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PubMed2025

Significance of GNAS mutations for morbid obesity in children.

BACKGROUND: Hereditary forms of obesity are characterized by early severe heterogeneous manifestations of the phenotype along with a rapid progression to morbid obesity, primary due to pathogenic variants of certain genes. Most forms are characterized by moderate to severe neuropsychic developmental delays, dysmorphic features and organ-specific developmental anomalies. RESULT: We searched for hereditary causes of morbid obesity in children by exome sequencing. As a result, we have identified 5 variants in the GNAS locus, two of which were identified for the first time: NM_000516.7(GNAS):c.201del, (p.Phe68Leufs*32) and NM_000516.7(GNAS):c.586 - 18_591del. Children showed tolerance to parathyroid hormone and thyroid-stimulating hormone. It has been observed that almost all the children with frameshift variants or nonsense mutations presented with subcutaneous ossifications. CONCLUSIONS: The search for variants in a group of patients with morbid obesity, as conducted in our research, reaffirms the need for use molecular genetic testing to determine the main diagnosis and facilitate early detection of the disease. This is particularly relevant given the wide clinical variability of monogenic forms of obesity.

Humans↗

PubMed2026

Genetic mutations in metastatic adenocarcinoma of unknown primary.

INTRODUCTION: Although several genomic alterations have been reported in adenocarcinoma of unknown primary (ACUP), molecularly targeted therapies are not yet clinically established, and comprehensive genomic profiling (CGP) is rarely used in daily practice. AIM: We aimed to clarify the molecular landscape and prognostic impact of key mutations in recurrent or metastatic ACUP. MATERIALS AND METHODS: Data from 480 consecutive ACUP patients registered in Japan's National Cancer Center (C-CAT) between June 2019 and August 2025 were analyzed. Somatic mutations were identified using the FoundationOne CDx platform. Overall survival (OS) was assessed by Kaplan-Meier analysis, log-rank tests, and multivariate Cox proportional hazards modeling. RESULTS: The most frequent alterations were TP53 (59.4%), KRAS (31.5%), CDKN2A (26.3%), KMT2D (22.3%), LTK (17.9%), NOTCH3 (16.9%), STK11 (16.3%), CDKN2B (15.8%), ERBB2 (15.4%), and GNAS (15.2%). Patients harbored an average of 17.3 9.9 mutations. Mutations in GNAS (p = 0.046) and PIK3CA (p = 0.025) were associated with better OS, whereas ARID1A (p = 0.049) and NOTCH1 (p = 0.038) predicted worse OS. In Cox analysis, hazard ratios (HR [95% CI]) were 0.57 (0.36-0.92, p = 0.020) for GNAS, 0.57 (0.33-0.96, p = 0.033) for PIK3CA, 1.98 (1.27-3.09, p = 0.0024) for ARID1A, and 1.84 (1.17-2.91, p = 0.0090) for NOTCH1. CONCLUSIONS: GNAS and PIK3CA mutations were linked to favorable outcomes, while ARID1A and NOTCH1 alterations indicated poor prognosis in ACUP. These results highlight the prognostic significance of specific genomic alterations and support integrating CGP into the clinical management of ACUP.

Humans↗

PubMed2025

In vivo genome-wide CRISPR screens in human T cells to enhance T cell therapy for solid tumors.

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that can enhance cellular immunotherapy. However, many genetic regulators of T cell performance in solid tumors may not be readily revealed in vitro. In vivo screening in tumor-bearing mice offers greater physiological relevance, but has historically been limited by low intratumoral T cell recovery. Here, we developed a new model system that achieves significantly higher human T cell recovery from tumors, enabling genome-wide in vivo screens with small numbers of mice. Tumor-infiltrating T cells in this model exhibit hallmarks of dysfunction compared to matched splenic T cells, creating an ideal context for screening for genetic modifiers of T cell activity in the tumor microenvironment. Using this platform, we performed two genome-wide CRISPR knockout screens to identify genes regulating T cell intratumoral abundance and effector function (e.g., IFN-γ production). The intratumoral abundance screen uncovered the P2RY8-Gα13 GPCR signaling pathway as a negative regulator of human T cell infiltration into tumors. The effector function screen identified GNAS (Gαs), a central signaling mediator downstream of multiple GPCRs that sense different suppressive ligands, as a key regulator of T cell dysfunction in tumors. Targeted GNAS knockout rendered T cells resistant to multiple suppressive cues and significantly improved therapeutic performance across diverse solid tumor models. Moreover, combinatorial knockout of P2RY8 (trafficking) and GNAS (effector function) further enhanced overall tumor control, demonstrating that genetic modifications targeting distinct T cell phenotypes can be combined to improve therapeutic potency. This flexible and scalable in vivo screening platform can be adapted to diverse tumor models and pooled CRISPR libraries, enabling future discovery of genetic strategies that equip T cell therapies to overcome barriers imposed by solid tumors.

