literature are individual case reports. With the accumulation in the number of clinical cases and the development of precision medicine technology, the understanding of UCOGCP is also deepening. Researchers have begun to recognize that UCOGCP is a pancreatic tumor with distinctive clinical and molecular characteristics. In this review, we focus on the latest research status and future exploration directions in the diagnosis, treatment, and prognosis of UCOGCP.

Complex evolutionary trajectories in vivo of two novel KPC variants conferring ceftazidime-avibactam resistance.

More and more ceftazidime-avibactam resistant KPC-producing K. pneumoniae have been reported with its widespread use, and the detection rate of KPC variants has increased dramatically. However, the evolutionary mechanism and fitness effects during KPC mutation remained unknown. Here, we report the complex in vivo evolutionary trajectories of two novel KPC variants, KPC-155 (L169P/GT242A) and KPC-185 (D179Y/GT242A), from Klebsiella pneumoniae in the same patient. The novel variants were shown to confer ceftazidime-avibactam resistance but restore carbapenem susceptibility based on the results of plasmid transformation assays, cloning experiments, and enzyme kinetic measurements. In vitro competition experiments highlighted the adaptive advantage conferred by strains carrying these KPC variants, which could lead to the rapid spread of these ceftazidime-avibactam resistant strains. The growth curve indicated that blaKPC-185 had better growth conditions at lower avibactam concentration compared to blaKPC-155, which was consistent with ceftazidime-avibactam use in vivo. In addition, replicative transposition of the IS26-flanked translocatable unit (IS26-ISKpn6-blaKPC-ISKpn27-IS26) also contributes to the blaKPC amplification and formation of two copies (blaKPC-2 and blaKPC-185), conferring both carbapenem and ceftazidime-avibactam resistance. However, strains with double copies showed reduced competitive advantage and configuration stability. The comparative plasmid analysis of IS26 group (IS26-blaKPC-IS26) and Tn1721 group (Tn1721-blaKPC-IS26) revealed that IS26-insertion could influence the distribution of resistance genes and ability of self-conjugation. The dynamic changes in blaKPC configuration highlight the need for consistent monitoring including antimicrobial susceptibility testing and determination of blaKPC subtypes-during clinical treatment, especially when ceftazidime-avibactam is administered.

SEPHS1 Gene: A new master key for neurodevelopmental disorders.

The SEPHS1 (Selenophosphate Synthetase 1) gene encodes a critical enzyme for synthesizing selenophosphate, the active donor of selenium (Se) necessary for selenoprotein biosynthesis. Selenoproteins are vital for antioxidant defense, thyroid hormone metabolism, and cellular homeostasis. Mutations in SEPHS1 gene, are associated with neurodevelopmental disorders with developmental delay, poor growth, hypotonia, and dysmorphic features. Due to Se's critical role in brain development and function, SEPHS1 gene has taken center stage in neurodevelopmental research. This review explores the structure and function of the SEPHS1 gene, its role in neurodevelopment, and the implications of its dysregulation for neurodevelopmental disorders. Therapeutic strategies, including Se supplementation, gene therapy, and targeted therapies, are discussed as potential interventions to address SEPHS1 associated neurodevelopmental dysfunction. The study's findings reveal how SEPHS1 mutations disrupt neurodevelopment, emphasizing the gene's intolerance to loss of function. Future research should focus on functional characterization of SEPHS1 variants, broader genetic screenings, and therapeutic developments.

Optimal variable identification for accurate detection of causal expression Quantitative Trait Loci with applications in heart-related diseases.

