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PubMed2025

Small cell bladder carcinoma with a high tumor mutational burden responding to sequential cisplatin-etoposide and pembrolizumab: a case report.

Small cell carcinoma of the urinary bladder (SCCB) is a rare and aggressive malignancy with limited treatment options and a poor prognosis. We present the case of a 63-year-old man who was initially diagnosed to have non-metastatic high-grade non-muscle invasive urothelial carcinoma with sarcomatoid subtype and later developed bone metastases. A bone biopsy confirmed small cell carcinoma, and retrospective review of the original tumor revealed mixed histology comprising small cell, sarcomatoid-like, and conventional urothelial carcinoma components. The patient was treated with six cycles of cisplatin and etoposide, during which genomic profiling identified a high tumor mutational burden (22 mutations/megabase). Based on this finding, pembrolizumab was administered sequentially as monotherapy. The patient achieved a complete response that lasted for more than 1 year, but subsequently developed lymph node metastases and recurrences in bone. This case highlights the role of genomic profiling test for clinical decision-making as tumor mutational burden predicts the efficacy of immune checkpoint inhibitor therapy in SCCB. This case also underscores the urgent need for novel treatment approaches for SCCB.

Case report↗

PubMed2026

Comprehensive genomic profiling and tumor mutational burden in parathyroid carcinoma: a nationwide real-world study from Japan.

PURPOSE: Parathyroid carcinoma (PC) is an extremely rare endocrine malignancy with limited treatment options for unresectable or recurrent cases. With the increasing use of comprehensive genomic profiling (CGP), treatment based on genomic findings is becoming more common. However, the frequency and clinical significance of elevated tumor mutational burden (TMB) in PC remain unclear because previous studies have been limited by small sample sizes. METHODS: We retrospectively analyzed genomic and clinical data of patients with PC registered in the Center for Cancer Genomics and Advanced Therapeutics database in Japan between June 2019 and March 2025. TMB values were obtained as reported by each CGP assay. TMB-H was defined as TMB ≥ 10 mut/Mb for descriptive analyses. We also assessed genomic alterations, microsatellite instability (MSI) status, and clinicogenomic characteristics. RESULTS: Twenty-five patients with PC were included. The median assay-reported TMB was 4.0 mut/Mb (range, 0-35). Seven tumors (28.0%) had assay-reported TMB values of ≥ 10 mut/Mb, including three (12.0%) with TMB ≥ 20 mut/Mb. The most frequently altered genes were CDC73 (40%), TP53 (32%), and MEN1 (24%). No co-alterations were observed between CDC73 and MEN1 or between CDC73 and TP53. One tumor was MSI-high and was included in the TMB-H group. POLE alterations were detected in three cases, including two tumors in the TMB-H group. CONCLUSION: This nationwide, real-world study demonstrated that a subset of PCs showed elevated assay-reported TMB values and genomic features potentially related to abnormalities in DNA replication or repair pathways. These findings support the clinical relevance of comprehensive genomic profiling in identifying the molecular heterogeneity and potential therapeutic opportunities for this rare malignancy.

Humans↗

PubMed2026

High tumor mutational burden and PIK3CA mutations correlate with poor Merkel cell carcinoma-specific survival.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04-25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10-3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.

Humans↗

PubMed2021

Deep generative neural network for accurate drug response imputation.

Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.

Antineoplastic Agents↗

PubMed2026

Integrated bioinformatics analyses for GSDMB in carcinogenesis and progression of bladder cancer.

