Cancer Genetics[JOURNAL]
Sun
200 papers
Integrative transcriptomic and CRISPR dependency analysis identifies hepatoblastoma-specific essential genes and actionable vulnerabilities.
Desterke C, Jarén A, Francés R … +4 more , Casafont Í, Barrachina MD, Esplugues JV, Mata-Garrido J
Cancer Genet · 2026 Jun · PMID 42385356 · Publisher ↗
BACKGROUND: Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, yet its molecular determinants, functional dependencies, and therapeutic vulnerabilities remain incompletely characterized. Integr...
BACKGROUND: Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, yet its molecular determinants, functional dependencies, and therapeutic vulnerabilities remain incompletely characterized. Integrative analyses combining transcriptomic profiling with functional genomic datasets provide a strategy to identify essential genes, biomarkers predictive of tumor behavior and treatment response. METHODS: Differential expression analysis comparing HB tumors with normal liver was processed on training cohort. These genes were integrated with DepMap CRISPR-Cas9 dependency scores to prioritize HB-essential candidates. Elastic Net regression was used to derive a 16-gene predictive signature, which was validated in an external cohort. Single-cell RNA-seq datasets were analyzed to assess expression patterns across hepatic and tumor-associated cell populations. A supervised deep-learning classifier was trained on single-cell profiles to distinguish tumor cells from hepatocytes, and SHAP values were computed to interpret gene contributions. Drug-gene interactions were queried using curated repressive compounds from DGIdb, and approved drugs were screened for relevance in pediatric cancer clinical trials. RESULTS: A total of 789 genes were found overexpressed in HB tumors from the training transcriptome cohort. Chronos DepMap analysis identified 73 HB-essential genes that were not essential in adult liver cancer cell lines (hepatocellular carcinoma and cholangiocarcinoma). Elastic-net tuning based on the expression of 16 HB-essential genes in the split training cohort enabled robust tumor-normal discrimination, with AUC = 0.88, specificity = 0.90, and sensitivity = 0.90 in internal validation. This performance was confirmed in an independent external cohort, achieving AUC = 0.99, specificity = 1.00, and sensitivity = 0.98. Single-cell validation further demonstrated tumor-specific enrichment of the signature. The deep-learning classifier (tumor cells vs. normal hepatocytes) reached high accuracy (AUC = 0.99; F1-score = 0.97), with SHAP analysis highlighting PEG10, GREB1, PLCB4, RHOBTB1, CRIM1, FSD1L, CORO2A, KIT, ANKRD50, HDAC11, ZNF233, SEMA7A, and FABP4 as major contributors. Six of these genes were confirmed to be absent or lowly expressed in the background liver microenvironment. Drug-gene interaction analysis identified HDAC11 as a potential therapeutic target of approved drugs used in pediatric oncology. CONCLUSIONS: This integrative framework combining transcriptomics, CRISPR dependency mapping, machine learning, and pharmacogenomic annotation identifies clinically relevant HB-essential genes and predictive molecular signatures for tumor identity. The derived expression-based scores provide tools for patient stratification, while drug-gene mapping highlights actionable vulnerabilities on HDAC11 with pediatric approved drugs that support rational drug repurposing strategies in hepatoblastoma.
An atypical RUNX1::ETV6::RUNX1 fusion in a pediatric patient with precursor B-cell acute lymphoblastic leukemia.
Nagarajan A, Herriges J, Lansdon LA … +4 more , Farooqi MS, Repnikova E, Pushel I, Zhang L
Cancer Genet · 2026 Jun · PMID 42361417 · Publisher ↗
ETV6::RUNX1 fusion is one of the most common genetic alterations among children with precursor B-cell acute lymphoblastic leukemia (B-ALL). This fusion generally results from a t(12;21), which fuses the 5' region of ETV6...
ETV6::RUNX1 fusion is one of the most common genetic alterations among children with precursor B-cell acute lymphoblastic leukemia (B-ALL). This fusion generally results from a t(12;21), which fuses the 5' region of ETV6 to the 3' region of RUNX1. Here we report a novel atypical fusion in a 2-year-old male patient with B-ALL. Chromosome, FISH, and microarray were first performed to define a genetic subtype. Chromosome analysis showed three copies of chromosome 21. FISH results revealed ETV6::RUNX1 fusion. However, the signal pattern was atypical with the two fusion signals sitting on two different chromosome 21s, a RUNX1 signal on the third chromosome 21, and two ETV6 signals on two chromosome 12s. Microarray did not readily resolve the FISH signal pattern but confirmed gain of the entire chromosome 21 without any imbalances and showed two losses affecting exon 2 and exons 6-8 of ETV6. Subsequently, optical genome mapping (OGM) identified the fusion created by excision and insertion of ETV6 exons 3-5 into intron 2 of RUNX1. Long-read DNA and RNA sequencing confirmed the fusion identified by OGM and resolved the fusion breakpoints. The identified novel RUNX1::ETV6::RUNX1 fusion contains all important elements reported in the classical ETV6::RUNX1 fusion and is assumed to be oncogenic. Further, transcriptome profiling demonstrated that this case clusters with other typical ETV6::RUNX1 fusion B-ALL cases, suggesting similar functional behavior from this atypical fusion. The patient was treated using a standard risk ALL protocol and is in remission for two years. This report demonstrates how comprehensive genomic profiling with OGM and long-read sequencing can help resolve atypical findings from conventional methods, enable proper sub-classification and potentially inform risk assessment in relapsed or drug-resistant disease.
