SEARCH · PubMed Health

Results for “driver mutations”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

Targeted Therapy in Acute Myeloid Leukemia: Current Approaches and Novel Directions.

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm of hematopoietic stem and progenitor cells. The advent of high-resolution genomic sequencing has uncovered several genetic drivers of AML which spurred a surge of therapies that target the disease at a mutational, clonal, or epigenetic level. Currently, the molecular profiling of AML patients before treatment is commonplace and crucial for ensuring that patients receive the most optimal therapy for any driver mutations they may have. Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.

BCL2↗

PubMed2025

Unraveling the Role of Mutations Outside the Basal Promoter and Precore Regions in the HBeAg-Negative Stage of Chronic Hepatitis B.

Hepatitis B e antigen (HBeAg) seroconversion is a crucial event in the natural history of chronic hepatitis B virus (HBV) infection, marked by a significant decrease in viral load and the emergence of mutations that suppress HBeAg expression. However, these mutations alone do not fully account for the reduction in viral load. This study investigated the biological features and pathogenic roles of mutations outside the basal core promoter (BCP) and precore regions during the HBeAg-negative stage of chronic infection. Full-length HBV genomes from HBeAg-positive (n = 180) and HBeAg-negative (n = 328) genotype D datasets were analyzed, revealing significantly higher genomic heterogeneity in HBeAg-negative sequences compared with HBeAg-positive genomes (50.4 ± 16.0 vs. 26.6 ± 10.5 nucleotide changes per genome). Twenty-six hotspot amino acid mutations associated with the HBeAg-negative stage were identified, with over half located in the Core region. Subsequently, full-length HBV genomes from six HBeAg-negative patient-derived serum samples were obtained by PCR amplification followed by Sanger sequencing. Infectious clones generated from these genomes, each carrying between 21 and 66 amino acid substitutions, were characterized, showing that mutations in this stage differentially affected viral fitness in vitro by up- or downregulating HBV-DNA levels (ranging from 0.2 to 5 times those of the wild-type isolate), modulating capsid assembly, and altering the expression, secretion, and subcellular localization of viral proteins. In conclusion, while mutations in the BCP and precore regions are the primary drivers of HBeAg seroconversion, mutations outside these regions significantly influence HBV biology and potentially contribute to viral pathogenicity, underscoring the complex interplay between host and virus during the HBeAg-negative stage of chronic infection.

Humans↗

PubMed2006

Recurrent KRAS codon 146 mutations in human colorectal cancer.

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.

Adenocarcinoma↗

PubMed2025

Characterization of a PRKCE::ETV6 fusion as a potential oncogenic driver in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by mutation accumulation during hematopoiesis. The characterization of chromosomal abnormalities may provide significant insights into genetic mechanisms of malignant transformation in hematopoietic cells. However, T-ALL is genetically very heterogenous and driving mutations as well as clonal markers for the assessment of minimal residual disease are not always identifiable. Hence, there is a clinical need to further refine the genetic landscape of T-ALL including previously unrecognized fusion partners of commonly translocated genes in T-ALL of childhood. RESULTS: In this study, we screened n = 229 T-ALL cases by our targeted genomic capture high-throughput sequencing (gc-HTS) approach. In total, we identified n = 60 gene–gene fusions, present in n = 57 (25%) of the patients. Nine rare or even unrecognized translocations were identified and validated. Furthermore, owing to its interesting chromosomal structure, we studied the oncogenic potential of the complex rearrangement of chromosome 2 and 12, found in a near-early T-cell progenitor (ETP) ALL that leads to the fusion events PRKCE::ETV6 and ETV6::INO80D. Exogenous expression of PRKCE::ETV6 in Ba/F3 pro-B and D1 T-cells caused interleukin-independent proliferation and enhanced survival upon interleukin withdrawal, respectively. CONCLUSION: Our study underlines the heterogenous mutational landscape in T-ALL. The previously unrecognized PRKCE::ETV6 resulting from a complex rearrangement involving chromosome 2 and 12 demonstrated transforming potential in cytokine-dependent cellular models support the notion of a driver mutation in near ETP-ALL. Our data reconfirm the relevance of ETV6-fusion proteins in the pathogenesis of undifferentiated T-ALL. Importantly, genomic breakpoints at the ETV6 locus represent potentially robust MRD markers for (near) ETP-ALL that lack IG/TR rearrangements.

