Genes, Chromosomes & Cancer最新文献

{"title":"Extrachromosomal DNA Detection and Ultrastructural Profiling in Lung and Colorectal Cancer Models","authors":"Astari Dwiranti,&nbsp;Gina Zulfa Nabila,&nbsp;Tiara Aulia Zalyanti,&nbsp;Shadira Anindieta Irdianto,&nbsp;Anom Bowolaksono","doi":"10.1002/gcc.70115","DOIUrl":"10.1002/gcc.70115","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung and colorectal cancers are malignancies ranked as the leading cause of cancer-related mortality worldwide. Their high mortality rate is closely associated with drug resistance driven by cancer cell heterogeneity. One of the major contributors to this heterogeneity is the presence of extrachromosomal DNA (ecDNA), circular DNA fragments located outside linear chromosomes and generated through DNA damage. ecDNA is found exclusively in cancer cells, frequently carries highly amplified oncogenes, and contributes to cancer aggressiveness. To date, no study has characterized ecDNA in A549 and HT-29 cells, representative lung and colorectal cancer cell lines. This study aimed to detect and characterize ecDNA in A549 and HT-29 cells using Giemsa staining, DAPI staining, and scanning electron microscopy (SEM). Our findings revealed the presence of ecDNA, with the percentage of 15% in A549 and 10% of HT-29 cells from the total of 180 metaphase spread chromosomes. Among these, some spreads contained a single ecDNA and two ecDNA elements, either solitary or paired. The ecDNA area ranged from 0.537 μm² to 1.162 μm², with an average of 0.85 μm² in A549 cells. The fluorescence intensity of ecDNA ranged from 152.204 A.U. to 196.109 A.U., with an average of 179.847 A.U. While the ecDNA of HT-29 exhibited an average area of 0.455 μm² with an average DAPI fluorescence intensity of 102.747 A.U. SEM imaging further revealed ring-like circular structures with an area consistent with previously reported ecDNA ultrastructural characteristics. These results suggest that ecDNA is present across different cancer cell lines and may serve as a potential biomarker as well as a promising target for future cancer therapies.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 3","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377129","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":"Synonymous Variants of Potential Significance Identified by a 52-Gene Clinical Sequencing Panel in Non-Small Cell Lung Cancer","authors":"Kathleen Varty,&nbsp;Leah MacLean,&nbsp;Doha Itani,&nbsp;Monowar Hossain,&nbsp;Cenk Acar,&nbsp;James Michael,&nbsp;Trisha Daigle-Maloney,&nbsp;Robert Thompson,&nbsp;Brian Johnston,&nbsp;Crispin Russell,&nbsp;Jeanette E. Boudreau,&nbsp;Daniel Gaston,&nbsp;Tony Reiman","doi":"10.1002/gcc.70111","DOIUrl":"https://doi.org/10.1002/gcc.70111","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Next-generation sequencing (NGS) is routinely used for lung cancer genomic profiling to identify known, actionable, non-synonymous driver mutations. Recent findings suggest that synonymous variants may also be cancer drivers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>We analyzed genomic data and clinical outcomes for patients (<i>n</i> = 353) with non-small cell lung cancer (NSCLC) sequenced with the Oncomine Focus 52-gene NGS panel (ThermoFisher Scientific, Waltham, MA, USA) at the Saint John Regional Hospital in New Brunswick, Canada, from January 2019 to January 2023.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>KRAS was the most commonly mutated gene in this cohort from Saint John, New Brunswick, with a higher prevalence than reported in other populations. Several novel synonymous variants were identified, including in <i>ALK</i>, <i>EGFR, FGFR2</i>, <i>FGFR3</i>, <i>MYC, NF1, NRAS</i>, and <i>PIK3CA</i>, with potential effects on MAPK/ERK and PI3K/AKT signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This cohort demonstrates both expected and distinct genomic features, including novel synonymous variants in oncogenic pathways. These findings suggest regional variation in NSCLC genomics and support further study of synonymous variants in disease progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224464","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":"Novel