The identification of cancer drivers is a cornerstone to delivery of precision oncology. So far sequencing of renal cell cancer (RCC) has largely been confined to the clear cell subtype of RCC. In contrast, sequencing analyses of the less common forms of RCC, papillary RCC (pRCC) and chromophobe RCC (ChRCC), have so far been limited. We analysed whole genome sequencing data on 164 tumour-normal pairs from the Genomics England 100,000 Genomes Project, providing a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genomic features, including mutational signatures, intra-tumour heterogeneity and analysis of extrachromosomal DNA formation. Our research establishes correlations between genomic alterations and histological diversification and the extent to which genetically-mediated immune escape contributes to the development of these RCC subtypes. Implications: We demonstrate the distinctive genetics which characterises pRCC and ChRCC and how this information has the potential to inform patient treatment and clinical trials.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 1st identified in breast cancer and subsequently in multiple other cancer types, is an innate immune checkpoint regulator that recently emerged as a promising biomarker and therapeutic target. Homologous recombination deficiency (HRD) has gained clinical relevance with therapeutic vulnerability, particularly in breast and ovarian cancers. Despite the increasing significance of ENPP1 and HRD in cancer biology and treatment, their potential relationships have not yet been comprehensively investigated. We analyzed the relationship between ENPP1 expression and HRD score across the Cancer Genome Atlas pan-cancer and individual tumor types using the Pearson and Spearman correlations. To account for heterogeneity, pan-cancer samples were clustered using linear regression into 3 groups based on Bayesian Information Criterion. Differential expression, functional enrichment, and survival analyses were performed for these clusters at both the pan-cancer and representative tumor type levels. Although the pan-cancer relationship between ENPP1 expression and HRD score was heterogeneous, significant correlations were observed in 11 tumor types. Linear regression-based clustering resolved this heterogeneity into 3 functionally and clinically distinct groups: Cluster 1 was characterized by proliferation programs; Cluster 2 by extracellular matrix remodeling, differentiation, and immune response; and Cluster 3, by metabolic reprogramming. Clinically, Cluster 3 was associated with better survival than Clusters 1 and 2 in a pan-cancer analysis (P < .0001). At the individual tumor type level, these global cluster features were further modified in tissue-specific contexts, reflecting local microenvironment adaptation. Significant survival differences were observed in patients with adrenocortical carcinoma, chromophobe renal cell carcinoma, low grade glioma, and mesothelioma, further underscoring the tissue-specific modification of global cluster features. Our comprehensive pan-cancer analysis revealed the intrinsic heterogeneity of ENPP1 expression and HRD score, which may arise from complex and dynamic interactions with diverse cancer hallmarks, including proliferation, extracellular matrix remodeling, immune response, and metabolic reprogramming, and can be generalized into 3 clusters with distinct molecular and clinical characteristics. At the individual tumor type level, these global cluster features were further modified to adapt to a tissue-specific microenvironment, manifesting distinct tissue-specific patterns. Collectively, these findings provide a foundation for refining biomarker-driven precision medicine strategies for diverse tumor types.