ETV6::INO80D↗

PubMed2026

Proteomics as a theranostic compass in BCR::ABL1-negative myeloproliferative neoplasms: Integrating biomarker discovery with therapeutic stratification.

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.

Humans↗

PubMed2026

iMTSS: an integrated framework for biology- and patient-driven prognosis in myelofibrosis undergoing transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation is the only curative treatment for myelofibrosis, but failure occurs by two mechanistically distinct routes: relapse of the neoplasm, which reflects its underlying genetics, and non-relapse mortality, which reflects whether the patient and graft tolerate the procedure. Established prognostic systems either lack molecular granularity or were derived in the non-transplant setting, and all collapse these two routes into a single survival estimate. None can indicate why an individual patient is at risk, or which class of intervention might reduce that risk. OBJECTIVE: To determine why an individual patient is at risk and to develop and validate an integrated framework that quantifies biology- and patient-driven prognosis. STUDY DESIGN: We analyzed 1,550 adults undergoing first allogeneic transplantation for primary or secondary myelofibrosis across international centers, the largest genomically annotated transplant cohort in this disease. The cohort was split into development (n=930) and validation (n=620) sets. Overall survival was modeled by Cox regression; relapse and non-relapse mortality were modeled as competing events by Fine-Gray subdistribution-hazard regression at 2 years. Discrimination was assessed by the concordance index with bootstrap confidence intervals. The molecular contribution was quantified by variance decomposition of, and robustness to the analytic choices was examined by resampling. RESULTS: A genetically defined disease-intrinsic axis, including TP53 allelic state, RAS pathway mutations, ASXL1 and driver genotype, blasts and blood counts, predicted 2 year relapse incidence (validation concordance 0.69, 95% CI 0.63 to 0.74), whereas a non-overlapping host and structural axis, including portal vein thrombosis, donor type, patients' performance status, and age predicted 2-year non-relapse mortality (0.63, 95% CI 0.59 to 0.68). The two scores shared only 3.4% of their variance, indicating that a patient's disease genetics carried almost no information about non-relapse mortality. Variance decomposition showed that TP53 allelic state alone accounted for 30% of the relapse score. Recombined, the framework discriminated overall survival (concordance 0.640, 95% CI 0.616 to 0.662) better than every established prognostic system. For proof of concept, 3 risk groups separated in the validation cohort, with 5 year survival of 72%, 58%, and 39% (P<0.001), and the models were well calibrated. CONCLUSIONS: Relapse and non-relapse mortality after transplantation for myelofibrosis are governed by distinct dimensions. Estimating both outcomes independently with genetic and clinical information, in addition to overall survival, establishes an individualized basis for transplant decision-making. The calculator is openly available (https://imtss-calculator.com).

mortality↗

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

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

PubMed2026

Enozertinib Is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non-Small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations.

UNLABELLED: EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and approximately half of patients develop brain metastases over the course of their disease. Patients with nonclassic EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared with patients with classic EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR-mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to address the unmet need for brain-penetrant therapies in NSCLC with EGFR exon 20 insertions or other atypical mutations. SIGNIFICANCE: Preclinical and initial phase I clinical data demonstrate the potency, kinome selectivity, efficacy, and brain penetration of enozertinib in NSCLC with EGFR exon 20 insertions and atypical mutations, warranting further clinical development.

Carcinoma, Non-Small-Cell Lung↗

PubMed2026

Epigenetic Liquid Biopsy Enables Universal Mutation-Agnostic Molecular Surveillance for High-Risk Neuroblastoma.