Prohibitins in cancer: Multifaceted regulators of mitochondrial homeostasis, oncogenic signaling, tumor microenvironment, and therapeutic resistance.
Fang L, Yang Y, Tian X … +8 more , Guan J, Liu Y, Luo Z, Lu W, Du Y, Li Z, Song B, Huang L
Cancer Genet · 2026 Jun · PMID 42341379 · Publisher ↗
Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are highly conserved, ubiquitously expressed scaffold proteins that play central roles in cellular physiology by forming heterodimeric ring-shaped complexes. Their subcellular...
Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are highly conserved, ubiquitously expressed scaffold proteins that play central roles in cellular physiology by forming heterodimeric ring-shaped complexes. Their subcellular localization to mitochondria, the nucleus, cytoplasm, and plasma membrane underpins a remarkable functional pleiotropy that is profoundly exploited in cancer. This review provides a comprehensive synthesis of the current understanding of PHBs in tumor biology, spanning structural features, post-translational modifications, and their integration into multiple oncogenic signaling networks. We systematically describe how PHB1 directly activates the RAS-RAF-MEK-ERK cascade through regulated phosphorylation, how both PHB1 and PHB2 fine-tune the PI3K/Akt/mTOR axis through ubiquitination-dependent scaffolding and degradation of negative regulators, and how they exert bidirectional control over Wnt/β-catenin and NF-κB pathways. A major focus is the dual role of the mitochondrial PHB complex: protecting cristae architecture and regulating the OMA1-OPA1 axis, orchestrating respiratory chain supercomplex assembly, metabolic substrate switching, and mitophagy, while simultaneously suppressing or, in specific contexts, promoting reactive oxygen species signaling and ferroptosis. The review further dissects how dynamic nucleocytoplasmic shuttling of PHBs couples metabolic status to cell cycle progression, stemness, and epigenetic remodeling through interactions with transcription factors (E2F1, p53, Sp1) and chromatin modifiers (MLL2, HDAC1). Within the tumor microenvironment, PHBs emerge as critical immunometabolic hubs that influence macrophage polarization, cGAS-STING activation, and sexual dimorphism in immune responses. We summarize the cancer-type-specific expression patterns of PHB1/2 and their prognostic value, and provide an in-depth analysis of the mechanisms by which PHBs confer resistance to platinum drugs, paclitaxel, PARP inhibitors, and radiotherapy through stabilization of anti-apoptotic proteins, mitochondrial protection, and maintenance of cancer stem cell properties. Finally, we catalogue the expanding armamentarium of PHB-targeted interventions, including small-molecule ligands, stapled peptides, DNA aptamers, and siRNA delivery platforms, and discuss the challenges and opportunities for clinical translation. By integrating molecular mechanisms with translational perspectives, this review highlights PHBs as unique regulatory nodes at the intersection of metabolism, signaling, and immunity, and advocates for precision strategies that exploit context-specific PHB functions to overcome therapy resistance and improve cancer treatment.
Beyond ATRX: The heterogeneous basis of Alternative Lengthening of Telomeres in osteosarcoma.
Goncalves T, Mattis NS, Mitchell AFM … +1 more , Rose AM
Cancer Genet · 2026 Jun · PMID 42330800 · Publisher ↗
The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent telomere maintenance mechanism, which is frequently observed in osteosarcoma. In this study, we performed a systematic review of studies...
The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent telomere maintenance mechanism, which is frequently observed in osteosarcoma. In this study, we performed a systematic review of studies assessing ALT in patient-derived osteosarcoma samples using direct experimental assays, alongside bioinformatic analysis of large public genomic datasets to evaluate the prevalence of canonical ALT-associated alterations. Across seven eligible studies comprising 342 tumours, ALT activity was identified in 62.9% of cases. In contrast, analysis of the Target-OS and PeCan datasets demonstrated that mutations in ATRX or DAXX, and amplification of TOP3A, occur at substantially lower frequencies, collectively accounting for only a minority of tumours. Statistical comparison confirmed a significant discrepancy between experimentally-observed ALT prevalence and the frequency of these canonical ALT-associated genetic alterations. These findings indicate that canonical genomic events are insufficient to explain ALT activation in osteosarcoma and support a model of marked biological heterogeneity. Potential alternative mechanisms include non-mutational disruption of chromatin remodelling pathways, replication stress-associated processes, and epigenetic dysregulation. The data highlights the limitations of relying on sequencing-based approaches alone to infer telomere maintenance mechanisms, which could have important clinical consequences for potential ALT-pathway targeting therapies. In conclusion, ALT is highly prevalent in osteosarcoma but is not adequately captured by known genetic correlates. Functional assays remain essential for accurate classification, and improved understanding of non-canonical ALT drivers will be critical for biomarker development and the design of targeted therapeutic strategies.
Identification of a novel class of early exon ALK rearrangements across two pan-tumor sequencing databases.