FGL2::PDGFD and TGFBI::PDGFB Fusions Expand the Molecular Spectrum of Dermatofibrosarcoma Protuberans","authors":"Jeffrey M. Cloutier,&nbsp;Mohamed A. Yakoub,&nbsp;Meera Hameed,&nbsp;Silvia Cavalchini,&nbsp;Carina A. Dehner,&nbsp;Cyril Fisher,&nbsp;Khin Thway,&nbsp;Konstantinos Linos","doi":"10.1002/gcc.70110","DOIUrl":"10.1002/gcc.70110","url":null,"abstract":"<div>\u0000 \u0000 <p>Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive fibroblastic neoplasm characterized by recurrent <i>COL1A1::PDGFB</i> fusions that drive autocrine PDGFR-β activation. Recent sequencing studies have revealed rare DFSPs with alternative noncanonical <i>PDGFB</i> or <i>PDGFD</i> rearrangements, underscoring the genetic diversity of PDGF-ligand activation in this tumor. Here, we describe two conventional DFSPs harboring previously unreported fusions: <i>FGL2::PDGFD</i> and <i>TGFBI::PDGFB</i>. In the first case, <i>FGL2(ex1)::PDGFD(ex6)</i> replaces the PDGFD N-terminal CUB domain with the FGL2 signal peptide, a configuration predicted to generate a constitutively active, secreted PDGFD ligand. In the second case, <i>TGFBI(ex14)::PDGFB(ex3)</i> juxtaposes <i>PDGFB</i> to the highly expressed extracellular matrix gene <i>TGFBI</i>, providing an alternative promoter context for PDGFB overexpression. Both cases showed classic DFSP morphology and diffuse CD34 expression. These findings expand the molecular landscape of DFSP and illustrate convergent mechanisms of PDGFR-β activation achieved through diverse yet functionally equivalent genomic rearrangements.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226525","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":"IRF2BP2::JAK2 Defines a Novel Kinase-Activating Fusion in Pediatric T-Cell Acute Lymphoblastic Leukemia","authors":"Fatimah B. Jalud,&nbsp;Tasnia Ibnat,&nbsp;Kaitlyn Kew,&nbsp;Lauren M. Brown,&nbsp;Kimberly Dias,&nbsp;Chelsea Mayoh,&nbsp;Hansen J. Kosasih,&nbsp;Daniel Thomas,&nbsp;Loretta M. S. Lau,&nbsp;Diane Hanna,&nbsp;Bhavna Padhye,&nbsp;Charles E. de Bock,&nbsp;Paul G. Ekert,&nbsp;Teresa Sadras","doi":"10.1002/gcc.70112","DOIUrl":"https://doi.org/10.1002/gcc.70112","url":null,"abstract":"<div>\u0000 \u0000 <p>T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous and clinically aggressive malignancy, where outcomes remain poor for patients with early relapse or refractory disease. Although tyrosine kinase alterations represent potentially actionable lesions, understanding of their functional and therapeutic relevance in T-ALL is limited. Here, we report the first case of an <i>IRF2BP2::JAK2</i> fusion in a pediatric patient with high-risk T-ALL, identified through whole-genome and transcriptome sequencing. Using CRISPR-Cas9 genome engineering, we modeled the <i>Irf2bp2::Jak2</i> fusion in Ba/F3 cells and showed that it confers cytokine-independent growth, localizes to the cytoplasm, and drives constitutive JAK–STAT signaling. Importantly, both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibited the fusion. These findings establish <i>IRF2BP2::JAK2</i> as a novel oncogenic driver and druggable vulnerability in T-ALL and represent the first reported instance of an <i>IRF2BP2</i> fusion directly activating a non-receptor tyrosine kinase. More broadly, this work underscores the critical role of functional modeling in defining the biological and therapeutic significance of rare genomic alterations to enable the translation of precision medicine to the clinic.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224466","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":"Novel EWSR1::TEAD3 Fusion in an Adolescent With a Highly Aggressive Peritoneal Mesothelioma","authors":"Qixing Gong,&nbsp;Jia Wei,&nbsp;Sheng Xiao","doi":"10.1002/gcc.70113","DOIUrl":"https://doi.org/10.1002/gcc.70113","url":null,"abstract":"<div>\u0000 \u0000 <p>Malignant peritoneal mesothelioma (MPM) is an exceptionally rare entity in children and adolescents, exhibiting distinct clinicopathological features compared to its adult counterpart. Unlike adult cases, it typically occurs without a history of asbestos exposure or <i>BAP1</i> inactivation. Although several driver gene fusions have been documented, the primary oncogenic triggers and molecular pathways involved remain largely undefined. Herein, we present an 18-year-old male who presented with ascites and abdominal distension. Computed tomography imaging revealed diffuse thickening of the peritoneum, including the omentum and mesentery. Histopathological examination showed a neoplasm composed of a mixture of atypical epithelioid and spindled cells infiltrating the adipose tissue. Immunohistochemically, the tumor cells were positive for cytokeratin, calretinin, CK5/6, and D2-40, and negative for CK20, MOC-31, and Ber-EP4, supporting the diagnosis of a biphasic mesothelioma. Molecular genetic studies identified a novel <i>EWSR1::TEAD3</i> gene fusion. This is the first reported case of a peritoneal mesothelioma harboring this fusion.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224465","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":"PTEN Deletions Are Associated With Tumor Progression But Unrelated to Patient Prognosis in Muscle-Invasive Urothelial Bladder Carcinomas: A Large Multi-Center Validation Study on 2710 Urothelial Bladder Carcinomas","authors":"Martina Kluth,&nbsp;Henning Plage,&nbsp;Kira Furlano,&nbsp;Sebastian Hofbauer,&nbsp;Sarah Weinberger,&nbsp;Annika Fendler,&nbsp;Bernhard Ralla,&nbsp;Simon Schallenberg,&nbsp;Sefer Elezkurtaj,&nbsp;Maximilian Lennartz,&nbsp;Andreas H. Marx,&nbsp;Henrik Samtleben,&nbsp;Margit Fisch,&nbsp;Michael Rink,&nbsp;Marcin Slojewski,&nbsp;Krystian Kaczmarek,&nbsp;Thorsten Ecke,&nbsp;Nico Adamini,&nbsp;Joachim Weischenfeldt,&nbsp;Henrik Zecha,&nbsp;Ronald Simon,&nbsp;Guido Sauter,&nbsp;Thorsten Schlomm,&nbsp;David Horst,&nbsp;Sarah Minner","doi":"10.1002/gcc.70105","DOIUrl":"10.1002/gcc.70105","url":null,"abstract":"<p>The tumor suppressor gene <i>PTEN</i> plays an important role in many cancer types. Mechanism of <i>PTEN</i> inactivation includes gene mutations and deletions. In this large multi-center study, we analyzed the impact of <i>PTEN</i> deletions on tumor aggressiveness, patient prognosis, and p53 and p16 alterations, especially in muscle-invasive urothelial bladder carcinomas to expand the results from our previous study on 686 pTa to pT4 urothelial bladder carcinomas. The <i>PTEN</i> copy number status was analyzed by fluorescence in situ hybridization (FISH) on more than 2700 urothelial bladder carcinomas in a tissue microarray format. <i>PTEN</i> deletion data were compared with clinico-pathological parameters in pTa and pT2-4 carcinomas and clinical outcomes in pT2-4 carcinomas, immunohistochemical p16 and p53 expression, and <i>TP53</i> copy number status measured by FISH from previous studies. <i>PTEN</i> deletions occurred in 18.8% of 1854 analyzable carcinomas, including 17.6% heterozygous and 1.2% homozygous deleted tumors. The <i>PTEN</i> deletion rate increased markedly from pTaG2 low-grade (3.1%), to pTaG2 high-grade (4.5%) and pTaG3 (20.7%, <i>p</i> &lt; 0.0001) carcinomas, and was 23.8% in pT2-4 carcinomas (<i>p</i> &lt; 0.0001 for pTa vs. pT2-4). In pT2-4 cancers, <i>PTEN</i> deletions were unrelated to histopathological parameters of tumor aggressiveness and patient outcome. <i>PTEN</i> deletions were significantly associated with parameters of p53 alterations and p16 overexpression. It is concluded that <i>PTEN</i> deletions accumulate with grade progression in non-invasive urothelial carcinomas of the urinary bladder. The absence of a prognostic role of <i>PTEN</i> deletions in pT2-4 urothelial carcinomas is in line with our notorious inability to predict the clinical course of these tumors by only one morphological or molecular feature.