Chromophobe thyroid carcinoma (CTC) is a rare thyroid carcinoma with distinct morphology, often occurring in patients with tuberous sclerosis complex (TSC). The molecular drivers remain poorly understood. We report two additional CTC cases and review the literature including genetic query. Patient 1, an 11-year-old boy, had a 10.3-cm bilateral thyroid mass with tumoral capsular and vascular invasion. Microscopically, the tumor showed trabecular and nested growth, prominent cell membranes, raisinoid nuclei, eosinophilic granular cytoplasm, and perinuclear halos resembling chromophobe renal cell carcinoma. The tumor expressed thyroid markers (TTF-1, PAX-8, thyroglobulin) and renal cell markers (colloidal iron, parvalbumin, CD117) with peripheral mitochondrial accentuation by anti-mitochondrial staining. A somatic TSC2 p.Y1650Cfs*4 frameshift mutation was identified. Patient 2, a 24-year-old woman, had a 3.8-cm infiltrative, angioinvasive right lobe tumor with similar morphology and marker expression and positive lymph nodes. Molecular analysis showed somatic TSC2 c.2071dupC p.R691Pfs*12 and TSC2 c.2353C > T p.Q785* mutations. A cBioPortal query (2285 cases) found TSC1 alterations in 2% and TSC2 in 1%, mostly deletions, enriched in poorly differentiated and anaplastic thyroid carcinomas. Literature review identified seven CTC cases; 42.8% had TSC association and 42.8% showed locoregional recurrence. Median follow-up of 36months showed all patients alive. Common morphologic and immunophenotypic features were consistent; 85.7% exhibited vascular invasion. None harbored common mutations like BRAF p.V600E and RAS. CTC is a distinct, rare thyroid carcinoma often linked to TSC or TSC mutations, characterized by unique morphology and immunophenotype.

Renal cell carcinoma with biphasic morphology: A cohort showing similar morphology but distinct clinicopathological and molecular features.

Conventional FLCN-mutated tumor: a retrospective study of 5 cases with emphasis on diagnostic challenges.

Outcomes of Patients with Metastatic Non-clear Cell Renal Cell Carcinoma Receiving Contemporary or Traditional First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Novel tissue markers in renal neoplasms using molar-scale quantitative proteomics via the total protein approach normalised with protein deglycase DJ-1 (PARK7).

Re: Tumor-intrinsic and Microenvironmental Determinants of Impaired Antitumor Immunity in Chromophobe Renal Cell Carcinoma.

Streptozotocin (STZ) is known to induce renal tumors in rodents, but their similarity to human tumors remains poorly defined. We characterized and comparatively validated a mouse model of STZ-induced renal tumorigenesis by administering a single intraperitoneal dose of STZ (250 mg/kg) to female CBA/NSlc mice and maintaining them for 182 days. Renal tumors developed in 25 of 28 surviving mice (89%), with mean and median numbers of 3.4 and 2.5 tumors per animal, respectively. Histopathologically, the tumors were diagnosed as adenomas or adenocarcinomas and exhibited clear, eosinophilic, or mixed cytoplasm. Immunohistochemical analysis of four representative adenocarcinomas revealed positivity for CK AE1/AE3, CK7, PAX8, CD10, CD82, E-cadherin, CD117, and S100A1, and negativity for CK20 and vimentin. These morphological and immunohistochemical features resembled those of human chromophobe renal cell carcinoma (chRCC). Furthermore, the tumors expressed collecting duct markers (uromodulin, CD15, MUC1, and GLUT-1) but lacked proximal convoluted tubule markers (AQP1 and megalin), suggesting a collecting duct origin. Taken together, STZ-induced mouse renal tumors closely resemble human chRCC, providing a reproducible model for investigating the biology and potential therapeutic approaches for this tumor type.

Performance of 99mTc-Sestamibi Single-Photon Emission Computed Tomography/Computed Tomography for Characterizing Renal Masses: Combined Results From a Prospective Scan-and-Resect Trial and Clinical Experience.

BackgroundRenal cell carcinoma (RCC) is the most common adult kidney malignancy, yet regional data from the Middle East are limited. This study characterized the clinicopathological, immunohistochemical, and survival features of RCC in a Jordanian cohort.MethodsA retrospective analysis of 295 RCC cases (2020–2024) from Yarmouk University affiliated hospitals was conducted. Clinical and pathological parameters, immunohistochemical markers, and survival were analyzed using Kaplan–Meier and log-rank tests.ResultsClear-cell RCC was the predominant subtype (72.2%), followed by papillary (10.5%), chromophobe (9.1%), and others (8.1%). The mean age was 62.1 years, with male predominance (66.4%). Clear-cell RCC showed higher rates of high-grade histology, sarcomatoid and rhabdoid differentiation, capsule invasion, renal vein involvement, and metastasis (p < 0.05), while chromophobe RCC was indolent with no metastases. CK7, Hale’s iron, and c-kit characterized chromophobe RCC, vimentin was typical of clear-cell, and AMACR of papillary RCC. Survival was significantly worse with older age, higher T stage, sarcomatoid features, and higher ISUP grade, while nephrectomy type had no effect.ConclusionsClear-cell RCC demonstrated aggressive pathology, whereas chromophobe RCC was indolent. Age, subtype, stage, and sarcomatoid features were key prognostic factors, highlighting the need for early detection and expanded nephron-sparing surgery in the region.