Leong M, Azimpouran M, Li X … +15 more , Fields PA, Hockenberry AJ, Patel R, Rode S, Abraham E, Nakasaki M, Heneidi S, Barrena B, Gayhart M, Eno C, Jiang N, Balzer B, Mercer J, Khullar G, Vail E
Cancer Genet · 2026 Jun · PMID 42322689 · Publisher ↗
PURPOSE: The vast majority of reported ALK rearrangements occur at exons 17-20. ALK-rearrangements occurring earlier in the ALK gene (eALK) are poorly characterized and rarely reported, potentially because most clinicall...
PURPOSE: The vast majority of reported ALK rearrangements occur at exons 17-20. ALK-rearrangements occurring earlier in the ALK gene (eALK) are poorly characterized and rarely reported, potentially because most clinically available biomarker testing is optimized for detecting common ALK rearrangement regions. METHODS: Two databases, the Tempus deidentified database and Cedars-Sinai database, were retrospectively queried to characterize eALK rearrangements, as defined by rearrangements involving ALK exons 1-16. Select specimens harboring eALK rearrangements were evaluated using available FDA-approved methods (immunohistochemistry [IHC] and fluorescent in-situ hybridization [FISH]); clinical management and outcomes were evaluated for these cases. RESULTS: 39 eALK rearrangements were detected in the Tempus database and 3 were identified in the Cedars-Sinai database. Across these 42 rearrangements, there were 35 unique partner genes; rearrangements were identified in all early exons except exons 8, 10, 13 and 15, with exons 2 and 4 being most common. Prostatic, breast, leiomyosarcoma, and ovarian serous carcinoma were the most common tumor types, which may reflect database bias. In three cases, IHC and FISH were unreliable at detection (0/ 3 IHC positive, 1/3 FISH atypical positive). Limited clinical information shows partial response to ALK targeted therapies. CONCLUSIONS: Novel eALK rearrangements are a distinct subclass of ALK rearrangements and were not reliably detected through FDA-approved testing modalities. Limited clinical data suggests these cancers could still respond to ALK targeted therapy.
Comprehensive genome-wide association study into multiple recurrence and progression risk in non-muscle invasive bladder cancer.
Hof JP, Galesloot TE, Aben KKH … +14 more , Bryan RT, Catto JWF, Cheng KK, Conroy S, Fleshner NE, van der Heijden AG, James ND, Mengual L, Uunk FM, Verhaegh G, Vrieling A, Zeegers MP, Kiemeney LALM, Vermeulen SH
Cancer Genet · 2026 Jun · PMID 42320430 · Publisher ↗
BACKGROUND: Patients with non-muscle invasive bladder cancer (NMIBC) frequently experience recurrence and may progress to muscle-invasive disease. Although several common germline variants associated with bladder cancer...
BACKGROUND: Patients with non-muscle invasive bladder cancer (NMIBC) frequently experience recurrence and may progress to muscle-invasive disease. Although several common germline variants associated with bladder cancer risk have been identified, their prognostic value in NMIBC remains unclear. We performed an updated genome-wide association study (GWAS), incorporating additional cohorts and analysing multiple NMIBC recurrences, to identify germline genetic variants associated with recurrence and progression. METHODS: We analysed eight cohorts (N = 5009) from the Netherlands, UK, Canada, and Spain. Cohort-specific GWAS were conducted using Cox regression for recurrence-free survival (RFS) and progression-free survival (PFS), including recurrent-event analysis and gene-based analyses. Analyses included chromosome X and were stratified by sex and Bacillus Calmette-Guérin (BCG) treatment. Previously reported variants for bladder cancer risk and prognosis were also evaluated. RESULTS: We observed 4237 recurrences, of which 2145 were first recurrences, and 742 cases of progression in stage and/or grade. No genome-wide significant associations were identified in the overall population, chromosome X, or sex-stratified analyses. In BCG-treated patients, two loci reached genome-wide significance for RFS, with the strongest signal for rs72744118, an intron variant in DISP-1 (HR = 0.43; 95% CI (0.32, 0.56), p = 5.8 × 10). Gene prioritization identified 101 candidate genes from SNP associations (p < 1 × 10) and colocalization analyses, of which 16 genes showed nominally significant association between gene expression and NMIBC outcome in UROMOL. CONCLUSIONS: In the largest GWAS of NMIBC prognosis to date, we prioritized a set of 16 genes. Future research should independently validate the prognostic and functional roles of identified genes.
Molecular etiology and therapeutic advances in retinoblastoma.
Ouarhache M, Bouguenouch L, Ouldim K
Cancer Genet · 2026 Jun · PMID 42284883 · Publisher ↗
Retinoblastoma is an aggressive intraocular tumor that originates from the developing retina in early childhood. Biallelic loss of RB1 has long been considered the main event for initiating RB development in most cases....
