Molecular Oncology最新文献

{"title":"Landscape of BRAF transcript variants in human cancer.","authors":"Maurizio S Podda, Danilo Tatoni, Gianluca Mattei, Alberto Magi, Romina D'Aurizio, Laura Poliseno","doi":"10.1002/1878-0261.70043","DOIUrl":"10.1002/1878-0261.70043","url":null,"abstract":"<p><p>The BRAFV600E mutant kinase is widely studied as a cancer driver and therapeutic target. Here, we investigated how the annotation of the BRAF-reference (ref) and BRAF-X1 variants has evolved in public databases and addressed challenges posed by their discrimination and quantification from short-read sequencing. We built IsoWorm, a bioinformatic pipeline tailored to discriminate and quantify BRAF variants, and employed it to analyze > 600 cancer cell lines and > 1000 cancer tissue samples. Using FLIBase, we reanalyzed TCGA data from > 9000 cancer tissue samples. We consistently found that BRAF-X1 (now BRAF-204) is very abundant in human cancer and its expression is 1.5-75 times greater than that of BRAF-ref (now BRAF-220). Crucially, we identified KIRP-kidney renal papillary cell carcinoma as a cancer subtype in which a high BRAF-204/BRAF-220 ratio is an independent prognostic factor of poor outcome. Our in silico analyses establish BRAF as a mix of two protein-coding transcript variants, with BRAF-204 being more highly expressed than BRAF-220. These findings prompt us to undertake the systematic benchmarking of BRAF-204 against BRAF-220 in terms of molecular mechanisms, biological activities, druggability, and clinical relevance.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2700-2714"},"PeriodicalIF":4.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of ROS1 fusion partners and resistance mechanisms in ROS1-TKI-treated non-small cell lung cancer patients.","authors":"Fenneke Zwierenga, Christa Dijkhuizen, Patrick Korthuis, Wim Timens, Harry Groen, Jeroen Hiltermann, Anke van den Berg, Lyndsay Drayer, Anthonie van der Wekken","doi":"10.1002/1878-0261.70109","DOIUrl":"https://doi.org/10.1002/1878-0261.70109","url":null,"abstract":"<p><p>Clinical outcomes in ROS1-fusion positive (ROS1+) non-small cell lung cancer (NSCLC) by fusion partner and resistance mechanisms are limited. This cohort study included 56 ROS1+ patients (FISH or NGS confirmed); fusion partners were identified in 27 cases, including CD74 (n = 10), EZR (n = 7), and SDC4 (n = 7). Clinical data were available for 50 patients (median age 62; 51% female; 32% never-smokers). Forty patients received tyrosine kinase inhibitors (TKIs), mostly crizotinib (n = 38). Crizotinib showed a 55% objective response rate (ORR) and a median progression-free survival (mPFS) of 5.3 months. Brain metastases (HR 2.65, 95% CI 1.06-6.60, P = 0.037) and prior chemotherapy (HR 3.17, 95% CI 1.35-7.45, P = 0.008) had a higher risk of progression. Sixteen patients received subsequent lorlatinib, with an ORR of 28% and mPFS of 3.7 months. G2032R and L2026M resistance mutations were identified in four lorlatinib non-responders, and in vitro studies confirmed resistance to lorlatinib. Fusion partners did not affect crizotinib outcomes. Lorlatinib was ineffective against on-target resistance. Real-world data showed lower TKI efficacy than clinical trials, highlighting the role of clinical and molecular factors in treatment response.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression and DNA methylation of 20S proteasome subunits as prognostic and resistance markers in cancer.","authors":"Ruba Al-Abdulla, Simone Venz, Ruslan Al-Ali, Martin Wendlandt, Mandy Radefeldt, Elke Krüger","doi":"10.1002/1878-0261.70038","DOIUrl":"https://doi.org/10.1002/1878-0261.70038","url":null,"abstract":"<p><p>Proteasomes are involved in the maintenance of cellular protein homeostasis and the control of numerous cellular pathways. Single proteasome genes or subunits have been identified as important players in cancer development and progression without considering the proteasome as a multisubunit protease. We here conducted a comprehensive pan-cancer analysis encompassing transcriptional, epigenetic, mutational landscapes, pathway enrichments, and survival outcomes linked to the 20S proteasome core complex. The impact of proteasome gene expression on patient survival exhibited a cancer type-dependent pattern. Increased proteasome expression correlated with elevated activation of oncogenic pathways, such as DNA repair, MYC-controlled gene networks, MTORC1 signalling, oxidative phosphorylation, as well as metabolic pathways including glycolysis and fatty acid metabolism. Accordingly, potential loss of function variants of proteasome subunit genes are associated with improved patient survival. The TCGA-derived outcomes were further supported by gene expression analysis of THP-1 cells. Our study highlighted the importance of studying the proteasome as an enzymatic functional unit rather than separated subunits.