PURPOSE: Liquid biopsy monitoring in pediatric solid tumors is limited by low mutational burden and lack of trackable genomic drivers. We sought to develop a mutation-agnostic, methylation-based liquid biopsy framework enabling universal molecular surveillance of high-risk neuroblastoma. EXPERIMENTAL DESIGN: Using whole-genome Oxford Nanopore Technologies sequencing of high-risk neuroblastoma tumors, we compared tumor-derived methylation profiles with a comprehensive atlas of normal human cell types and identified 72 neuroblastoma-specific differentially methylated regions (meNBL) that were reliably detectable in cell-free DNA (cfDNA). Marker robustness and specificity were validated using independent neuroblastoma methylation datasets and assessed against methylation profiles from other cancer types. We established neuroblastoma as a distinct methylation entity within the reference atlas by integrating a panel of 25 meNBLs, enabling quantitative estimation of tumor-derived cfDNA. Assay performance was evaluated across diagnostic, remission, relapse, and healthy control samples and compared with mutation-based and copy number-based approaches. RESULTS: Neuroblastoma-derived cfDNA was consistently detected at diagnosis and relapse but was absent in healthy controls and during confirmed remission. Methylation-based deconvolution demonstrated high specificity, with no detectable background signal in controls, and improved performance relative to copy number-based tumor fraction estimation. Longitudinal profiling enabled early molecular detection of relapse and reliable disease monitoring. CONCLUSIONS: We establish a robust, mutation-independent methylation-based liquid biopsy strategy for neuroblastoma that enables accurate, quantitative disease monitoring across all high-risk patients, including those lacking trackable genomic alterations. This approach supports the clinical translation of methylation-based cfDNA deconvolution as a broadly applicable platform for pediatric precision oncology.

Humans↗

PubMed2026

Establishment of induced pluripotent stem cell line TRNDi045-A-38 carrying homozygous DOK7-related Congenital Myasthenia patient-mutation knock-in variant from parental KOLF2.1J.

DOK7-related Congenital Myasthenic Syndrome (CMS) is a rare genetic neuromuscular junction disorder. This is one of the most common of the recessive forms of CMS, often presenting with more static proximal weakness (hence also referred to as limb girdle CMS). Whole-genome sequencing of affected patients implicates frameshift duplication mutations in DOK7 as drivers of impaired neuromuscular-junction signaling. In this study, we generated a human induced pluripotent stem cell (hiPSC) line TRNDi045-A-38 from the KOLF2.1J reference line, engineered to carry homozygous DOK7 c.1124_1127dupTGCC mutation knock-in using CRISPR/Cas9. This iPSC line could be used for in vitro disease modeling to study disease pathophysiology and for therapeutic development.

Humans↗

PubMed2026

Liquid biopsies reveal dual compartments of cancer risk from tumor and host-derived mutations.

MOTIVATION: Circulating tumor DNA (ctDNA) and clonal hematopoiesis of indeterminate potential (CHIP) are two biologically distinct sources of somatic mutations detectable in blood. While ctDNA captures tumor-intrinsic alterations, CHIP arises from age-related hematopoietic clones and is often considered background noise. Here, we conduct a large-scale, tumor-type-resolved analysis of over 9000 patients with CHIP data and 1500 patients with ctDNA data across solid tumors profiled at Memorial Sloan Kettering Cancer Center. RESULTS: Our results reveal that CHIP and ctDNA mutations exhibit non-overlapping, clinically meaningful signals. CHIP mutations, particularly in DNA damage response and epigenetic regulators (e.g. PPM1D, CHEK2, ATM, TP53, ASXL1), are associated with worse overall survival, increased metastatic potential, and site-specific dissemination. ctDNA mutations in canonical oncogenic drivers (e.g. TP53, EGFR, KRAS, STK11) reflect tumor aggressiveness and correlate with poor prognosis and metastasis across multiple cancer types. Joint modeling in lung adenocarcinoma confirms the independent prognostic contributions of both compartments. Additionally, longitudinal clonal analysis links specific CHIP mutations to the emergence of hematologic malignancies under therapeutic pressure. These findings support a dual-compartment model of liquid biopsy, in which tumor- and host-derived mutations jointly inform on cancer risk, progression, and metastatic behavior. Integrating both compartments may enhance the clinical utility of blood-based biomarkers in oncology. AVAILABILITY: All genomic and clinical data used in this study are available through cBioPortal. Summarized outputs and processed results tables are provided in Supplementary Data.