Retinoblastoma is an aggressive intraocular tumor that originates from the developing retina in early childhood. Biallelic loss of RB1 has long been considered the main event for initiating RB development in most cases. Additional genetic events following RB1 loss, such as MYCN amplification, were found to be required for RB progression. Advancements in next-generation sequencing technologies have enabled a deeper understanding of the contributors to RB origin and development, revealing that secondary genetic alterations following RB1 inactivation are infrequent. In contrast, epigenetic changes were shown to be critical promoters of RB tumorigenesis. Several epigenetic regulators, including DNA methylation, histone modifications and noncoding RNAs, have been proven to be dysregulated in RB, contributing to its progression. Understanding the underlying mechanisms involved in RB and exploring new treatment strategies is a crucial step toward developing more effective and less invasive therapeutic approaches that can improve patient outcomes. This review summarizes the significant genetic and epigenetic alterations involved in RB tumorigenesis, current therapeutic strategies, and future treatment prospects for patients with RB.
Acquired ring chromosomes in hematological malignancies: A systematic evidence review for diagnostic advances, cytogenomic insights, and clinical significance by an International Consortium on Human Ring Chromosomes (ICHRC) working group.
Zeineldin M, Murry JB, Shetty D … +8 more , Middlezong W, Parish R, Xiao Z, Cui C, Li P, Wen J, Tang G, Zou YS
Cancer Genet · 2026 Jun · PMID 42263477 · Publisher ↗
Recent studies have described acquired ring chromosomes (aRCs), marker chromosomes, and extrachromosomal DNA (ecDNA) in various tumors. However, the genomic copy number aberrations (CNAs) and gene rearrangements within t...
Recent studies have described acquired ring chromosomes (aRCs), marker chromosomes, and extrachromosomal DNA (ecDNA) in various tumors. However, the genomic copy number aberrations (CNAs) and gene rearrangements within these aRCs require further genomic analysis, and the knowledge base to interpret their clinical implications remains largely unformed. A working group was organized by the International Consortium of Human Ring Chromosomes (ICHRC) to conduct a systematic evidence review of the role of aRCs in hematologic malignancies. This retrospective review summarizes the current molecular cytogenetic and genomic technologies for aRC analysis, presents an overview of the types of aRCs in various hematological malignancies, and provides evidence to support cytogenomic analysis and diagnostic interpretation. The findings from this study recommend an integrated cytogenomic analysis for aRCs and prompt further functional analyses to elucidate the molecular mechanisms for disease causation and targeted treatment.
A decision-oriented framework for genomic testing across the prostate cancer continuum.
Cobran EK, Samadder NJ, Schaid DJ … +5 more , Conti DV, Haiman C, Vargas L, Gionfriddo MR, Tilburt JC
Cancer Genet · 2026 Jun · PMID 42251787 · Publisher ↗
Genomic testing is now embedded in contemporary prostate cancer care, yet the clinical meaning of different genomic platforms varies substantially by disease state and clinical context. In localized disease, tissue-based...
Genomic testing is now embedded in contemporary prostate cancer care, yet the clinical meaning of different genomic platforms varies substantially by disease state and clinical context. In localized disease, tissue-based genomic classifiers primarily serve prognostic functions by refining risk estimates beyond clinicopathologic variables, whereas in advanced disease, germline and somatic testing identify predictive biomarkers linked to therapy selection. This distinction is clinically consequential because the supporting evidence, endpoints, and implementation challenges differ across assays and across points on the disease continuum. In this review, we position tissue-based assays, germline testing, somatic sequencing, circulating tumor DNA (ctDNA), and artificial intelligence-enabled biomarkers within a unified clinical framework spanning localized disease, biochemical recurrence, and metastatic progression. We critically compare commercially available genomic assays with respect to methodology, specimen type, intended use, validation cohorts, and clinically relevant outcomes. We distinguish prognostic classifiers from predictive biomarkers such as homologous recombination repair deficiency and mismatch repair deficiency, and we evaluate emerging approaches, including liquid biopsy, multimodal integration with imaging, and digital pathology-based algorithms. We further address implementation barriers that may limit real-world impact, including reimbursement uncertainty, disparities in access to next-generation sequencing, limited provider familiarity with genomic interpretation, and the need for patient-centered communication and navigation in genomics-informed care. A clinically useful framework for prostate cancer genomics must therefore move beyond cataloging tests and instead clarify when genomic results change management, where evidence remains immature, and how implementation strategies can improve equity and actionability.
Cytogenomic landscape of adult Philadelphia chromosome-positive acute lymphoblastic leukemia in Malaysia.
Phan CL, Zakaria Z, Yegappan S … +2 more , Khang TF, Ng CC
Cancer Genet · 2026 May · PMID 42247916 · Publisher ↗
BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (-Ph+ ALL) is a high-risk leukemia often accompanied by additional genomic abnormalities beyond BCR::ABL1. METHODS: We analyzed 74 newly diagnosed...
BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (-Ph+ ALL) is a high-risk leukemia often accompanied by additional genomic abnormalities beyond BCR::ABL1. METHODS: We analyzed 74 newly diagnosed adult -Ph+ ALL patients. Additional chromosomal abnormalities (ACAs) were assessed by conventional cytogenetics in 51 patients and copy number variations (CNVs) by combined array comparative genomic hybridization plus single nucleotide polymorphism (array-CGH+SNP) in 43 patients. RESULTS: ACAs were detected in 31 cases (60.8%), including complex karyotypes in 11 (35.5%). CNVs were identified in 38 cases (88.4%) and were predominantly deletions (69.2%). Recurrent abnormalities included double Ph chromosome, monosomy 7, chromosomal gains at 8q, 9q34, 22q11, and losses at 7p, 9p, and 20q. The t(3;9;22) was the most frequent t(9;22) variant (12.9%), despite being rare in previous studies of adult Ph+ ALL. IKZF1 deletions were most frequent (91.7%), followed by CDKN2A/B (44.4%), PAX5 (38.9%) and RB1 (30.6%). IKZF1 co-deletions with CDKN2A/B and/or PAX5 occurred in 66.7%. IKZF1 and 22q11.22 co-deletions occurred in 34.2%, and VPREB1 deletions in 15.8%; both have been associated with adverse outcomes in ALL. Copy-neutral loss of heterozygosity >5 Mb was detected in 16.3%, frequently involving chromosome 9p and encompassing the CDKN2A/B loci. DISCUSSIONS: Adult Ph+ ALL in this multi-ethnic cohort exhibited marked genomic heterogeneity, with frequent submicroscopic alterations detectable only through integrated genomic profiling. Comprehensive genomic characterization is needed to better understand leukemogenesis and refine risk stratification.
Regulation of exosomal miR-513a and miR-149 expression by APE1 in PD-L1 and TCR immune regulation pathways to promote immune evasion in osteosarcoma.
Luo H, Jian D, Zhong L … +9 more , Lu X, Yang F, Liu C, Dai X, Peng Y, Tong X, Feng Y, Li M, Dai N
Cancer Genet · 2026 May · PMID 42217848 · Publisher ↗
Osteosarcoma is a highly malignant bone tumor with a complex immune evasion mechanism involving various molecules and signaling pathways. This study aims to clarify how APE1 regulates the expression of miR-513a and miR-1...
Osteosarcoma is a highly malignant bone tumor with a complex immune evasion mechanism involving various molecules and signaling pathways. This study aims to clarify how APE1 regulates the expression of miR-513a and miR-149 and to explore its role in osteosarcoma immune evasion. The results indicate that APE1 levels are inversely related to those of miR-513a and miR-149. Exosomal miR-513a and miR-149 significantly impair T-cell function by decreasing TNFα secretion. APE1 contributes to osteosarcoma's immune evasion by modulating exosomal miR-513a and miR-149, influencing the PD-L1 and TCR pathways, thus presenting a potential molecular target for therapy.
Rare and complex three-way t(8;11;21) translocation in core-binding factor acute myeloid leukemia transforming into refractory mediastinal myeloid sarcoma: cytogenetic and molecular insights.
Wery AR, Dalborgo M, Heimann P … +6 more , Sidon P, Dewispelaere L, Poutakidou D, Wittnebel S, Lewalle P, Farhat H
Cancer Genet · 2026 May · PMID 42208169 · Publisher ↗
Core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21)(q22;q22)/RUNX1::RUNX1T1 is typically considered as a favorable-risk AML in the context of cytarabine-based intensive chemotherapy. However, in some situ...
Core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21)(q22;q22)/RUNX1::RUNX1T1 is typically considered as a favorable-risk AML in the context of cytarabine-based intensive chemotherapy. However, in some situations such as additional adverse-risk mutations or cytogenetics, the prognosis and disease course may be more uncertain. Here, we report the case of a young patient diagnosed with CBF-AML and RUNX1::RUNX1T1 fusion gene, carrying a rare and complex three-way t(8;11;21)(q22;q13;q22) translocation, with mutated KIT, ASXL1 and TET2 genes, transforming into an aggressive and multi-refractory mediastinal myeloid sarcoma. This case illustrates that this scarcely reported variant might negatively impact the favorable prognosis of CBF-AML.
TFRC-mediated immune exclusion as a therapeutic vulnerability in cervical cancer: A comprehensive analysis based on the cancer immunoediting process.
Ling HJ, Zhou JL, Cao LQ … +3 more , Li R, Chen ZS, Yi Q
Cancer Genet · 2026 May · PMID 42202548 · Publisher ↗
BACKGROUND: Advanced and recurrent cervical cancer (CC) remains a clinical challenge due to limited therapeutic options and a poor 5-year survival rate (<20%). While immunotherapy has reshaped the treatment landscape, pr...