BACKGROUND: Emerging evidence suggests that pyroptosis influences the development of various diseases. Gasdermin B (GSDMB), an intracellular protein that executes pyroptosis, has recently attracted attention for its potential role in tumor biology. However, its specific function in bladder cancer (BLCA) remains unclear. Therefore, this study aimed to investigate the potential role of GSDMB in the carcinogenesis and prognosis of BLCA patients. METHODS: Mendelian randomization (MR) studies were conducted to examine relationships between the expression of GSDMB and BLCA with expression quantitative trait loci (eQTL) data. Then, GSDMB mRNA expression data and clinical characteristics of BLCA patients were retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression was used to explore the relationship between GSDMB mRNA expression and patients' survival. Additionally, the correlation between GSDMB and the immune microenvironment, tumor mutational burden (TMB), tumor microenvironment (TME), and drug sensitivity in BLCA was examined. RESULTS: According to MR analysis based on eQTLs, GSDMB mRNA expression has positive causal effects on bladder carcinogenesis and the need for bladder surgery (P<0.05). The analyses of TCGA demonstrated an increased expression of GSDMB in BLCA tissues, correlating with improved patient survival. Additionally, elevated GSDMB mRNA expression was identified as an independent protective prognostic factor for BLCA, and it was associated with immune cell infiltration, TMB, TME score, and drug sensitivity. CONCLUSIONS: Elevated mRNA expression of GSDMB has a causal link to a higher risk of BLCA and the likelihood of bladder surgery, but also indicates a better prognosis. Thus, GSDMB exhibits dual effects and might serve as a potential biomarker for predicting onset and progression of BLCA. Nevertheless, further investigation of pathogenesis and mechanisms underlying GSDMB is warranted.

Bladder cancer (BLCA)↗

PubMed2025

Comparative Analysis of Somatic and Germline Polymerase Proofreading Deficiencies in Cancer: Molecular and Clinical Implications.

Polymerases ε and δ maintain genome integrity through exonuclease proofreading. Germline and somatic pathogenic variants (PVs) in the exonuclease domain (ED) of POLE and POLD1 impair proofreading, causing hypermutated tumors. Despite shared mutational features that make these tumors highly immunogenic, molecular and clinical distinctions between POLE and POLD1 mutations and between somatic and germline variants remain incompletely understood. We compared the molecular and clinical characteristics of POLE and POLD1 ED PVs (n = 31), assessing their location, pathogenicity, clinical phenotypes, mismatch repair (MMR) status, tumor mutational burden, and signatures. We analyzed 360 proofreading-deficient tumors (source: The Cancer Genome Atlas [TCGA] and Catalogue Of Somatic Mutations In Cancer [COSMIC]) and 70 families (249 individuals) with polymerase proofreading-associated polyposis. All germline and somatic PVs had high AlphaMissense scores (0.87-1) and clustered within or near Exo motifs. Recurrent, nonfounder germline PVs, POLE L424V and POLD1 S478N, showed low/modest REVEL scores. Somatic variants occurred mainly in endometrial cancers (75% of proofreading-deficient TCGA cancers), whereas colorectal cancer predominated in polymerase proofreading-associated polyposis (56% of carriers). Cancer risks and tumor spectra differed between POLE and POLD1 PV carriers. Aggressive hereditary phenotypes were linked to either specific POLE PVs (eg, S297F, V411L, P436R, M444K, A456P, and S461T) or the co-occurrence of germline ED PVs with germline MMR gene PVs. Distinct hypermutator profiles were confirmed for polymerase ε and polymerase δ proofreading deficiencies via unique mutational signatures (Polymerase ε: SBS10a/b, SBS28; Polymerase δ: SBS10c/d). Tumors with combined proofreading and MMR deficiencies had significantly higher tumor mutational burden and a shift in the associated mutational spectra. Unlike POLE, POLD1 ED PVs exhibited haplosufficiency, typically requiring a somatic second hit (eg, loss of heterozygosity) or MMR deficiency to drive hypermutation. In conclusion, differences between POLE and POLD1 and between somatic and germline mutations influence clinical presentation, mutagenic potential, and reliance on cooperating defects in tumorigenesis. These insights advance the understanding of proofreading-deficient cancers, with implications for diagnostics, genetic counseling, and precision oncology.

Humans↗

PubMed2025

Unveiling non-small cell lung cancer treatment effect heterogeneity: a comparative analysis of statistical methods.