Humans↗

PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗

PubMed2026

Detection of House Dust Mite-derived DNA in Human Lung Tumors by Whole-Genome Sequencing.

Lung cancer in never-smokers (LCINS) accounts for an increasing proportion of lung cancer cases, yet its risk factors remain poorly understood. House dust mites (HDM) are common aeroallergens that induce airway inflammation, but their potential contribution to lung cancer is unknown. We analyzed unmapped whole-genome sequencing reads from 783 lung cancers from the Sherlock-Lung (n = 621 never-smokers) and EAGLE (n = 162 smokers) cohorts, including 328 matched adjacent normal lung tissues. After removal of human sequences, reads were aligned to reference genomes from the two major HDM species and confirmed by BLAST. Samples with top BLAST matches were classified as HDM-detected. Associations between HDM detection and genomic, microbiome, and bulk RNA-seq-derived immune features were evaluated. HDM-derived DNA was detected at low abundance in a subset of tumors and adjacent normal tissues, with higher detection frequencies in tumors than matched normal tissues and in smokers than never-smokers. In LCINS tumors, HDM detection was not associated with tumor mutational burden or recurrent driver alterations but was associated with modest differences in immune cell composition and a limited but reproducible bacterial co-detection pattern. These findings provide a foundation for investigating aeroallergen-derived DNA signatures and their potential relationship to the lung tumor microenvironment.

Environmental exposure↗

PubMed2004

Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility.

Humans heterozygous for PKD1 or PKD2 develop autosomal dominant polycystic kidney disease, a common genetic disorder characterized by renal cyst formation and extrarenal complications such as hypertension and vascular aneurysms. Cyst formation requires the somatic inactivation of the wild type allele. However, it is unknown whether this recessive mechanism applies to life-threatening vascular aneurysms, which could involve weakening of the endothelial lining or surrounding vascular smooth muscle cells (SMCs). Drosophila Pkd2 at 33E3 (Pkd2) encodes a PKD2 family of Ca(2+)-activated Ca(2+)-permeable cation channels. We show here that loss-of-function Pkd2 mutations severely reduced the contractility of the visceral SMCs, which was restored by expressing wild type Pkd2 cDNA via a muscle-specific Gal4 driver. The effect of Pkd2 mutations alone on the skeletal muscle was minimal but was exacerbated by ryanodine-induced perturbation of intracellular Ca(2+) stores. Consistent with this, Pkd2 interacted strongly with a ryanodine receptor mutation, causing a synergistic reduction of larval body wall contraction rate that is normally regulated through Ca(2+) oscillation during excitation-contraction coupling in the skeletal muscle. These results suggest that PKD2 cooperates with the ryanodine receptor to promote optimal muscle contractility through intracellular Ca(2+) homeostasis. Further genetic analysis indicated that Pkd2 is strongly haploinsufficient for normal SMC contractility. Since Ca(2+) homeostasis is a conserved mechanism for optimal muscle performance, our results raise the possibility that inactivation of just one PKD2 copy is sufficient to compromise vascular SMC contractility and function in PKD2 heterozygous patients, thus explaining their increased susceptibility to hypertension and vascular aneurysms.

Animals↗

PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗

PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗

PubMed2025

Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration.

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Humans↗