Renal tumours with oncocytic morphology are among the most difficult to classify at renal mass biopsy (RMB), and a number of emerging entities with low-grade oncocytic morphology have been recently described. This study aimed to evaluate pathological concordance between RMB and subsequent nephrectomy or repeat biopsy for oncocytic renal neoplasms and to identify pathological factors contributing to diagnostic discordance, including the impact of evolving tumour classification. We retrospectively reviewed 145 cases of oncocytic renal neoplasms diagnosed on RMB, including 114 with subsequent nephrectomy and 31 with repeat biopsy only. Overall concordance was 92.9% between RMB and nephrectomy and 96.7% between initial and repeat RMB. Concordance for oncocytoma at nephrectomy was lower (81.4%), likely reflecting selection bias, but was 100% in cases with repeat biopsy. Review of discordant cases (n = 9) revealed that 55% (5/9) were reclassified as emerging tumour entities, specifically low-grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT). Additional discordant cases were due to heterogeneous tumour morphology in chromophobe renal cell carcinoma (ChRCC) and incomplete immunohistochemical work-up leading to misclassification of rarer renal cell carcinoma subtypes. Despite inherent diagnostic challenges, there was overall good concordance between RMB and nephrectomy or subsequent biopsy for the diagnosis of oncocytic tumours. Recognition of emerging tumour entities may reduce diagnostic uncertainty, improve classification in challenging cases, and further improve diagnostic concordance over time. Nonetheless, limitations of RMB, particularly related to tumour heterogeneity, highlight the importance of integrating pathological, clinical, and radiologic data to inform patient management.

Chromophobe renal cell carcinoma (chRCC) is a distinct subtype of non–clear cell renal cell carcinoma (ncRCC), arising from intercalated cells of the distal nephron collecting ducts. No standard treatments are specifically approved for chRCC, which is further hindered by lack of a universally accepted grading system. This study sought to find molecular drivers that may aid in the diagnosis or development of treatments for chRCC. A retrospective analysis of chRCC was conducted using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository, accessed through cBioPortal (version 17.0-public) on 21 July 2025. The study examined recurrent somatic mutations and assessed co-occurrence with Benjamini–Hochberg False Discovery Rate (FDR) correction. Additional analyses evaluated mutation by sex and race, with significance set at p < 0.05. The cohort included 180 tumor samples from 170 chRCC patients. Most patients were adults (n = 167, 98.2%) and White (n = 115, 67.6%). Recurrent alterations occurred in genes part of the p53, PI3K/mTOR, Hippo, and NOTCH signaling pathway. Exploratory demographic analyses identified isolated single-patient mutations in select genes across sex and race; however, these rare events are not interpretable as population-level differences. This study provides a comprehensive genomic profile of chRCC across multiple demographic categories.