BACKGROUND: For patients with advanced non-small cell lung cancer lacking targetable genomic alterations, the impact of clinicogenomic characteristics on the effectiveness of combining chemotherapy with immunotherapy is unclear. METHODS: We evaluated 4 statistical methods for detecting heterogeneous treatment effects related to clinical factors, including programmed death-ligand 1 expression, tumor mutation burden, and stage at diagnosis, using the American Association for Cancer Research Project Genomics Evidence Neoplasia Exchange BioPharma Collaborative dataset supplemented with institutional data collected under the same data curation model. A 2-sided P value of no more than .05 was used to denote statistical significance for all analyses. RESULTS: The mixture model revealed 2 latent subgroups: in one subgroup, there was no meaningful treatment effect, with average progression-free survival (PFS) only 5% longer with immunotherapy alone (95% confidence interval [CI] = -19% to 35%); in the second subgroup, immunotherapy alone was associated with a 35% decrease in average PFS (95% CI = -59% to 2%), corresponding to a ratio in treatment effects of 1.62 (95% CI = 1.02 to 2.57). There was a marginal association between lower tumor mutation burden levels and membership in the subgroup with improved PFS following receipt of chemoimmunotherapy. The causal survival forest highlighted the importance of tumor mutation burden (variable importance ranking: 1) and programmed death-ligand 1 (variable importance ranking: 3) when assessing heterogeneity. In contrast, the accelerated failure time and Cox proportional hazards models did not detect any statistically significant heterogeneous treatment effects. In simulations, the mixture model identified heterogeneous treatment effects more frequently than other methods, especially with weak covariate relationships, demonstrating its utility for informing personalized treatment approaches. CONCLUSIONS: The application of novel statistical methods to large scale clinico-genomic databases offers an opportunity to more accurately identify heterogeneous treatment effects in some settings as compared to traditional statistical methods. Applying such methods to the AACR Project GENIE BPC non-small cell lung cancer data indicated a potential association between decreasing tumor mutation burden and improved outcomes with chemoimmunotherapy as compared to immunotherapy alone.

Humans↗

PubMed2026

Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.

BACKGROUND AND AIMS: Comprehensive genomic profiling (CGP) for tumors and germline genetic testing (GGT) inform precision therapy and clinical management of patients with colorectal cancer (CRC), and evidence is growing in support of universal paired CGP-GGT patient testing. However, the utility of combining CGP and GGT for early-stage CRC (ESC) and early-onset CRC (EOC) is unclear. METHODS: We performed a prospective, multisite study featuring GGT using an 80+ gene next-generation sequencing platform and exome-based CGP among CRC patients (unselected for age, stage, family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: A total of 150 CRC patients had GGT and exome-based CGP performed. ESC patients had an enrichment of high microsatellite instability and high tumor mutation burden. High microsatellite instability was also enriched in those with smoking history, and in tumors with mutated BRAF, homologous recombination deficiency, or at least 1 variant in the rat sarcoma virus pathway. Moreover, patients with smoking history were enriched in BRAF and other Tier 1 or 2 variants overall. Sixteen percent of patients harbored a pathogenic germline variant, most frequent being in Lynch syndrome genes. Paired GGT and CGP testing had high rates of clinically significant findings (≈70%) with the most frequent being high tumor mutation burden status. Pathway and mutational signature analysis revealed frequent CGP mutations in DNA repair and cell cycle pathways. CONCLUSION: These data suggest that universal, combined GGT-CGP increases clinical utility for EOC and ESC patients. This is key for EOC patients who tend to experience poorer outcomes. CGP-GGT expedites germline resolution for tumor mutations in hereditary cancer genes, reducing delays and facilitating identification of relevant therapies, clinical trials, and management recommendations.

Colorectal Cancer↗

PubMed2026

Predictive biomarkers in cancer immunotherapy for genitourinary malignancies.

Immunotherapy has transformed the management of genitourinary cancers, offering durable responses in selected patient groups. However, the clinical benefit of immune checkpoint inhibitors varies significantly across renal cell carcinoma, urothelial carcinoma, and prostate cancer, underscoring the need for reliable predictive biomarkers. This review summarizes current knowledge on established and emerging biomarkers, including PD L1 expression, tumor mutational burden, molecular subtypes, genomic alterations, tumor microenvironment characteristics, circulating biomarkers, microbiome influences, and multi omic integrative approaches. We discuss their potential clinical relevance, limitations, and applicability across different tumor types. Future directions emphasize the development of composite biomarkers, standardization of testing platforms, real time monitoring strategies, and the integration of advanced technologies such as artificial intelligence and spatial profiling. Understanding and validating these biomarkers will be essential for optimizing personalized immunotherapy in genitourinary cancers.