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12831224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040794","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":"Biallelic NF1 Inactivation and Widespread Loss of Heterozygosity in a Subset of Unclassified Fibromyxoid Mesenchymal Neoplasms","authors":"Carla Saoud,&nbsp;Narasimhan Agaram,&nbsp;Samuel Singer,&nbsp;Liliana B. Villafania,&nbsp;Jamal Benhamida,&nbsp;Cristina R. Antonescu","doi":"10.1002/gcc.70109","DOIUrl":"10.1002/gcc.70109","url":null,"abstract":"<div>\u0000 \u0000 <p>The integration of next generation sequencing into clinical practice has revolutionized the diagnosis of soft tissue tumors, enabling the discovery of novel tumor entities. We encountered a group of unclassified fibromyxoid mesenchymal neoplasms harboring biallelic <i>NF1</i> loss of function (LOF) mutations, lacking features of neurofibroma or neurofibromatosis. The tumors were investigated by immunohistochemistry (IHC), targeted DNA and RNA sequencing and DNA methylation profiling. All cases occurred in male patients aged 4–76 years (median, 53 years). Tumor sites included the thigh (2), pelvis (2), and retroperitoneum (1), with size range of 5.7–12.2 cm (median, 9.1 cm). The tumors were well-demarcated with minimal infiltration of adjacent tissue and shared morphologic features. The stroma ranged from predominantly myxoid, fibromyxoid to mostly fibrous. Tumor cells were spindle with scant cytoplasm and ovoid nuclei with fine chromatin and inconspicuous nucleoli. Mitoses were rare (≤ 2/2 mm²), and necrosis was absent. IHC findings were largely nonspecific, with variable CD34 staining and lack of neural markers expression. All cases harbored <i>NF1</i> LOF, four were somatic, and one was germline, all with accompanying loss of heterozygosity (LOH), leading to biallelic inactivation. No other recurrent somatic alterations were identified. Tumor mutational burden was consistently low, while fraction of genome altered was high, ranging from 0.25 to 0.93 (median, 0.46). Allele-specific copy number analysis showed widespread LOH in four of five cases (&gt; 70%). The remaining case demonstrated a high but subthreshold LOH (38%). Targeted RNA sequencing, performed in four cases, was negative for fusions. Dimensionality reduction of DNA methylation placed four cases in a distinct cluster near well-differentiated/dedifferentiated liposarcoma, while the remaining case was placed near malignant peripheral nerve sheath tumor. All patients underwent surgical resection. Two patients developed local recurrences and are alive with disease, while the remaining three had no evidence of disease. We describe an unclassified fibromyxoid mesenchymal neoplasm of uncertain malignant potential characterized by recurrent biallelic <i>NF1</i> LOF and widespread genomic LOH.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018223","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":"Endogenous Processes Underlying Clock-Like Mutational Signatures","authors":"Teresa Druck,&nbsp;Rami I. Aqeilan,&nbsp;C. Marcelo Aldaz,&nbsp;Nicola Zanesi,&nbsp;Kay Huebner","doi":"10.1002/gcc.70106","DOIUrl":"10.1002/gcc.70106","url":null,"abstract":"<p>Wellcome Trust scientists have shown that “mutational signatures” in specific nucleotide contexts accumulate in genomes of mammalian tissues, providing clues to underlying causes of specific signatures. Analysis of cancer genomes has identified more than 50 single-base substitution (SBS) signatures, with SBS1, SBS5, and SBS40 linked to aging and present in normal tissues. SBS1 results from cytosine demethylation, whereas SBS5 and SBS40 arise from unknown endogenous mechanisms. We hypothesized that loss of fragile-site genes drives these two signatures. FHIT, located at FRA3B, is frequently deleted in cancers, and Fhit-deficient mouse tissues exhibit a mutation profile resembling human SBS5. Data mining of cancer genome sequences showed that <i>FHIT/Fra3B</i> was the gene loss most significantly correlated with human SBS5 mutations, likely representing the endogenous molecular process determining SBS5 mutations in soma, germ cells, and cancers, and inversely associated with lifespan in mammals. Exome sequences of Fhit knockout tissues revealed ~1000 SBS1 and ~4000 SBS5 mutations per sample, compared to markedly fewer in wild-type controls. Using SigProfilerAssignment, similar analyses performed with Fhit ko samples where Wwox is also frequently lost identified SBS40c. These findings implicate fragile-site gene inactivation as a major source of clock-like mutational signatures, contributing to lifelong mutation accumulation and potentially influencing aging, evolution, and speciation.