Gene expression plays a pivotal role in various diseases, contributing significantly to their mechanisms. Most GWAS risk loci are in non-coding regions, potentially affecting disease risk by altering gene expression in specific tissues. This expression is notably tissue-specific, with genetic variants substantially influencing it. However, accurately detecting the expression Quantitative Trait Loci (eQTL) is challenging due to limited heritability in gene expression, extensive linkage disequilibrium (LD), and multiple causal variants. The single variant association approach in eQTL analysis is limited by its susceptibility to capture the combined effects of multiple variants, and a bias towards common variants, underscoring the need for a more robust method to accurately identify causal eQTL variants. To address this, we developed an algorithm, CausalEQTL, which integrates L 0 +L 1 penalized regression with an ensemble approach to localize eQTL, thereby enhancing prediction performance precisely. Our results demonstrate that CausalEQTL outperforms traditional models, including LASSO, Elastic Net, Ridge, in terms of power and overall performance. Furthermore, analysis of heart tissue data from the GTEx project revealed that eQTL sites identified by our algorithm provide deeper insights into heart-related tissue eQTL detection. This advancement in eQTL mapping promises to improve our understanding of the genetic basis of tissue-specific gene expression and its implications in disease. The source code and identified causal eQTLs for CausalEQTL are available on GitHub: https://github.com/zhc-moushang/CausalEQTL.

Unraveling the Role of BRCA1 variants in Dysregulation of Transcriptional and Post-Transcriptional Mechanisms in Breast Cancer.

Objective: To screen BRCA1 gene variants and predict potential role of the identified variants in breast cancer. Method: This case-control study included two hundred and fifty breast cancer patients and equal healthy individuals from the Federal Breast Cancer Screening Centre, Pakistan Institute of Medical Sciences, Islamabad from March 2021- January 2023. Demographic data was collected through questionnaires and clinical data was assessed using mammograms, ultrasound, histopathology and immunohistochemistry reports. Polymerase chain reaction and Sanger sequencing approach were used to detect variants in BRCA1 gene. In-silico analyses were carried out to predict mutation effect, miRNA binding site alterations and change in mRNA structure and stability. Results: Invasive ductal carcinoma was the most prevalent type of breast cancer. Old age [OR: 2.8149 (1.5995 to 4.9538) p value = 0.0003] and family history [OR: 4.3186 (1.7336 to 10.7581) p value = 0.001] were significant breast cancer risk. Six variants were identified. Two novel missense variants, Chr17:43082553A>T and Chr17:43093710A>T were predicted deleterious as these disrupted interaction with PALB2 and importin alpha's NLS2 site, respectively. In silico analysis predicted the loss of hsa-miR-1179 binding site due to variant Chr17:43093220T>C. Moreover, four variants were predicted to affect the mRNA structure and stability. Conclusion: Two novel variants were predicted to be pathogenic. In-silico analysis predicted the loss of miRNA binding site along with change in mRNA secondary structure plus stability, possible mechanisms for oncogenesis. Further, expressional studies are required to confirm BRCA1 gene dysregulation in breast cancer due to these variants.

Predictive genetic panel for adult asthma using machine learning methods.

Background: Asthma is a chronic inflammatory disease of the airways that is heterogeneous and multifactorial, making its accurate characterization a complex process. Therefore, identifying the genetic variations associated with asthma and discovering the molecular interactions between the omics that confer risk of developing this disease will help us to unravel the biological pathways involved in its pathogenesis. Objective: We sought to develop a predictive genetic panel for asthma using machine learning methods. Methods: We tested 3 variable selection methods: Boruta's algorithm, the top 200 genome-wide association study markers according to their respective P values, and an elastic net regression. Ten different algorithms were chosen for the classification tests. A predictive panel was built on the basis of joint scores between the classification algorithms. Results: Two variable selection methods, Boruta and genome-wide association studies, were statistically similar in terms of the average accuracies generated, whereas elastic net had the worst overall performance. The predictive genetic panel was completed with 155 single-nucleotide variants, with 91.18% accuracy, 92.75% sensitivity, and 89.55% specificity using the support vector machine algorithm. The markers used range from known single-nucleotide variants to those not previously described in the literature. Our study shows potential in creating genetic prediction panels with tailored penalties per marker, aiding in the identification of optimal machine learning methods for intricate results. Conclusions: This method is able to classify asthma and nonasthma effectively, proving its potential utility in clinical prediction and diagnosis.