Circulating tumor DNA↗

PubMed2026

Pan-cancer Bioinformatics Analysis Combined with Colon Cancer Experimental Validation: A Study on TMED3 as a Diagnostic and Prognostic Biomarker.

Transmembrane Emp24 Protein Transport Domain 3 (TMED3), a member of the p24 protein family, has been implicated in tumor proliferation, invasion, and migration. This study aimed to evaluate the expression patterns, prognostic significance, immune associations, and potential biological functions of TMED3 across multiple cancer types using pan-cancer bioinformatics analysis combined with immunohistochemical (IHC) validation in colon cancer. Multiomics datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, UALCAN, Human Protein Atlas, and cBioPortal databases were analyzed to investigate TMED3 expression and genetic alterations in pan-cancer. Immunohistochemistry was performed to evaluate TMED3 protein expression in colon cancer tissues. Kaplan-Meier survival analysis and Cox regression analysis were used to assess the prognostic value of TMED3. Spearman correlation analysis was conducted to evaluate the associations of TMED3 with tumor mutational burden, microsatellite instability (MSI), immune cell infiltration, and immune checkpoints. Gene Set Enrichment Analysis was performed to investigate potential biological pathways associated with TMED3 in colon cancer. TMED3 expression was elevated in most tumor types and was associated with unfavorable overall survival and disease-specific survival in adrenocortical carcinoma, colon adenocarcinoma, and uveal melanoma. The greatest frequency of TMED3 genetic alterations was identified in mesothelioma, with amplification representing the predominant alteration type. In addition, TMED3 expression showed significant correlations with tumor mutational burden and microsatellite instability in kidney renal clear cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. TMED3 expression was also associated with immune infiltration and immune checkpoint expression in several tumors. IHC analysis demonstrated increased TMED3 expression in colon cancer tissues compared with normal colon tissues and showed an association with T stage. Functional enrichment analysis identified pathways related to ribosome, antigen processing and presentation, oxidative phosphorylation, and pentose phosphate. These findings indicate that TMED3 may represent a promising biomarker for the diagnosis and prognostic evaluation of colon cancer as well as other tumor types.

Humans↗

PubMed2024

A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer.

BACKGROUND: Although there is evidence that ribonucleotide reductase subunit M2 (RRM2) is associated with numerous cancers, pan-cancer analysis has seldom been conducted. This study aimed to explore the potential carcinogenesis of RRM2 in pan-cancer using datasets from The Cancer Genome Atlas (TCGA). METHODS: Data from the UCSC Xena database were analyzed to investigate the differential expression of RRM2 across multiple cancer types. Clinical data such as age, race, sex, tumor stage, and status were acquired to analyze the influence of RRM2 on the clinical characteristics of the patients. The role of RRM2 in the onset and progression of multiple cancers has been examined in terms of genetic changes at the molecular level, including tumor mutational burden (TMB), microsatellite instability (MSI), biological pathway changes, and the immune microenvironment. RESULTS: RRM2 was highly expressed in most cancers, and there was an obvious correlation between RRM2 expression and patient prognosis. RRM2 expression is associated with the infiltration of diverse immune and endothelial cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). Moreover, the cell cycle is involved in the functional mechanisms of RRM2. CONCLUSIONS: Our pan-cancer study provides a comprehensive understanding of the carcinogenesis of RRM2 in various tumors.