Journal Article↗

PubMed2026

Somatic genetic alterations in pituitary neuroendocrine tumors.

The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS) and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

Humans↗

PubMed2026

Risk of Relapse and Efficacy of Adjuvant Chemotherapy in Localized Appendiceal Adenocarcinoma.

IMPORTANCE: Relapse risk and benefit of adjuvant chemotherapy after resection of appendiceal adenocarcinoma (AA) are uncertain. OBJECTIVE: To identify clinicopathologic and genomic factors associated with relapse and assess efficacy of adjuvant chemotherapy in localized AA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study (January 2000 through February 2024; median follow-up, 62.6 months) used Kaplan-Meier and Cox proportional hazards modeling. It took place at the University of Texas MD (UT MD) Anderson Cancer Center with validation from Memorial Sloan Kettering Cancer Center (MSKCC). Participants included a complete localized cohort of 439 patients with stage I to III AA from UT MD Anderson, of whom 202 underwent surgery at UT MD Anderson and also included a validation cohort of 128 patients with stage II AA from MSKCC. EXPOSURES: Surgical resection with or without adjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: Rate of recurrence, recurrence-free survival (RFS), and overall survival (OS). RESULTS: There were 439 patients with localized AA (median age, 56.5 [IQR, 22.2-83.7] years; 50% female and 50% male) managed at MD Anderson between January 2000 and February 2024. Of 202 MDA surgical patients, 19 (9.4%) had a relapse including 9 (6%) patients with stage II and 8 (19.5%) of patients stage III disease. Five-year OS was 95.7% without vs 77.2% with relapse (hazard ratio [HR], 5.50; 95% CI, 3.07-9.83; P < .001). Relative to goblet cell tumors, mucinous (HR, 5.60; 95% CI, 2.1-15; P < .001) and enteric-type (HR, 6.60; 95% CI, 2.9-15; P < .001) histologies were independently associated with relapse, as was pathologic T4 (HR, 3.30; 95% CI, 1.9-5.7; P < .001). Importantly, poor differentiation, perforation, lymphovascular invasion, and perineural invasion, known risk factors in colorectal cancer, were not significantly associated with relapse. For the complete localized cohort, adjuvant chemotherapy was not associated with improved RFS (univariate HR, 2.06; 95% CI, 1.36-3.13; P = .001 and multivariable HR, 0.98; 95% CI, 0.43-2.28; P = .90) or OS (univariate HR, 1.80; 95% CI, 1.0-3.2; P = .04 and multivariable HR, 0.71; 95% CI, 0.24-2.1; P = .53). TP53 mutation in goblet cell tumors (HR, 6.93; 95% CI, 1.50-31.00; P = .01) and GNAS mutation in nongoblet tumors (HR, 17.0; 95% CI, 3.09-93.3; P = .001) were associated with greater risk of relapse. CONCLUSIONS AND RELEVANCE: These results demonstrate that relapse after resection of localized AA is uncommon. Molecular profiling and histopathologic subtype refine risk. Adjuvant chemotherapy were not associated with benefit.

Journal Article↗

PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗

PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗

PubMed2026

Simultaneous quantitative detection of multiple low-frequency variants by high-dynamic-range capillary electrophoresis.