Renal cell carcinomas are among the most common malignant tumours of the urogenital tract. The current WHO classification of renal tumours comprises over 20 distinct subtypes, some of which have a specific molecular genetic background. The new WHO classification divides tumours into morphologically and molecularly defined tumours. In addition to the established subtypes - clear cell, papillary, and chromophobe renal cell carcinomas - new entities have been defined, such as eosinophilic solid and cystic renal cell carcinoma. The category of molecularly defined renal tumours includes renal cell carcinomas with TFE3 rearrangement, TFEB-altered renal cell carcinomas, ELOC-mutated renal cell carcinomas, fumarate hydratase-deficient renal cell carcinomas, succinate dehydrogenase-deficient renal cell carcinomas, renal cell carcinomas with ALK rearrangement, and SMARCB1-deficient medullary renal cell carcinomas. Based on recent findings of prolonged survival times and the absence of distant metastasis, several subtypes are no longer classified as carcinoma but as renal tumours, such as multilocular cystic renal tumours or clear cell papillary renal tumours. The WHO classification emphasizes the importance of genetically defined renal tumours, which are addressed in a dedicated chapter. Currently, molecular analyses guide treatment decisions in advanced cases following discussions in molecular tumour boards. Therefore, the classification of subtypes, together with their specific molecular alterations and signalling pathways, is gaining importance not only for targeted systemic therapy but also for the identification of patients with a hereditary tumour syndrome.The task of pathologists is to identify new tumour entities and genetically inherited tumour forms in order to ensure the best possible clinical care for patients.

Abstract Immune escape is a critical hallmark of cancer, driving disease progression, poor prognosis, and resistance to therapies. However, how immune escape evolves in cancer is poorly understood. Existing studies are limited by a narrow focus on escape mechanisms and the inability of conventional methods to resolve the temporal order of clonal mutations. To overcome these challenges, we developed an integrative approach that combines systematic mining of immunomodulatory genes and novel computational reconstruction of tumor evolution history. Using this framework, we generated the first pan-cancer atlas of genetic evolution of immune escape. We find that immunomodulatory pathways are mutated at varying frequencies across cancers. For example, antigen presentation machinery is highly mutated in chromophobe renal cell carcinoma and lung squamous cell carcinoma, while the protein methylation pathway is highly mutated in bladder transitional cell carcinoma. Furthermore, cancers exhibit distinct evolutionary trajectories of immune escape. Pancreatic adenocarcinoma acquires late mutations in amino acid metabolism, esophageal adenocarcinoma shows early mutations in neuroactive ligand−receptor interaction and IFNγ signaling, and breast adenocarcinoma has late mutations in protein methylation. These findings systematically map the genetic evolution of immune escape across cancer types and lay the groundwork for novel approaches in early detection, immunoprevention, and therapeutic intervention. Citation Format: Wenjie Chen, Toby Baker, Zhihui Zhang, Huw Alexander. Ogilvie, Peter Van Loo, Shengqing Gu. Genetic evolution of immune escape across cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B022.

Chromophobe renal cell carcinoma: Emerging vulnerabilities as a promise for a new therapeutic landscape.

Reactivity of carbonic anhydrase IX (CA IX) across the spectrum of renal cell carcinomas with sarcomatoid differentiation.