Association of polymorphisms within P2RX4 with type 2 diabetes mellitus: a preliminary case-control study.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a complex heterogenic metabolic with a wide range of etiology. Purinergic receptors have pivotal roles in different processes and are hypothesized to have roles in the pathogenesis of T2DM. MATERIALS AND METHODS: Three hundred subjects affected by T2DM and 300 healthy subjects were genotyped by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). SPSS V16.0 was recruited for statistical analysis. RESULTS: The findings showed that the G allele of rs25644A > G increases the risk of T2DM in our population statistically (OR = 1.51, 95% CI = 1.14-1.99, p = 0.003). This allele in some genotype models, including the dominant model, caused an increase in the risk of T2DM. The interaction of genotypes between studied variants in the P2XR4 gene increased the risk of T2DM. Haplotype analysis showed that Ars1169727/Grs25644 haplotype caused an increase in the risk of T2DM. CONCLUSIONS: The findings suggest that rs25644A > G plays a role in our population's increased risk of T2DM.

Novel RPTPγ and RPTPζ splice variants from mixed neuron-astrocyte hippocampal cultures as well as from the hippocampi of newborn and adult mice.

Receptor protein tyrosine phosphatases γ and ζ (RPTPγ and RPTPζ) are transmembrane signaling proteins with extracellular carbonic anhydrase-like domains that play vital roles in the development and functioning of the central nervous system (CNS) and are implicated in tumor suppression, neurodegeneration, and sensing of extracellular [CO2] and [HCO3 -]. RPTPγ expresses throughout the body, whereas RPTPζ preferentially expresses in the CNS. Here, we investigate differential RPTPγ-RPTPζ expression in three sources derived from a wild-type laboratory strain of C57BL/6 mice: (a) mixed neuron-astrocyte hippocampal (HC) cultures 14 days post isolation from P0-P2 pups; (b) P0-P2 pup hippocampi; and (c) 9- to 12-week-old adult hippocampi. Regarding RPTPγ, we detect the Ptprg variant-1 (V1) transcript, representing canonical exons 1-30. Moreover, we newly validate the hypothetical assembly [XM_006517956] (propose name, Ptprg-V3), which lacks exon 14. Both transcripts are in all three HC sources. Regarding RPTPζ, we confirm the expression of Ptprz1-V1, detecting it in pups and adults but not in cultures, and Ptprz1-V3 through Ptprz1-V7 in all three preparations. We newly validate hypothetical assemblies Ptprz1-X1 (in cultures and pups), Ptprz1-X2 (in all three), and Ptprz1-X5 (in pups and adults) and propose to re-designate them as Ptprz1-V0, Ptprz1-V2, and Ptprz1-V8, respectively. The diversity of RPTPγ and RPTPζ splice variants likely corresponds to distinct signaling functions, in different cellular compartments, during development vs later life. In contrast to previous studies that report divergent RPTPγ and RPTPζ protein expressions in neurons and sometimes in the glia, we observe that RPTPγ and RPTPζ co-express in the somata and processes of almost all HC neurons but not in astrocytes, in all three HC preparations.

Functional distinction in oncogenic Ras variant activity in Caenorhabditis elegans.

Ras genes are important oncogenes that are frequently mutated in cancer. Human oncogenic variants exhibit functional distinctions in terms of their representation in different cancer types, impact on cellular targets, and sensitivity to pharmacological treatments. However, how these distinct variants influence and respond to the cellular networks in which they are embedded is poorly understood. To identify novel participants in the complex interplay between Ras genotype and cell interaction networks in vivo, we have developed and tested an experimental framework using a simple vulva development assay in the nematode C. elegans. Using this system, we evaluate a set of Ras oncogenic substitution changes at G12, G13 and Q61. We find that these variants fall into distinct groups based on phenotypic differences, sensitivity to gene dose and inhibition of the downstream kinase MEK, and their response to genetic modulators that influence Ras activity in a non-autonomous manner. Together, our results demonstrate oncogenic C. elegans Ras variants exhibit clear distinctions in how they interface with the vulva development network, and show that extracellular modulators yield variant-restricted effects in vivo.

