SEARCH · Search PubMed

Results for “Recurrent mutation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2026

Clinicopathological and genetic analysis of primary intraosseous carcinoma not otherwise specified (PIOC NOS).

BACKGROUND: Primary intraosseous carcinoma not otherwise specified (PIOC NOS) is an extremely rare jawbone cancer, accounting for approximately 1-2% of all oral cancers. Considering its rarity, no established standard treatment exists for postoperative recurrence or metastasis. This study aimed to analyse the clinical manifestations of this disease and identify novel genomic abnormalities to aid identification of potential treatment strategies. METHODS: We examined the clinical information of 14 PIOC NOS cases treated at our institution in recent years and compared it with previous reports. Genomic analysis was conducted on seven formalin-fixed paraffin-embedded surgical specimens, assessing 523 DNA and 55 RNA cancer-related genes using next-generation sequencing. RESULTS: Our findings, along with previous literature, revealed the posterior mandible as the primary site in most cases, though this was rarely identified at the time of initial diagnosis. Recurrence within two years of surgery was common. Hotspot mutations in PIK3CA were observed in 60% of cases. Additionally, one patient had high TMB status. CONCLUSIONS: Given the challenges in diagnosis and the potential for rapid recurrence or metastasis, early detection is crucial. Comprehensive genomic profiling is highly desirable, as genomic analysis may direct the development of targeted therapeutic agents to treat relapse.

Humans↗

PubMed2026

In-host adaptation of Staphylococcus aureus during recurrent prosthetic joint infections: a retrospective longitudinal study.

UNLABELLED: The aim of this study was to characterize the in vivo evolution of Staphylococcus aureus strains involved in recurrent prosthetic joint infections (PJIs) both phenotypically and genomically. We conducted a monocentric retrospective study in a 1,437-bed French teaching hospital between 2013 and 2021. All patients presenting a recurrent S. aureus-related PJI-defined as at least two strains isolated from distinct clinical samples more than 90 days apart-of the knee, hip, or shoulder were included. Clinical data were reviewed, and all isolates underwent phenotypic characterization, including antimicrobial susceptibility testing, growth rate determination, biofilm production assays, metabolic profiling (API 50 CH), and virulence evaluation using the Galleria mellonella infection model. Whole-genome sequencing (WGS) was performed for all strains, followed by analyses of core-genome multilocus sequence typing (cgMLST), resistome, virulome, and mobilome composition, and single-nucleotide polymorphisms (SNPs). Thirteen patients met inclusion criteria, yielding 55 S. aureus isolates. Eight patients experienced recurrent infections caused by genetically closely related strains throughout the clinical course (median: three strains per patient; range: 2-6), whereas five patients were infected by genetically distinct strains. At baseline, isolates were genetically diverse and susceptible to methicillin and rifampicin; two showed fluoroquinolone resistance due to grlA and/or gyrA mutations. In one patient (patient C), a recurrent isolate acquired an rpoB S486L mutation, conferring rifampicin resistance after rifampicin exposure. Due to the limited sample size, it is difficult to draw definitive conclusions from the phenotypic analyses. This study highlights the adaptive evolution of S. aureus during chronic PJIs and underscores the need for further research to better understand intra-host dynamics in long-standing infections. IMPORTANCE: This study conducted in a 1,437-bed French teaching hospital analyzed the genomic and phenotypic evolution of 55 Staphylococcus aureus strains recovered in recurrent PJIs from 13 patients. The first strains showed high genotypic diversity across 12 different sequence types. Among the 13 patients, only eight experienced a true recurrence with the same strain, while five were contaminated with a different strain of S. aureus, indicating a new infection. Moreover, this study underscores the complex within-host evolution of S. aureus and highlights the phenotypical and genotypical adaptation during chronic infection.

Staphylococcus aureus↗

PubMed2025

MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

BACKGROUND/OBJECTIVES: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. METHODS: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. RESULTS: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. CONCLUSIONS: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.

ATR↗

PubMed2025

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

BACKGROUND: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS: 64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION: The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

Humans↗

PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗

PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗

PubMed2026

Paired Whole-Genome Sequencing of Scalp Angiosarcoma and Matched Lung Metastasis Reveals Common Clonal Origin and Lung-Specific Evolution.