BACKGROUND: Advanced and recurrent cervical cancer (CC) remains a clinical challenge due to limited therapeutic options and a poor 5-year survival rate (<20%). While immunotherapy has reshaped the treatment landscape, primary resistance driven by immune exclusion often limits its efficacy. This study aims to identify the key molecular determinants governing T-cell infiltration and to develop a robust prognostic framework by systematically analyzing the cancer immunoediting process. METHODS: We integrated transcriptomic data from TCGA and multiple GEO cohorts (n = 7) with CIC scores via the Tumor Immunotherapy Gene Expression Resource (TIP). Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify gene modules negatively correlated with T-cell infiltration (Step 5 of CIC). A refined prognostic signature was constructed using an ensemble of machine learning algorithms, including LASSO, Random Forest, and XGBoost. The clinical relevance, immune microenvironment landscape, and single-cell expression patterns of the lead candidate, TFRC, were validated using multi-omics integration. Finally, the oncogenic role of TFRC was characterized through in vitro functional assays and an in vivo xenograft model. RESULTS: WGCNA identified a key module of 973 genes significantly associated with impaired T-cell recruitment. A 4-gene prognostic model (FOXRED2, RAB5IF, SHC1, TFRC) was developed, demonstrating high predictive accuracy for 1-, 3-, and 5-year overall survival (AUC up to 0.74), which was further validated in independent cohorts. Among these, TFRC emerged as a critical biomarker, showing significant overexpression in CC tissues and correlating with disease progression. Bioinformatic analysis linked high TFRC expression to a "cold" tumor microenvironment characterized by reduced CD8+ T-cell infiltration and elevated TIDE exclusion scores. Functionally, TFRC silencing significantly suppressed CC cell proliferation, migration, and invasion, and markedly attenuated tumor growth in nude mice. CONCLUSION: Our study provides a novel CIC-based stratification tool for CC patients and identifies TFRC as a pivotal regulator of immune exclusion. These findings suggest that targeting TFRC not only inhibits intrinsic tumor progression but also potentially sensitizes CC to immunotherapy by remodeling the immune microenvironment.
Gut microbiota-metabolite axis in gastric cancer: Genetic causality and Ruminococcus subgroup shifts.
Ji J, Feng X, Sun Y … +4 more , Cai Q, Shaw M, Yu B, Zhang J
Cancer Genet · 2026 May · PMID 42202547 · Publisher ↗
Observational studies have long suggested an association between gut microbiota dysbiosis and gastric cancer, yet the causal relevance and underlying biological pathways remain poorly defined. Here, we applied a comprehe...
Observational studies have long suggested an association between gut microbiota dysbiosis and gastric cancer, yet the causal relevance and underlying biological pathways remain poorly defined. Here, we applied a comprehensive Mendelian randomization (MR) framework to gut microbiota and gastric cancer GWAS summary statistics to identify 14 microbial taxa significantly associated with gastric cancer risk. Sensitivity analyses, including tests for horizontal pleiotropy, heterogeneity, and genetic co-localization, revealed no strong evidence of shared causal variants (H4 < 2%); however, convergent results across five complementary MR models support overall causal inference. Mediation analysis further identified a partial pathway from the taxon ebi-a-GCST90027718 to gastric cancer via the metabolite met-c-926 (sdLDL), accounting for 4.31% of the total effect. Preliminary 16S rRNA sequencing in a pilot cohort (n = 5 per group) revealed divergent shifts in Ruminococcus subgroups without disrupting overall community stability, though these observations require replication. Collectively, this study establishes a genetically anchored evidence chain linking host genetics, gut microbiota, and gastric cancer pathogenesis, providing insights for microbiota-targeted prevention strategies.
Enhancing cell type annotation for cancer transcriptomics using retrieval-augmented generation.
Yang R, Le NQK, Chua MCH
Cancer Genet · 2026 May · PMID 42184649 · Publisher ↗
Single-cell RNA sequencing has become an essential approach for investigating cellular heterogeneity in cancer, enabling detailed characterization of malignant cells, tumor microenvironments, and genetically distinct sub...
Single-cell RNA sequencing has become an essential approach for investigating cellular heterogeneity in cancer, enabling detailed characterization of malignant cells, tumor microenvironments, and genetically distinct subpopulations. However, accurate and reproducible cell type annotation remains a major analytical bottleneck, limiting the reliability of downstream genetic and molecular interpretation. In this study, we develop a robust retrieval-augmented generation framework for automated cell type annotation that improves stability, biological grounding, and reproducibility. The proposed approach integrates hybrid lexical-semantic information retrieval with ontology-aware evaluation, combining keyword-based search and biomedical domain-specific embeddings to enhance semantic relevance. Retrieval performance is further strengthened through query expansion, paraphrasing, and lightweight reranking, while biological validity is ensured using Cell Ontology-grounded similarity scoring. The framework is systematically evaluated across nine publicly available single-cell RNA sequencing datasets spanning diverse human tissues. Compared with baseline prompting, naïve retrieval-based pipelines, and established annotation tools, the optimized framework demonstrates consistently higher annotation accuracy, reduced performance variability, and improved resolution of ambiguous and rare cell populations. By strengthening the reliability of cellular annotation, this approach facilitates more accurate analysis of genetic and molecular alterations relevant to cancer biology and provides a scalable foundation for translational and diagnostic applications in cancer genetics.
ISG15 drives cervical cancer progression by hyperactivating the NOD-like receptor signaling pathway.
Jia Z, Zhang J, Liu X … +2 more , Liu C, Zhang Y
Cancer Genet · 2026 May · PMID 42172712 · Publisher ↗
The function of the interferon-stimulated gene ISG15 in cervical cancer (CC) is complex and remains unclear. We analyzed the expression and clinical significance of ISG15 in the TCGA-CESC cohort. Its function was investi...