Humans↗

PubMed2026

A PMS2-deficient pediatric high-grade glioma with PI3K-pathway mutations and adjacent developmental venous anomaly suggestive of CMMRD.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment. METHODS: Clinical, radiological, histopathological, immunohistochemical, and molecular findings of an 8-year-old girl presenting with a high-grade glioma were retrospectively evaluated. Immunohistochemistry included glial and mismatch repair markers. Targeted next-generation sequencing was performed to assess tumor mutational burden and pathogenic variants. RESULTS: Neuroimaging revealed a right frontoparietal mass associated with an adjacent developmental venous anomaly. Histopathology demonstrated a diffuse pediatric-type high-grade glioma with pseudopapillary architecture and marked mitotic activity. Immunohistochemistry showed diffuse p53 overexpression in tumor cells and complete loss of PMS2 expression in both tumor and non-neoplastic cells, supporting constitutional mismatch repair deficiency. Molecular analysis revealed an ultra-hypermutated profile with a tumor mutational burden of 117.4 mutations/Mb, a pathogenic PMS2 frameshift variant, and co-occurring alterations in TP53, PIK3CA, PIK3R1, and PTEN. The presence of PI3K-pathway mutations alongside a venous anomaly suggested a potential biological association. CONCLUSION: This case illustrates the characteristic clinicopathological and molecular features of CMMRD-associated pediatric high-grade glioma and underscores the critical role of routine mismatch repair immunohistochemistry. Integrated histological and genomic evaluation is essential for accurate diagnosis, appropriate genetic counseling, and potential therapeutic implications. Key Points • This case represents a pediatric high-grade glioma arising in the setting of PMS2-related constitutional mismatch repair deficiency (CMMRD). • The tumor exhibited an ultra-hypermutated profile with co-occurring TP53, PIK3CA, PIK3R1, and PTEN mutations. • Loss of PMS2 expression in both tumor and non-neoplastic cells was critical in establishing the diagnosis of CMMRD. • The presence of a developmental venous anomaly may relate to underlying PIK3R1 pathway alterations. • Routine mismatch repair immunohistochemistry is essential in pediatric high-grade gliomas, even in the absence of a family history.

Humans↗

PubMed2026

Molecular Profiling Across 80,000 Patients With Lung Cancer.

INTRODUCTION: Biomarker testing is an essential component of optimal therapeutic management in NSCLC, enabling the use of both Food and Drug Administration-approved and emerging targeted therapies. Despite well-established biomarker testing guidelines and the availability of many approved targeted therapies, a substantial proportion of patients with advanced NSCLC are not benefiting from precision oncology. In this study, we analyze the distribution of actionable genomic alterations across histologic subtypes and clinicodemographic subgroups of NSCLC using data in 82,328 samples profiled with a single comprehensive genomic profiling assay, aiming to support universal molecular testing across all NSCLC subtypes to ensure equitable access to available therapeutics. METHODS: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested with comprehensive genomic profiling by next-generation sequencing between 2014 and 2022 using Foundation One/Foundation CDx. All cases were centrally reviewed by board-certified anatomic pathologist to determine histologic type and subtype. RESULTS: A total of 82,328 patients with NSCLC were included. An actionable genomic alteration (GA) was found in 35.1% of the cases. Lung adenocarcinoma (LUAD) and adenosquamous carcinoma were more frequently associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (27.6%), large cell (21.1%), and squamous cell (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutation (mut) frequency (9.95% versus 2.43% in LUAD). Tumor mutation burden more than or equal to 10 mut/Mb was associated with histology (50.91% in large cell, 40.79% in not otherwise specified, 39.08% in squamous cell, and 36.30% in sarcomatoid versus 31.22% in LUAD and 29.22% in adenosquamous carcinoma). Patients with actionable GA had usually a low tumor mutation burden (80.88%). A significant correlation (p < 0.005) between age and actionable GA was reported for BRAF/ERBB2 muts, ALK/RET/ROS1 rearrangements, and MET amplification. EGFR actionable muts and KRAS G12C were more frequently observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation for EGFR actionable muts and South/East Asia and America, but not for other GA. CONCLUSIONS: This is the largest NSCLC data set analyzed for biomarker distribution across histologies, age, sex, and genetic ancestry. This data set confirms sufficient enough biomarker prevalence across many histologic subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

Humans↗

PubMed2026

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

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

Humans↗

PubMed2025

Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer.

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Humans↗

PubMed2026

Marked response to dabrafenib plus trametinib in a patient with BRAF V600E-mutant pancreatic hepatoid carcinoma: a case report and systematic analysis of 57 cases.