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-agnostic detection of circulating tumor DNA in patients with advanced pancreatic cancer using targeted DNA methylation sequencing and cell-free DNA fragmentomics.","authors":"Morten Lapin, Kjersti Tjensvoll, Karin Hestnes Edland, Satu Oltedal, Herish Garresori, Bjørnar Gilje, Saga Ekedal, Trygve Eftestøl, Jan Terje Kvaløy, Filip Janku, Oddmund Nordgård","doi":"10.1002/1878-0261.70116","DOIUrl":"https://doi.org/10.1002/1878-0261.70116","url":null,"abstract":"<p><p>We investigated whether DNA methylation and cell-free DNA (cfDNA) fragmentation patterns can improve circulating tumor DNA (ctDNA) detection in advanced pancreatic cancer. In a cohort of 33 patients, ctDNA detection was performed in a tumor-agnostic fashion using DNA methylation, cfDNA fragment lengths, and 4-mer 5' end motifs. Machine learning models estimating ctDNA levels were built for each individual detection method and their combination. All models significantly differentiated ctDNA levels in patients from healthy individuals (P < 0.001). Using the highest estimated levels in healthy volunteers as cutoffs, ctDNA was detected in 79%, 67%, 67%, and 55% of patients using methylation, fragment length, end motifs, and the combined model, respectively. Univariable Cox regression showed that all ctDNA level estimates were associated with increased hazard ratios (HR, all P < 0.001) for progression-free survival (PFS) and overall survival (OS). Multivariable Cox regression confirmed ctDNA levels as an independent predictor of PFS (HR = 1.9, P < 0.001) and OS (HR = 2.7, P < 0.001). Our findings suggest that machine learning models based on DNA methylation, cfDNA fragment lengths, and cfDNA end motifs can estimate ctDNA levels and predict clinical outcomes in advanced pancreatic cancer.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota diversity is prognostic in metastatic hormone receptor-positive breast cancer patients receiving chemotherapy and immunotherapy.","authors":"Andreas Ullern, Kristian Holm, Nikolai Kragøe Andresen, Andreas Hagen Røssevold, Corinna Bang, Bjørn Naume, Johannes R Hov, Jon Amund Kyte","doi":"10.1002/1878-0261.70117","DOIUrl":"https://doi.org/10.1002/1878-0261.70117","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) is standard treatment in several cancer types, despite not being proven efficacious in metastatic hormone receptor-positive breast cancer (HR+ mBC). The gut microbiota is associated with patient outcome and toxicity from cancer therapy, although limited data are available for breast cancer. In the randomized phase 2b trial ICON, immunomodulating chemotherapy was investigated in combination with dual ICB in HR+ mBC. To determine whether gut microbiota could inform prognosis, we performed 16S (V3-V4) rRNA sequencing on fecal samples collected at baseline and after 8 weeks of study treatment. We showed that high alpha diversity before treatment was associated with prolonged progression-free survival (PFS; primary trial endpoint) and overall survival. Alpha diversity was lower in patients with prior chemotherapy in the metastatic setting. However, alpha diversity remained significantly associated with PFS after correcting for prior chemotherapy and other factors in bivariate analyses. High-grade immune-related toxicity was also associated with high alpha diversity. These findings suggest that high alpha diversity should be further investigated as a positive prognostic factor in HR+ mBC and approaches to increase alpha diversity could potentially improve clinical outcome.