Expanding the targeting scope of CRISPR/Cas9-mediated genome editing by Cas9 variants in Brassica.

CRISPR/Cas9, presently the most widely used genome editing technology, has provided great potential for functional studies and plant breeding. However, the strict requirement for a protospacer adjacent motif (PAM) has hindered the application of the CRISPR/Cas9 system because the number of targetable genomic sites is limited. Recently, the engineered variants Cas9-NG, SpG, and SpRY, which recognize non-canonical PAMs, have been successfully tested in plants (mainly in rice, a monocot). In this study, we evaluated the targeted mutagenesis capabilities of these Cas9 variants in two important Brassica vegetables, Chinese cabbage (Brassica rapa spp. pekinensis) and cabbage (Brassica oleracea var. capitata). Both Cas9-NG and SpG induced efficient mutagenesis at NGN PAMs, while SpG outperformed Cas9-NG at NGC and NGT PAMs. SpRY achieved efficient editing at almost all PAMs (NRN > NYN), albeit with some self-targeting activity at transfer (T)-DNA sequences. And SpRY-induced mutants were detected in cabbage plants in a PAM-less fashion. Moreover, an adenine base editor was developed using SpRY and TadA8e deaminase that induced A-to-G conversions within target sites using non-canonical PAMs. Together, the toolboxes developed here induced successful genome editing in Chinese cabbage and cabbage. Our work further expands the targeting scope of genome editing and paves the way for future basic research and genetic improvement in Brassica. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00155-7.

Extracellular vesicle transfer of lncRNA H19 splice variants to cardiac cells.

The delivery of therapeutic long non-coding RNAs (lncRNA) to the heart by extracellular vesicles (EVs) is promising for heart repair. H19, a lncRNA acting as a major regulator of gene expression within the cardiovascular system, is alternatively spliced, but the loading of its different splice variants into EVs and their subsequent uptake by recipient cardiac cells remain elusive. Here, we dissected the cellular expression of H19 splice variants and their loading into EVs secreted by Wharton-Jelly mesenchymal stromal/stem cells (WJ-MSCs). We demonstrated that overexpression of the mouse H19 gene in WJ-MSCs induces the expression of H19 splice variants at different levels. Interestingly, EVs isolated from the H19-transfected WJ-MSCs (EV-H19) showed similar expression levels for all tested splice variant sets. In vitro, we further demonstrated that EV-H19 was taken up by cardiomyocytes, fibroblasts, and endothelial cells (ECs). Finally, analysis of EV tropism in living rat myocardial slices indicated that EVs were internalized mostly by cardiomyocytes and ECs. Collectively, our results indicated that EVs can be loaded with different lncRNA splice variants and successfully internalized by cardiac cells.

Novel TMPRSS6 variants and their impact on iron-refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study.

Iron-refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness. It identified a final cohort of 10 (2.15% prevalence) individuals with IRIDA phenotype. Haematological and biochemical analysis revealed significant differences between iron responders and iron non-responders, with iron non-responders showing lower haemoglobin, red blood cell count, serum iron and serum ferritin levels, along with elevated HEPC (9.47 ± 2.75 ng/mL, p = 0.0009) and erythropoietin (4.58 ± 4.07 µ/mL, p = 0.0196) levels. Genetic sequencing of the TMPRSS6 gene in this final cohort identified 10 novel variants, including seven missense and three frame-shift mutations, with four missense variants showing high functional impact defining the IRIDA phenotype. Structural analysis revealed significant damage caused by two variants (p.L83R and p.S235R). This study provides valuable insights into IRIDA among pregnant women in the Indian subcontinent, unveiling its underlying causes of unresponsiveness, genetic mechanisms and prevalence. Furthermore, research collaboration is essential to validate these findings and develop effective treatments.

Multigenic panels in breast cancer: clinical utility and management of patients with pathogenic variants other than BRCA1/2.