Sensitive and quantitative detection of low-frequency variants across multiple loci is critical for nucleic acid-based diagnostics, yet clinical implementation requires a balance among sensitivity, multiplexing capacity, cost, and operational simplicity. We previously developed a high-dynamic-range capillary electrophoresis system capable of detecting variants at allele frequencies below 1%; however, its application was limited to single-locus analysis. Here, we expanded this platform to multiplex detection by incorporating mobility-shift strategies into the assay design. This approach enabled simultaneous analysis of 15 hotspot variants across three clinically relevant loci: KRAS codons 12 and 13 and GNAS codon 201. Validation using synthetic oligonucleotides, formalin-fixed paraffin-embedded tissue, and liquid specimens demonstrated high quantitative accuracy over clinically relevant variant allele frequency ranges, with measured values closely matching expected values (R2 > 0.97). The assay showed high concordance with targeted amplicon sequencing and digital polymerase chain reaction for all variants at variant allele frequencies ≥1%, while also detecting selected variants below this threshold. Collectively, these results establish a multiplexed high-dynamic-range capillary electrophoresis assay for simultaneous, quantitative detection of low-frequency variants, offering a scalable and cost-effective approach for disease-focused gene panels in clinical laboratory settings.

HiDy↗

PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗

PubMed2026

Hepatocellular Carcinoma With JAK1 Mutations Harbors Distinct Histologic Features and Specific Mutational Hotspots in an Asian Cohort.

The pathogenesis and clinicopathological features of hepatocellular carcinoma (HCC) harboring JAK1 mutation have not been reported. Sixty inflammatory hepatocellular adenoma-like HCCs (IHA-like HCCs) and 16 IHAs were analyzed using targeted next-generation sequencing. Nearly all IHA-like HCCs (n=59, 98%) showed positive SAA/CRP expression. Genetic alterations of the JAK/STAT pathway were detected in 35 (58%) IHA-like HCCs, encompassing mutations in JAK1 (n=22), STAT3 (n=8), and IL6ST (n=5). Nine (56%) IHAs harbored mutations in STAT3 (n=3), IL6ST (n=4), GNAS (n=1), and FRK (n=1). All the mutations occurred in a mutually exclusive manner. JAK1 mutations were frequent (22/60, 37%) in IHA-like HCCs. JAK1-mutated IHA-like HCCs displayed distinctive cytologic characteristics, including abundant eosinophilic cytoplasm, vesicular chromatin, and prominent central nucleoli. Recurrent hotspot JAK1 mutations were identified at S703, S729, and L910. Surveillance for JAK1 mutations in the HCC genomics of other cohorts also revealed recurrent mutations at S703, S729, and L910. In particular, the S703 and S729 mutations were strongly associated with the features of Asian ethnicity, presence of chronic viral hepatitis, and hepatic fibrosis/cirrhosis. In conclusion, JAK1 mutations were frequent in HCC with IHA-like morphology in an Asian cohort. JAK1 mutation exhibited recurrent and specific hotspot mutations at S703, S729, and L910 in HCC. Patients diagnosed with JAK1-mutated HCC may be eligible for JAK-targeted molecular therapy.

JAK therapeutics↗

PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗

PubMed2026

Population-scale detection of methylation outliers from long-read genome sequencing.

BACKGROUND: Aberrant DNA methylation can mediate the functional effects of rare genetic variation and contribute to imprinting disorders, repeat expansion diseases, and other pathogenic regulatory mechanisms. Long-read sequencing technologies now enable genome-wide detection of CpG methylation alongside genetic variation from a single assay. However, methods for systematic identification and interpretation of methylation outliers from long-read sequencing data remain limited. METHODS: We developed METAFORA, a computational workflow for detecting methylation outlier regions from PacBio and Oxford Nanopore long-read sequencing data. METAFORA constructs population-level methylation references, segments the genome into correlated CpG blocks, infers technical and biological sources of variation through hidden factor estimation, models uncertainty due to variable depth sequencing, and computes covariate-adjusted methylation outlier scores for individual samples. We applied METAFORA across large long-read sequencing cohorts and integrated methylation outliers with multi-omic data. METAFORA is implemented as a snakemake workflow available at https://github.com/tjense25/METAFORA. RESULTS: METAFORA identified methylation outlier regions associated with rare structural variants, tandem repeat expansions, and imprinting abnormalities. We found outlier regions were enriched for molecular outliers across transcriptomic and chromatin accessibility datasets, supporting their functional relevance in gene regulation. In a representative case, METAFORA identified an imprinting defect affecting the GNAS locus associated with an STX16 deletion. CONCLUSIONS: METAFORA enables scalable detection and interpretation of methylation outliers from long-read sequencing data and provides a framework for integrating epigenetic outliers with genomic and multi-omic analyses. These approaches may improve interpretation of rare regulatory variation and support discovery of clinically relevant epigenetic abnormalities in genomic medicine.

DNA methylation↗