Background and Clinical Significance: Cutaneous angiosarcoma frequently metastasizes to the lungs, where it may rarely present as diffuse cystic lung disease with recurrent pneumothorax, resulting in substantial diagnostic difficulty. We report a case of pulmonary metastatic cutaneous angiosarcoma in which paired whole-genome sequencing (WGS) of the primary and metastatic lesions was performed to clarify clonal origin and characterize metastatic evolution. Case Presentation: A 65-year-old man with recurrent right-sided pneumothorax and progressive bilateral cystic lung lesions underwent skin and lung biopsies. Histopathological examination and immunohistochemistry established the diagnosis of cutaneous angiosarcoma with pulmonary metastases. Paired WGS was performed on matched scalp and lung tumor specimens to evaluate shared and lesion-specific genomic alterations, pathway enrichment, and copy-number changes. Histopathology confirmed metastatic angiosarcoma involving the lungs. WGS identified 128 shared somatic alterations, supporting a common clonal origin, together with lung-specific and skin-specific mutations indicative of continued genomic divergence. Recurrent alterations involving POT1 and FLT4 were preserved in both lesions, whereas additional POT1 and TP53 alterations were detected only in the pulmonary metastasis. Pathway analysis demonstrated preferential enrichment of IGF1-mTOR, RAS, and WNT/LRP6 signaling in the metastatic lesion, while Gene Ontology analysis suggested functional divergence associated with metastatic progression. Conclusions: Pulmonary metastatic angiosarcoma should be considered in patients presenting with unexplained diffuse cystic lung disease and recurrent pneumothorax, particularly when pathological findings are inconclusive. Paired WGS complemented conventional histopathology by confirming the metastatic origin and providing insights into clonal evolution and lesion-specific molecular alterations, highlighting its potential value in the investigation of rare metastatic malignancies.

angiosarcoma↗

PubMed1977

Frequency of occurrence of idiotypes associated with anti-p-azophenylarsonate antibodies arising in mice immunologically suppressed with respect to a cross-reactive idiotype.

Inoculation of rabbit anti-idiotypic (anti-id) antibodies suppresses the subsequent appearance of a cross-reactive idiotype (CRI) associated with the anti-p-azophenylarsonate (anti-Ar) antibodies of A/J mice. Such suppressed mice produce normal concentrations of anti-Ar antibodies which lack the CRI, but against which anti-id antisera can be prepared. The anti-Ar antibodies of an individual, suppressed mouse do not in general share idiotype with anti-Ar antibodies of other A/J mice, either suppressed or nonsuppressed. The present experiments were undertaken to quantitate several "private idiotypes" in a large number of hyperimmunized A/J mice. Anti-Ar antibodies of three mice, suppressed for the CRI, were labeled with 125I and subjected to isoelectric focusing. Four single peaks, that were over 90% reactive with autologous antiid, were randomly selected for use as ligands in a radioimmunoassay, and ascitic fluids containing anti-Ar antibodies from 181 A/J mice were tested as inhibitors. Two of the four idiotypes could not be detected in any mouse other than the donor. The concentration of the idiotype was less than 1 part in 1,250 to less than 1 part in 25,000 of the anti-Ar antibody population; these are minimum values. A third idiotype was detected in 3 of the 181 mice, but at very low concentrations. The fourth idiotype was present in 28% of the mice, again at a low concentration. The data support the existence of a very large repertoire of anti-Ar antibodies in the A/J strain and are consistent with a process of random somatic mutation for generating diversity in hypervariable regions. It is proposed that the cross-reactive idiotype may be controlled by a germ line gene or a gene related to a germ line gene through a small number of somatic mutations; and that the idiotypes that were not detectable in other mice were the products of genes that had undergone extensive mutations, with a low probability of recurrence in other mice.

Animals↗

PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗

PubMed2025

Comprehensive analysis of a novel LYST mutation in a Tunisian patient with Chediak-Higashi syndrome.

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking. OBJECTIVE: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation. METHODS: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations. RESULTS: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking. CONCLUSION: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

Adolescent↗

PubMed2026

RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.

RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+). Each of 20 PDACs with RNF43 mutations (RNF43mut) and without RNF43 mutations (RNF43wt) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+ T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.

Humans↗

PubMed2026

Ovarian Carcinoma Presenting Mucoepidermoid Carcinoma-Like Features in Association With Seromucinous Borderline Tumor: A Real Seromucinous Carcinoma?

Ovarian seromucinous carcinoma is generally classified within the spectrum of endometrioid carcinoma. We report a rare ovarian carcinoma with mucoepidermoid carcinoma-like features arising in direct association with a seromucinous borderline tumor. A 56-year-old postmenopausal female presented with a 10-cm pelvic multilocular cystic tumor and markedly elevated carbohydrate antigen 19-9. Histopathological examination showed a seromucinous borderline tumor with transition to invasive carcinoma composed of mucinous epithelial cells and p40-positive intermediate-like cells. The tumor was diffusely positive for PAX8 and negative for cytokeratin 20, supporting Mullerian differentiation. The p40-positive cell population persisted in the borderline, invasive, and para-aortic lymph node metastatic components. Comprehensive genomic profiling identified KRAS p.G12D without CTNNB1, PTEN, or ARID1A mutations. The patient developed platinum-resistant recurrence and died 11 months after diagnosis. This case is compatible with a potential endometriosis-independent pathway from seromucinous borderline tumor to an aggressive mucoepidermoid-like carcinoma.

mucoepidermoid carcinoma↗

PubMed2025

Identification of a novel heterozygous GPD1 missense variant in a Chinese adult patient with recurrent HTG-AP consuming a high-fat diet and heavy smoking.