BACKGROUND: Pancreatic hepatoid carcinoma (PHC) is an extremely rare pancreatic malignancy characterized pathologically by hepatocellular-like differentiation. Some patients may present with elevated serum alpha-fetoprotein (AFP). Owing to the limited number of reported cases, the clinical features, molecular characteristics, and systemic treatment strategies for PHC remain poorly defined. BRAF V600E is an actionable alteration with established therapeutic value in several solid tumors; however, its clinical significance in PHC remains unclear. CASE PRESENTATION: We report the case of a 64-year-old man with advanced PHC who presented with painless jaundice, dark urine, and recent weight loss. Laboratory tests showed marked cholestatic liver injury and significantly elevated AFP. Imaging revealed a pancreatic head-neck mass with portal vein tumor thrombus and regional lymph node metastases, corresponding to cT4N1M1, stage IV disease. Percutaneous transhepatic biliary drainage was first performed to relieve obstructive jaundice. Biopsy of the pancreatic lesion showed poorly differentiated carcinoma. Based on hepatoid morphology, immunophenotype, elevated serum AFP, imaging findings, and exclusion of primary hepatocellular carcinoma, the patient was diagnosed with PHC. Comprehensive genomic profiling identified a BRAF V600E mutation with a variant allele frequency of 31.89%, together with MDM2 and MYC amplification. The molecular profile was characterized by microsatellite stability, low tumor mutational burden, MGMT promoter methylation, and low PD-L1 expression. After two cycles of pembrolizumab-based first-line therapy combined with paclitaxel, S-1, and lenvatinib, AFP continued to increase and imaging showed rapid tumor enlargement, consistent with immune checkpoint inhibitor-related hyperprogressive disease. The treatment was then switched to dabrafenib plus trametinib. AFP declined rapidly and returned to the normal range within approximately two months. Imaging showed marked regression of the pancreatic primary lesion, disappearance of the portal vein tumor thrombus and metastatic lymph nodes, and conversion of peripheral blood minimal residual disease to negative. The best response was partial response. After approximately six months of targeted therapy, occult disease progression emerged. Subsequent addition of cetuximab, replacement of the MEK inhibitor, and dose escalation of targeted therapy did not restore sustained systemic disease control, although local disease remained manageable with subsequent treatment adjustments. Proton radiotherapy was then delivered to the residual pancreatic lesion, followed by CyberKnife radiotherapy for a newly detected 2.3-cm metastasis in the caudate lobe of the liver. As of April 2026, the patient's AFP level remained close to normal at 14 ng/mL, local lesions were well controlled, peripheral blood minimal residual disease had turned positive, and the patient remained in a stable tumor-bearing state. SYSTEMATIC ANALYSIS: We further summarized 57 previously reported cases of PHC. The median age was 54 years, and 66.7% of patients were male. Tumors occurred at different pancreatic sites, including the pancreatic head in 21 cases, body in 8 cases, tail in 13 cases, and multifocal lesions in 15 cases. More than half of the patients had metastatic disease at initial diagnosis. The immunophenotype of PHC was highly heterogeneous. Regarding treatment, 47 patients underwent surgery, 20 received chemotherapy, and 6 received targeted therapy. The 1-year and 3-year overall survival rates were 70.7% and 43.1%, respectively, indicating an overall poor prognosis. CONCLUSION: This case suggests that BRAF V600E may represent a clinically actionable driver alteration in PHC. Dabrafenib plus trametinib induced a rapid and deep response in this patient with advanced BRAF V600E-mutant PHC. Microsatellite stability, low tumor mutational burden, low PD-L1 expression, and MDM2 amplification may be associated with limited benefit from immunotherapy and a risk of hyperprogression. After resistance to targeted therapy, local radiotherapy may serve as an important strategy for controlling oligoresidual and oligometastatic lesions. Together with the literature review, this case supports early comprehensive molecular profiling and individualized multidisciplinary management for advanced PHC.