The function of the interferon-stimulated gene ISG15 in cervical cancer (CC) is complex and remains unclear. We analyzed the expression and clinical significance of ISG15 in the TCGA-CESC cohort. Its function was investigated in Caski cells using RNA-seq, siRNA, and pharmacological inhibition methods, and validated in vivo in a xenograft model. ISG15 was significantly overexpressed in cervical cancer tissues (P < 0.001). However, high ISG15 expression was associated with better overall survival (HR=0.67, 95% CI: 0.48-0.94, p = 0.02). Gene set enrichment analysis (GSEA) indicated that high ISG15 expression was associated with the NOD-like receptor signaling pathway. Mechanistically, ISG15 binds to and stabilizes the NOD2 protein via ISGylation. This binding promotes cell proliferation and invasion. The RIPK2 inhibitor (GSK583) eliminated the oncogenic effects of ISG15. In vivo experiments showed that ISG15 knockdown or GSK583 treatment inhibited tumor growth by approximately 50%. Our study reveals the dual nature of ISG15: it is both a prognostic biomarker and a functional oncoprotein in cervical cancer cells. Its pro-tumorigenic effect is mediated by the overactivation of the NLR pathway through ISGylation. The ISG15-NOD2/RIPK2 axis is a targetable vulnerability, suggesting that treatment strategies should be decoupled from its prognostic association.
PTPRN2-mediated silencing of tumor-intrinsic MHC-II promotes immune-excluded tumor microenvironment in colorectal cancer.
Cao Y, Zhou Q, Yang J … +10 more , Mo S, Yuan W, Che J, Luo R, Liang D, Ma B, Gao WQ, Cai G, Luo W, Zou H
Cancer Genet · 2026 Jun · PMID 42139752 · Publisher ↗
Colorectal cancer (CRC) frequently exhibits an immune-excluded tumor microenvironment that limits the efficacy of PD-1 blockade. Through systematic profiling of 106 protein tyrosine phosphatases (PTPs), we identify three...
Colorectal cancer (CRC) frequently exhibits an immune-excluded tumor microenvironment that limits the efficacy of PD-1 blockade. Through systematic profiling of 106 protein tyrosine phosphatases (PTPs), we identify three PTP-based molecular subtypes, among which the immune-excluded Cluster 2 is highly resistant to immunotherapy. Integrative analyses across patient cohorts highlight PTPRN2 as a prominent PTP enriched in immune-excluded tumors and strongly associated with anti-PD-1 non-response. Functional studies demonstrate that PTPRN2 promotes CRC cell proliferation and invasion, and more importantly, suppresses tumor-intrinsic MHC-II expression. Mechanistically, PTPRN2 may promote STAT1 Y701 dephosphorylation and inhibit STAT1 activation, thereby downregulating CIITA expression and impairing antigen presentation. PTPRN2 knockdown restores MHC-II, enhances CD4⁺ and CD8⁺ T-cell activation in organoid co-culture, and increases T-cell infiltration in vivo. Therapeutically, PTPRN2 knockdown combined with PD-1 blockade achieves more effective tumor suppression than either treatment alone. Furthermore, IL-15 rescues STAT1 phosphorylation and MHC-II expression in PTPRN2-overexpressing cells, revealing a cytokine-sensitive regulatory axis. Collectively, our study identifies PTPRN2 as a potential regulator of immune exclusion and a candidate therapeutic target to improve immunotherapy efficacy in CRC.
Novel truncating WT1 germline variant in a case of familial Wilms tumor.
Laustsen MM, Stoltze UK, Larsen KB … +7 more , Olsen TE, Wadt KAW, Sørensen PL, Klausen KG, Brok J, Winther TN, Ahlborn LB
Cancer Genet · 2026 Jun · PMID 42105606 · Publisher ↗
Wilms tumor (WT) is the most common pediatric renal tumor. Familial WT represents 1-2% of individuals with WT and is associated with increased risk of bilateral tumors, congenital anomalies of the kidney and urinary trac...
Wilms tumor (WT) is the most common pediatric renal tumor. Familial WT represents 1-2% of individuals with WT and is associated with increased risk of bilateral tumors, congenital anomalies of the kidney and urinary tract, disorders of sexual development, and other malformations. Wilms tumor etiology is heterogeneous, yet several monogenic causes have been identified including WT1 alterations. A 4-year-old boy presented with unilateral WT and a family history of WT. The proband's mother and her monozygotic twin were both treated for metachronous WTs at 9 and 10 months of age, with second primary at 33 and 30 months of age, respectively. The mother's twin died 34 months old. The boy underwent surgery, and histopathology revealed a mixed type, intermediate-risk group, stage II tumor. He received pre- and post-operative chemotherapy. A novel germline truncating heterozygous WT1 variant (c.634G>T, p.(Glu212Ter)) in exon 1 was identified in blood and a second WT1 hit was identified in the tumor (c.856C>T, p.(Gln286Ter)) in exon 3 using whole genome sequencing. Genetic testing of the family members identified the germline variant in the mother but not in the maternal grandparents. It was not possible to test the mother's twin. Additionally, we provide an overview of all reported WT1 germline variants described in Clinvar and HGMD in individuals with WT. The presence of a germline WT1 variant increases the risk of intralobar nephrogenic rests, bilateral WT, typically with onset at an earlier age. Because of this elevated and distinct risk profile management differs from that of sporadic WT.