BACKGROUND: Glycerol-3-phosphate dehydrogenase 1 (GPD1) gene defect can cause hypertriglyceridemia (HTG), which usually occurs in infants. The gene defect has rarely been reported in adult HTG patients. In the present study, we described the clinical and functional analyses of a novel GPD1 missense variant in a Chinese adult patient with recurrent hypertriglyceridemia‑related acute pancreatitis (HTG-AP), consuming a high-fat diet and smoking heavily. METHODS: Exome sequencing was used to analyze the DNA of the adult patient's blood sample. It was found that there was a new variant of GPD1 gene-p.K327N, which was verified by gold standard-sanger sequencing method. In vitro, the corresponding plasmid was constructed and transfected into human renal HEK-293T cells, and GPD1 protein levels were detected. A biogenic analysis was performed to study the population frequency, conservation, and electric potential diagram of the new variant p.K327N. Finally, the previously reported GPD1 variants were sorted and their phenotypic relationships were compared. RESULTS: A novel heterozygous variant of GPD1, p.K327N (c.981G > C), was found in the proband. Furthermore, the patient's daughter carried this variant, whereas his wife did not carry the variant. The proband with obesity suffered eight episodes of HTG-AP from the age of 36 years, and each onset of AP was correlated to high-fat diet consumption and heavy smoking. In vitro, this variant exerted a relatively mild effect on GPD1 functions, which were associated with its effect upon secretion (~ 25% of secretion decreased compared with that of the wild-type); thus, eventually impairing protein synthesis. Additionally, 36 patients with GPD1 variants found in previous studies showed significant transient HTG in infancy. The proband carrying the GDP1 variant was the first reported adult with recurrent HTG-AP. CONCLUSION: We identified a novel GPD1 variant, p.K327N, in a Chinese adult male patient with recurrent HTG-AP. The variant probably exerted a mild effect on GPD1 functions. The heterozygosity of this GPD1 variant, in addition to high-fat diet consumption and heavy smoking, probably triggered HTG-AP in the patient.

Adult↗

PubMed2026

Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.

BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.

Journal Article↗

PubMed2026

Serial CSF CA19-9 monitoring and CSF genomic profiling in ERBB2-mutant lung adenocarcinoma with leptomeningeal metastasis: a case report.

Leptomeningeal metastasis (LM) from ERBB2-mutant lung adenocarcinoma is difficult to treat and monitor because systemic disease and leptomeningeal disease may evolve discordantly. Evidence regarding cerebrospinal fluid (CSF) genomic profiling and serial CSF tumor marker monitoring in ERBB2-mutant non-small cell lung cancer with LM remains limited. We report a 48-year-old woman initially diagnosed with stage IB mucinous lung adenocarcinoma harboring an ERBB2 exon 20 p.G776delinsVC mutation. After surgery and adjuvant chemotherapy, she developed nodal recurrence and later presented with lower back pain and lower-limb numbness. LM was clinically diagnosed based on neurological symptoms, magnetic resonance imaging and CSF cytopathology. She received craniospinal irradiation, systemic therapy and subsequent intrathecal treatment. At month 33, CSF CA19-9 was markedly elevated despite no clear radiographic systemic progression. CSF next-generation sequencing(NGS) detected the same ERBB2 exon 20 p.G776delinsVC mutation as the primary lung tumor, with a higher variant allele fraction in CSF than in lung tissue.The patient subsequently received trastuzumab deruxtecan and sequential intrathecal therapy with pemetrexed, etoposide, cytarabine and pemetrexed rechallenge. Intrathecal treatment was adjusted according to serial CSF CA19-9 levels, neurological status, imaging findings, systemic disease activity and treatment-related toxicities. CSF CA19-9 was not used as a stand-alone criterion for progression or treatment modification.At the latest follow-up, she remained alive more than 36 months after the clinical diagnosis of LM. This case suggests that CSF NGS and serial CSF CA19-9 may provide further insights into disease activity within the integrated assessment of systemic and leptomeningeal disease. Their clinical applicability is still under investigation and necessitates future validation.

CA19-9↗

PubMed2025

AUTS2-related syndrome: Insights from a large European cohort.

PURPOSE: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. METHODS: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). RESULTS: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. CONCLUSION: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Humans↗

PubMed2025

Tracking Nongenetic Evolution from Primary to Metastatic ccRCC: TRACERx Renal.

While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.

Journal Article↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