BRAF V600E↗

PubMed2026

Construction of molecular signatures based on the co-expression network of NECSO-related gene TRPM4 and its prognostic value in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) demonstrates significant prognostic variability that is not entirely accounted for by traditional staging systems. Necrosis by sodium overload (NECSO) is an emerging programmed cell death pathway, but its clinical relevance in HCC remains undefined. Therefore, this study aimed to identify TRPM4-associated core genes, develop and validate a prognostic signature, and investigate its relationship with the tumor immune microenvironment, tumor mutational burden, and single-cell expression patterns in HCC. METHODS: We integrated transcriptomic, clinical, and mutational datasets from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (n=421) and Gene Expression Omnibus (GEO) cohorts (n=115) to identify genes co-expressed with TRPM4-a key NECSO mediator-and those differentially expressed in HCC. A prognostic signature was developed using least absolute shrinkage and selection operator (LASSO)-Cox regression and validated through survival analysis, time-dependent receiver operating characteristic (ROC) curves, and multivariate Cox regression analysis. The immune landscape was characterized using CIBERSORT, somatic mutation data were used to calculate tumor mutational burden (TMB) and assess its correlation with the risk score, and single-cell RNA sequencing (scRNA-seq) resolved cell-type-specific expression patterns. RESULTS: From 294 TRPM4-associated core genes, we identified an 11-gene signature (BRSK1, MMP1, GRIN2D, GP6, MYOM2, N4BP3, CCDC112, TSEN54, MAP3K9, SPP1, B3GNT4) that independently predicted overall survival (OS) (hazard ratio =5.419, P<0.001) with areas under the curve (AUCs) of 0.779, 0.693, and 0.701 at 1, 3, and 5 years. These values were superior or comparable to conventional clinicopathologic variables after direct comparison. High-risk patients exhibited an immunosuppressive microenvironment, characterized by enrichment of M0 macrophage, a higher M2/M1 ratio (P<0.001) and distinct immune checkpoint profiles. When integrated with TMB, the prognostic stratification was further refined: high-TMB/high-risk patients had poorest outcomes (median OS, 15.3 months), while low-TMB/low-risk patients had the most favorable survival (median OS, 68.7 months). Single-cell analysis revealed that MMP1 was induced in cancer-associated fibroblasts (CAFs) and SPP1 was downregulated in macrophages, single-cell risk scores confirmed TAFs and macrophages as the main contributors to the prognostic model. CONCLUSIONS: The TRPM4-centered 11-gene signature provides robust and independent prognostic stratification in HCC by integrating immune, mutational, and single-cell features. This signature serves as a potential tool for prognostic evaluation and may help inform immunotherapeutic strategies for HCC.

Hepatocellular carcinoma (HCC)↗

PubMed2026

A cuproptosis-related lncRNAs-based risk signature for predicting prognosis and immune status in glioma.

BACKGROUND: Glioma is one of the most prevalent primary malignant brain tumors, characterized by poor prognosis and limited treatment options. Recent studies have identified cuproptosis, a novel copper-dependent form of regulated cell death, as a critical mechanism involved in tumor progression. However, the role of cuproptosis-related long non-coding RNAs (lncRNAs) in glioma remains not fully clarified. This study aimed to develop and validate a prognostic model based on cuproptosis-associated lncRNAs to predict patient outcomes and guide individualizing therapeutic strategies. METHODS: Transcriptomic profiles and clinical data were obtained from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Cuproptosis -related prognostic lncRNAs were filtered via univariate and multivariate Cox and Least absolute shrinkage and selection operator (LASSO) regression analyses, which were selected to establish a prognostic model for glioma. Samples were divided into high- and low-risk groups, and the predictive performance of the prognostic model was evaluated based on receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) survival curves, and a nomogram. In addition, immune cell infiltration, tumor mutational burden (TMB), immunophenoscore (IPS), Tumor Immune Dysfunction and Exclusion (TIDE) and drug sensitivity were analyzed. Expression levels of selected lncRNAs and proteins were validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: An 11-lncRNA signature associated with cuproptosis was established, and the risk score derived from this model was identified as an independent prognostic factor for glioma. The model exhibited excellent predictive ability, with area under the curve (AUC) values of 0.880, 0.913, and 0.866 for 1-, 3-, and 5-year survival, respectively. Higher TMB, immune checkpoint expression, and IPS were observed in the high-risk group and no significant difference was observed in TIDE between risk groups. Drug sensitivity analysis identified TPCA-1, KIN001-135, and ispinesib mesylate as potential therapeutic agents. Expression validation in glioma cells further supported the biological relevance of the selected lncRNAs. CONCLUSIONS: This cuproptosis-related lncRNA-based signature demonstrates strong prognostic value and may serve as a promising tool for glioma risk stratification and personalized treatment selection.

Glioma↗