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP1::TFE3 mediates endothelial-to-mesenchymal plasticity in epithelioid hemangioendothelioma.","authors":"Ant Murphy, Samuel Hartzler, Paula A Vargas Carranza, Shyaman Jayasundara, Madison E Yates, Nimod D Janson, Bozhi Liu, Annaleigh Benton, Majid Kazemian, Jason A Hanna","doi":"10.1002/1878-0261.70112","DOIUrl":"10.1002/1878-0261.70112","url":null,"abstract":"<p><p>The rare vascular sarcoma epithelioid hemangioendothelioma (EHE) is defined by WWTR1 or YAP1 gene rearrangements that result in functional fusion proteins. Previous studies have demonstrated the ability of these gene fusions to function as constitutively active TEAD coactivators, while also retaining the ability to drive transcription of canonical CAMTA1 or TFE3 genes, respectively. To better understand the biology underlying EHE, we generated EHE in vitro models using endothelial cell lines and found that inducible expression of YAP1::TFE3 (YT) caused a significant change in cellular plasticity. Specifically, YT expression led to endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells lose their highly specialized identity and gain expression of genes typically associated with mesenchymal cells. This plasticity is associated with anoikis resistance and increased migratory phenotypes. Notably, YT drives this phenotypic change independent of TEAD activity but requires dimerization and DNA binding domains encoded by the C-terminal TFE3 gene. Overexpression of TFE3 is insufficient to fully recapitulate the EndMT phenotypes driven by YT; implying that, although dispensable for EndMT, YAP-TEAD activity provides a meaningful contribution. This work supports a growing body of evidence that YT and WWTR1-CAMTA1 driven EHE may have distinct biological mechanisms, underscoring a potentially targetable oncogenic molecular dependency.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the gap: Multi-stakeholder perspectives of molecular diagnostics in oncology.","authors":"Jorine Arnouts, Senada Koljenović, Elise Daems, Karolien De Wael, Marc Peeters, Léon C van Kempen, Greetje Vanhoutte, Karen Zwaenepoel, Timon Vandamme","doi":"10.1002/1878-0261.70103","DOIUrl":"https://doi.org/10.1002/1878-0261.70103","url":null,"abstract":"<p><p>Molecular diagnostics has revolutionized cancer management, enabling the identification of diagnostic, prognostic, and predictive biomarkers. Despite advancements in technologies such as whole genome sequencing, their translation into clinical practice remains challenging due to insufficiently demonstrated clinical utility. This study identifies unmet clinical needs and requirements for innovative molecular technologies in oncology through interviews (n = 22) and an online survey (n = 116), gathering insights from hospital professionals, industry representatives, and health policy and quality assessment experts. Our findings emphasize the increasing importance of liquid biopsies (LBx), particularly plasma-based assays. Key unmet needs in this area include therapy response monitoring, minimal residual disease detection, and predictive biomarker testing. Additionally, we outline technology requirements tailored to diverse clinical biomarker applications and both centralized and decentralized laboratory settings. A central challenge lies in achieving an optimal balance between multiplexing capacity and turnaround time. By bridging the gap between technology development and real-world application, this study paves the way for the implementation of new molecular technologies that better meet the needs of the oncology community, ensuring clinical utility and ultimately improving patient care.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFR-STAT3 activation provides a therapeutic rationale for targeting aggressive ETV1-positive prostate cancer.","authors":"Elsa Gomes Paiva, Bernardo Orr, Ana Azeredo, Andreia Brandão, Manuel R Teixeira, Paula Paulo","doi":"10.1002/1878-0261.70069","DOIUrl":"https://doi.org/10.1002/1878-0261.70069","url":null,"abstract":"<p><p>Prostate cancer (PCa) is the fifth leading cause of cancer-related death. The lack of data linking genomic alterations to targeted treatment strategies has hindered progress in disease management. Genomic rearrangements involving the ETS transcription factors ERG or ETV1 are among the most frequent genetic alterations in PCa; however, their clinical utility remains elusive. Using PCa cells overexpressing ETV1 or ERG, representing early and advanced disease stages, we unveiled a positive feedback loop between ETV1 and EGFR, with STAT3 acting as a downstream effector of ETV1-EGFR signaling. Analysis of external datasets revealed that both EGFR and STAT3 are significantly upregulated in ETV1-positive PCa, consistent with ChIP-seq data identifying them as direct ETV1 targets. Accordingly, combined inhibition of EGFR and STAT3 using Erlotinib and TTI-101, respectively, led to a significant reduction in 2D and 3D cell growth of early and advanced PCa cells overexpressing ETV1. Collectively, our findings highlight EGFR-STAT3 activation as a novel ETV1-regulated oncogenic pathway, providing a rationale for repurposing EGFR inhibitors in combination with STAT3 inhibitors as a therapeutic strategy for the 8-10% of prostate carcinomas characterized by ETV1 rearrangements/overexpression.