Multigene panels can analyze high and moderate/intermediate penetrance genes that predispose to breast cancer (BC), providing an opportunity to identify at-risk individuals within affected families. However, considering the complexity of different pathogenic variants and correlated clinical manifestations, a multidisciplinary team is needed to effectively manage BC. A classification of pathogenic variants included in multigene panels was presented in this narrative review to evaluate their clinical utility in BC. Clinical management was discussed for each category and focused on BC, including available evidence regarding the multidisciplinary and integrated management of patients with BC. The integration of both genetic testing and counseling is required for customized decisions in therapeutic strategies and preventative initiatives, as well as for a defined multidisciplinary approach, considering the continuous evolution of guidelines and research in the field.

A Critical Review of the Impact of Candidate Copy Number Variants on Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) influenced by genetic, epigenetic, and environmental factors. Recent advancements in genomic analysis have shed light on numerous genes associated with ASD, highlighting the significant role of both common and rare genetic mutations, as well as copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and unique de novo variants. These genetic variations disrupt neurodevelopmental pathways, contributing to the disorder's complexity. Notably, CNVs are present in 10%-20% of individuals with autism, with 3%-7% detectable through cytogenetic methods. While the role of submicroscopic CNVs in ASD has been recently studied, their association with genomic loci and genes has not been thoroughly explored. In this review, we focus on 47 CNV regions linked to ASD, encompassing 1,632 genes, including protein-coding genes and long non-coding RNAs (lncRNAs), of which 659 show significant brain expression. Using a list of ASD-associated genes from SFARI, we detect 17 regions harboring at least one known ASD-related protein-coding gene. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding gene with brain-enriched expression and a nervous system phenotype in mouse mutants, and one lncRNA with both brain-enriched expression and upregulation in iPSC to neuron differentiation. This review not only expands our understanding of the genetic diversity associated with ASD but also underscores the potential of lncRNAs in contributing to its etiology. Additionally, the discovered CNVs will be a valuable resource for future diagnostic, therapeutic, and research endeavors aimed at prioritizing genetic variations in ASD.

Genetic variant profiling of neonatal diabetes mellitus in Iranian patients: Unveiling 58 distinct variants in 14 genes.

INTRODUCTION: Neonatal diabetes mellitus (NDM) is a rare non-immunological monogenic disorder characterized by hyperglycemic conditions primarily occurring within the first 6 months of life. The majority of cases are attributed to pathogenic variants in genes affecting beta-cell survival, insulin regulation, and secretion. This study aims to investigate the genetic landscape of NDM in Iran. METHODS: We recruited a total of 135 patients who were initially diagnosed with diabetes at <12 months of age in Iran and referred to pediatric endocrinology clinics across the country. These patients underwent genetic diagnostic tests conducted by the Exeter Molecular Genetics Laboratory in the UK. The pathogenic variants identified were sorted and described based on type, pathogenicity (according to ACMG/AMP criteria), novelty, and the affected protein domain. RESULTS: Genetic defects were identified in 93 probands, presenting various pathogenic abnormalities associated with NDM and its associated syndromes. 76% of the patients were born as a result of consanguineous marriage, and a familial history of diabetes was found in 43% of the cases. A total of 58 distinct variants in 14 different genes were discovered, including 20 variants reported for the first time. Causative variants were most frequently identified in EIF2AK3, KCNJ11, and ABCC8, respectively. Notably, EIF2AK3 and ABCC8 exhibited the highest number of novel variants. DISCUSSION: These findings provide valuable insights into the genetic landscape of NDM in the Iranian population and contribute to the knowledge of novel pathogenic variants within known causative genes.

Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants (CNVs) were examined, with emphasis on de novo variants. We also performed enrichment test for rare variants in candidate genes previously proposed in association with systemic sclerosis. We identified 42 exonic and 34 ncRNA de novo SNV changes in 101 trios, from a total of over 6000 de novo variants genome wide. We observed higher than expected de novo variants in PRKXP1 gene. We also observed such phenomenon along with increased expression in patient group in NEK7 gene. Additionally, we also observed significant enrichment of rare variants in candidate genes in the patient cohort, further supporting the complexity/multi-factorial etiology of systemic sclerosis. Our findings identify new candidate genes including PRKXP1 and NEK7 for future studies in SSc. We observed rare variant enrichment in candidate genes previously proposed in association with SSc, which suggest more efforts should be pursued to further investigate possible pathogenetic mechanisms associated with those candidate genes.