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010026","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":"Molecular Landscape of TP53/RB1 Co-Altered Tumors Uncovers Emerging Therapeutic Vulnerabilities","authors":"Xuetao Li,&nbsp;Meifeng Ye,&nbsp;Xiaomei Huang,&nbsp;Zhong-Yin Huang,&nbsp;Juan Zhu,&nbsp;Zipeng He,&nbsp;Zhuxiang Zhao,&nbsp;Jun Hou,&nbsp;Shuquan Wei","doi":"10.1002/gcc.70100","DOIUrl":"10.1002/gcc.70100","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although <i>TP53</i> and <i>RB1</i> co-alterations play critical roles in promoting malignant development and progression, specific inhibitors targeting this co-alteration are lacking. We performed a pan-cancer analysis to characterize the biology of <i>TP53</i>/<i>RB1</i> co-alterations and identify therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed mutation data and copy number variation (CNV) data from 42 371 pan-cancer samples across 26 cancer types from the cBioPortal database. Among them, 2417 tumors with <i>TP53</i>/<i>RB1</i> co-alterations were used for further analysis. We characterized their epidemiology and molecular biology. Therapeutic vulnerabilities of co-altered tumors were examined using Cancer Cell Line Encyclopedia drug screening datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>TP53</i>/<i>RB1</i> co-alterations occurred in 5.70% of pan-cancer cases but exhibit striking heterogeneity across cancer types. Patients harboring co-alterations had significantly shorter overall survival (OS) in both primary and metastatic settings and poorer response to immune checkpoint inhibitors. Co-altered tumors displayed frequent alterations in chromatin remodeling genes (<i>CREBBP</i>, <i>ARID1A</i>, and <i>KMT2D</i>) and PI3K pathway (<i>PIK3CA</i> and <i>PTEN</i>), but with distinct tissue-specific mutational patterns: <i>EGFR</i> mutations dominated in lung adenocarcinoma (52%), <i>KRAS</i> in pancreatic cancer (88%), and <i>APC</i> in colorectal cancer (77%). Moreover, upregulated genes in co-altered tumors enriched in cell cycle pathways, DNA repair, and neuronal development, whereas immune/inflammatory signaling was suppressed. Critically, drug screening revealed that co-altered tumors showed increased sensitivity to CDK, AURKA, and PI3K/mTOR inhibitors, but resistance to MAPK/ERK pathway inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>TP53</i>/<i>RB1</i> co-alterations define an aggressive cancer subset with dysregulated cell cycle/chromatin pathways and reduced immunotherapy response. Targeting CDK, AURKA, or PI3K signaling offers promising therapeutic strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010099","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":"Clear Cell Tumor With MITF::CREM Fusion: A Rare Case Report of a Newly Described Entity","authors":"Michael Lie,&nbsp;Pranav Dorwal,&nbsp;Liyan Song,&nbsp;Aditya Mishra,&nbsp;Lynette Moore","doi":"10.1002/gcc.70099","DOIUrl":"10.1002/gcc.70099","url":null,"abstract":"<div>\u0000 \u0000 <p>The increasing application of molecular diagnostics in pathology has enabled the identification of novel tumor entities, including clear cell tumor with <i>MITF::CREM</i> translocation, as recognized in the 5th edition of the WHO Classification of Tumours. We describe a case involving a 2-year-old boy with a left scalp lesion, initially suspected clinically to represent a pyogenic granuloma. Histopathological assessment, corroborated by molecular analysis, established the diagnosis of clear cell tumor with <i>MITF::CREM</i> translocation. This case emphasizes the need to consider rare entities in the differential diagnosis of dermal lesions and highlights the critical role of molecular testing in diagnostic precision. Notably, this molecularly defined neoplasm demonstrated no immunohistochemical evidence of melanocytic differentiation, contrasting with the features described in the WHO classification.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"65 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010042","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}