CRYL1 inhibits tumorigenesis and metastasis in clear cell renal cell carcinoma through upregulation of CASR.
Xu Y, Li P, Liu X … +8 more , Zhao G, Wu Q, Zhang H, You S, Zhou Q, Wang H, Li Z, Ye J
Cancer Genet · 2026 Jun · PMID 42105605 · Publisher ↗
BACKGROUND: Identifying novel biomarkers and elucidating the underlying molecular mechanisms are crucial for improving the diagnosis and treatment of advanced clear cell renal cell carcinoma (ccRCC). In our previous inve...
BACKGROUND: Identifying novel biomarkers and elucidating the underlying molecular mechanisms are crucial for improving the diagnosis and treatment of advanced clear cell renal cell carcinoma (ccRCC). In our previous investigations, crystallin lambda 1 (CRYL1) was preliminarily identified as an emerging tumor suppressor. The present study expands upon this observation by further exploring its tumor-suppressive role and the underlying molecular mechanisms. METHODS: Seventy patients with ccRCC were selected to validate CRYL1 expression and its clinical significance. In vitro proliferation, migration, and apoptosis assays were performed to assess the effects of CRYL1 overexpression. Transcriptome sequencing combined with bioinformatics analysis identified the calcium-sensing receptor (CASR) as a key downstream target of CRYL1. In vitro functional assays of CASR and further bioinformatics analyses were subsequently conducted. Rescue experiments in vitro and immunohistochemistry (IHC) of tissues validated their regulatory relationship. Subcutaneous xenograft mouse models were used for in vivo validation. RESULTS: Low CRYL1 expression was significantly associated with advanced clinical stage (p = 0.012), poorer disease-free survival (DFS, p = 0.031), and poorer overall survival (OS, p = 0.049). CRYL1 overexpression potently suppressed proliferation, colony formation, and migration and induced apoptosis in Caki-1 and OSRC-2 cell lines. Integrated transcriptomic and bioinformatic analyses identified CASR as a major downstream effector of CRYL1. CASR expression was significantly reduced in ccRCC tissues and was inversely correlated with advanced T stage, grade, and metastasis. Low CASR expression predicted worse OS and DFS. Functional studies demonstrated that CASR overexpression inhibited ccRCC cell migration. Crucially, CASR knockdown partially reversed the anti-migratory effects of CRYL1 overexpression. Significant positive correlations were observed between CRYL1 and CASR expression in patient samples (r ≈ 0.2) and in xenograft tumors. Furthermore, CRYL1-overexpressing xenografts exhibited significantly reduced tumor growth, upregulated BAX and TIMP3, and downregulated BCL2 and MMP9. CONCLUSIONS: The results of this study indicate that CRYL1 functions as a tumor suppressor gene in ccRCC, and that its downregulated expression is closely associated with enhanced tumor aggressiveness and poor patient prognosis. CRYL1 may inhibit cell proliferation and migration and promote apoptosis through regulation of CASR. Therefore, the CRYL1/CASR signaling axis may serve as a novel potential therapeutic target for clear cell renal cell carcinoma.
Myeloid neoplasms with mutated KIT: comparative clinicopathologic analysis of D816 vs. non-D816 variants.
Aqil B, Santana-Santos L, Gao J … +6 more , Kaur A, Lu X, Jennings LJ, Abaza Y, Ji P, Sukhanova M
Cancer Genet · 2026 Jun · PMID 42102664 · Publisher ↗
KIT mutations are recurrent genetic alterations in myeloid neoplasms (MNs), with the D816 hot-spot variant recognized as a poor prognostic marker in acute myeloid leukemia (AML) with RUNX1::RUNX1T1 and as a diagnostic cr...
KIT mutations are recurrent genetic alterations in myeloid neoplasms (MNs), with the D816 hot-spot variant recognized as a poor prognostic marker in acute myeloid leukemia (AML) with RUNX1::RUNX1T1 and as a diagnostic criterion for systemic mastocytosis (SM). In contrast, the clinical and biological relevance of KIT mutations outside codon 816 remains insufficiently characterized. We retrospectively analyzed 40 MNs with pathogenic KIT mutations, comparing 26 cases harboring D816 variants to 14 cases with non-D816 changes. Clinicopathologic features, cytogenetics, molecular profiles, immunohistochemical data, and survival outcomes were evaluated. The two groups showed similar distributions of MN subtypes and cytogenetic abnormalities. However, the non-D816 group exhibited significantly lower mast-cell burden by CD117 immunohistochemistry and no cases of SM, whereas 31% of D816 cases showed concurrent or subsequent SM. D816 cases displayed more complex co-mutational profiles and a higher rate of KIT acquisition as a secondary event. Non-D816 cases demonstrated significantly longer overall survival. In the subset of AML with t(8;21), D816 variants trended toward inferior survival compared with non-D816 variants. Our findings suggest that non-D816 KIT mutations are associated with a less aggressive clinical phenotype, lower mast-cell differentiation, and improved outcomes. These results support a biologically distinct role of non-D816 KIT variants in MNs and highlight the need for refined risk stratification incorporating KIT variant classes.
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