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven discovery of gene expression markers distinguishing pediatric acute lymphoblastic leukemia subtypes.","authors":"Mona Nourbakhsh, Nikola Tom, Anna Schrøder Lassen, Helene Brasch Lind Petersen, Ulrik Kristoffer Stoltze, Karin Wadt, Kjeld Schmiegelow, Matteo Tiberti, Elena Papaleo","doi":"10.1002/1878-0261.70046","DOIUrl":"https://doi.org/10.1002/1878-0261.70046","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL), the most common cancer in children, is overall divided into two subtypes, B-cell precursor ALL (B-ALL) and T-cell ALL (T-ALL), which have different molecular characteristics. Despite massive progress in understanding the disease trajectories of ALL, ALL remains a major cause of death in children. Thus, further research exploring the biological foundations of ALL is essential. Here, we examined the diagnostic, prognostic, and therapeutic potential of gene expression data in pediatric patients with ALL. We discovered a subset of expression markers differentiating B- and T-ALL: CCN2, VPREB3, NDST3, EBF1, RN7SKP185, RN7SKP291, SNORA73B, RN7SKP255, SNORA74A, RN7SKP48, RN7SKP80, LINC00114, a novel gene (ENSG00000227706), and 7SK. The expression level of these markers all demonstrated significant effects on patient survival, comparing the two subtypes. We also discovered four expression subgroups in the expression data with eight genes driving separation between two of these predicted subgroups. A subset of the 14 markers could distinguish B- and T-ALL in an independent cohort of patients with ALL. This study can enhance our knowledge of the transcriptomic profile of different ALL subtypes.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine-to-inosine editing of miR-200b-3p is associated with the progression of high-grade serous ovarian cancer.","authors":"Magdalena Niemira, Anna Skwarska, Karolina Chwialkowska, Agnieszka Ostrowska, Gabriela Sokolowska, Anna Zeller, Anna Erol, Andrzej Eljaszewicz, Bartosz Hanczaruk, Anna Michalska-Falkowska, Agnieszka Tarasik, Joanna Reszec-Gielazyn, Pawel Knapp, Marcin Moniuszko, Adam Kretowski","doi":"10.1002/1878-0261.70106","DOIUrl":"https://doi.org/10.1002/1878-0261.70106","url":null,"abstract":"<p><p>Deamination of adenosine to inosine (A-to-I) in double-stranded microRNAs (miRNAs) has been demonstrated to affect their function as suppressors or oncogenes in various cancers. Nevertheless, the functional impact of miRNA editing in high-grade serous ovarian cancer (HGSOC) remains largely unexplored. Here, we identified A-to-I editing in miRNAs in 60 HGSOC tissues and 48 ovarian tissues received in nononcological procedures using small RNA sequencing (RNA-Seq). To investigate the functional impact of A-to-I modifications, we tested the effect of edited RNA mimics and small interfering RNA (siRNA)-mediated downregulation of the RNA-editing enzyme double-stranded RNA-specific editase Adar (ADAR1) on cell proliferation, migration and three-dimensional (3D) growth of HGSOC cells in vitro. Tumour suppressor miR-200b-3p was the most overedited miRNA in HGSOC tumours, and the increased editing level was associated with statistically significant worse overall survival (OS). Mechanistically, in contrast to wild-type miRNA, edited miR-200b-3p promoted cell proliferation, migration and formation of 3D spheroids. Loss of function of ADAR1 profoundly repressed proliferation, migration and 3D growth of HGSOC cells. RNA-Seq and Gene Set Enrichment Analysis (GSEA) analysis revealed that, whereas wild-type miR-200b-3p induced the apoptosis pathway, edited miR-200b-3p substantially inhibited cell-cycle-related pathways. Bioinformatic prediction revealed that edited miR-200b-3p gained the function to repress the expression of new targets, including tumour suppressor MAX interactor 1, dimerisation protein (MXI1), which was associated with a statistically significantly worse OS time in HGSOC patients. Our study reports the potential contribution of edited miR-200b-3p in HGSOC progression, and highlights its potential as a new therapeutic target.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}