BRCA-associated hereditary male cancers: can gender affect the prevalence and spectrum of germline pathogenic variants?

Introduction: Although hereditary male neoplasms are quite rare, individuals harbouring germline BRCA1/2 pathogenic variants (PVs) may have a risk of developing tumours associated with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, including male breast (MBC), prostate (PCa) and pancreatic (PC) cancers, and melanoma. Women and men showed a comparable genetic architecture of cancer susceptibility, but there are some gender-specific features. Since little is known about cancer genetic susceptibility in male population, our study was aimed at investigating the frequency of BRCA1/2 PVs in men with HBOC syndrome-associated tumors, in order to understand whether differences in gender may reflect in the prevalence and spectrum of germline alterations. Patients and methods: We retrospectively collected and analysed clinical information of 352 HBOC-associated male cancer patients genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis, enrolled, from February 2018 to January 2024, at the "Regional Center for the prevention, diagnosis and treatment of rare and heredo-familial tumors of adults" of the University-Hospital Policlinico "P. Giaccone" of Palermo (Italy). Results: Our investigation revealed that 7.4% of patients was carrier of a germline BRCA PV, with an almost total prevalence of BRCA2 alterations. In particular, 65.4% of BRCA-positive patients developed MBC, 19.2% had PC, 11.6% developed PCa, and only 3.8% had melanoma. Specifically, MBC individuals showed a BRCA-associated genetic predisposition in 17% of cases, whereas patients with PCa or PC exhibited a lower frequency of BRCA2 PVs, taking into account the current national criteria for access to germline genetic testing. Discussion: Our study showed a high heterogeneity in prevalence of germline BRCA2 PVs among men which could reflect a potential gender-specific genetic heterogeneity. Therefore, BRCA-associated male tumours could be due to BRCA2 PVs different from those usually detected in women. In the event that it is demonstrated, in future, that male cancers are genetically distinct entities from those female this could improve personalized risk evaluation and guide therapeutic choices for patients of both sexes, in order to obtain a gender equality in cancer care.

The Elusive Nature of ABCC8-related Maturity-Onset Diabetes of the Young (ABCC8-MODY). A Review of the Literature and Case Discussion.

PURPOSE OF REVIEW: Maturity-onset diabetes of the young (MODY) are monogenic forms of diabetes resulting from genetic defects, usually transmitted in an autosomal dominant fashion, leading to ß-cell dysfunction. Due to the lack of homogeneous clinical features and univocal diagnostic criteria, MODY is often misdiagnosed as type 1 or type 2 diabetes, hence its diagnosis relies mostly on genetic testing. Fourteen subtypes of MODY have been described to date. Here, we review ABCC8-MODY pathophysiology, genetic and clinical features, and current therapeutic options. RECENT FINDINGS: ABCC8-MODY is caused by mutations in the adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene, involved in the regulation of insulin secretion. The complexity of ABCC8-MODY genetic picture is mirrored by a variety of clinical manifestations, encompassing a wide spectrum of disease severity. Such inconsistency of genotype-phenotype correlation has not been fully understood. A correct diagnosis is crucial for the choice of adequate treatment and outcome improvement. By targeting the defective gene product, sulfonylureas are the preferred medications in ABCC8-MODY, although efficacy vary substantially. We illustrate three case reports in whom a diagnosis of ABCC8-MODY was suspected after the identification of novel ABCC8 variants that turned out to be of unknown significance. We discuss that careful interpretation of genetic testing is needed even on the background of a suggestive clinical context. We highlight the need for further research to unravel ABCC8-MODY disease mechanisms, as well as to clarify the pathogenicity of identified ABCC8 variants and their influence on clinical presentation and response to therapy.