ObjectiveTo investigate the diagnostic value of three-dimensional superb micro-vascular imaging (3D-SMI) combined with quantitative analysis of Area and VI in differentiating benign and malignant renal tumors.MethodsA total of 256 renal lesions from 254 patients who underwent gray-scale ultrasound (Gray US), two-dimensional superb micro-vascular imaging (2D-SMI), and 3D-SMI examinations at Tianjin Medical University Cancer Institute and Hospital between January 2022 and June 2024 were retrospectively analyzed. The imaging features on Gray US, 2D-SMI and 3D-SMI were recorded. Based on 3D-SMI, Vascular Architecture were classified into five types: Type I (avascular), Type II (spotty flow), Type III (sparse flow), Type IV (encircling), and Type V (rich flow). The plane with the most abundant blood flow was selected, and the Area and VI were calculated using Image Pro Plus (IPP) software. Histopathology from surgery or biopsy served as the reference standard. The differences in Vascular Architecture, Area, and VI between benign and malignant renal tumors were compared, and their diagnostic performance was evaluated.ResultsAmong the 256 lesions, 70 were benign and 186 were malignant. The interobserver agreement for Vascular Architecture classification was good (Kappa = 0.803), and the consistency for Area and VI was high (ICC = 0.835 and 0.864, respectively). Benign tumors Vascular Architecture were mainly type II or III, with mean Area and VI values of 945.87 ± 568.26 (range: 68–3125) and 5.93 ± 4.95 (range: 0.23–24.73), respectively. Malignant tumors were predominantly type IV or V, with mean Area and VI values of 3694.53 ± 2612.38 (range: 93–9965) and 18.21 ± 10.83 (range: 0.69–48.13), respectively. Significant differences were observed in Vascular Architecture, Area, and VI between benign and malignant lesions (all P < 0.001). The area under the ROC curve (AUC) values for 3D-SMI Vascular Architecture, Area, VI, 2D-SMI, and Gray US were 0.813, 0.807, 0.859, 0.750, and 0.718, respectively. VI demonstrated the highest diagnostic performance, with a cutoff value of 8.19 (sensitivity: 82.26%; specificity: 85.51%). Among benign subtypes, there were no significant differences in Vascular Architecture or Area (P > 0.05), while the VI of oncocytoma was significantly higher than epithelioid angiomyolipoma (EMAL), metanephric adenomas (MA), and angiomyolipoma (AML)(P < 0.01). Among malignant subtypes, clear cell renal cell carcinoma (ccRCC) showed distinct Vascular Architecture compared with papillary renal cell carcinoma(pRCC), chromophobe renal cell carcinoma(chRCC), and Xp11.2 translocation/TFE3 fusion-associated renal cell carcinoma(tRCC) (P < 0.01). The Area and VI of ccRCC were significantly higher than those of pRCC and chRCC (P < 0.05), but not significantly different from tRCC (P > 0.05).Conclusion3D-SMI provides three-dimensional visualization of Vascular Architecture. Quantitative analysis of the most vascularized plane using Area and VI differentiation between benign and malignant renal tumors, with VI demonstrating the best diagnostic efficacy. This technique offers a non-invasive diagnostic approach for renal tumors.

BackgroundIn recent years, the significance of sirtuins in cancer biology has become increasingly evident, but their molecular mechanisms and prognostic impacts remain elusive.ObjectiveThe present study aimed to investigate the differential expression of the sirtuin gene family across cancers and to evaluate their prognostic value.MethodsWe used various bioinformatics databases and methodologies, including Oncomine, GEPIA, OncoDB, cBioPortal, R2 Kaplan-Meier Scanner, STRING, etc., to determine the expression pattern of the sirtuin family genes, along with their mutations and prognostic values in human cancers.ResultsIn the current study, SIRT1, SIRT2, SIRT4, and SIRT5 were downregulated in lymphoma, whereas SIRT6 and SIRT7 were overexpressed. In breast cancer, SIRT3, SIRT5, and SIRT7 were overexpressed, and in terms of kidney cancer, higher expression of SIRT2, SIRT3, and SIRT5 was observed. In contrast, for leukemia, bladder, and brain cancers, most sirtuin family members showed reduced expression. We found that most mutations occurred in uterine cancer, chRCC (chromophobe renal cell carcinoma), DLBCL (diffuse large B-cell lymphoma), melanoma, pRCC (papillary renal cell carcinoma), and esophageal cancer. Moreover, we identified the relevant functional proteins through protein-protein interaction analysis to evaluate copy number alterations (CNAs) in sirtuins. The most frequent alterations were amplifications and deep deletions. Survival analysis demonstrated that SIRT1 and SIRT2 overexpression correlated with improved overall survival in low-grade glioma but predicted poorer outcomes in ovarian cancer. Downregulation of SIRT1, SIRT3, and SIRT5 was associated with better prognosis in DLBCL, while SIRT3 and SIRT4 upregulation predicted favorable survival in testicular germ cell tumors. SIRT6 overexpression was linked to favorable prognosis in esophageal carcinoma and sarcoma, while unfavorable outcomes were observed in hepatocellular carcinoma and cholangiocarcinoma. SIRT7 upregulation was significantly associated with reduced survival in esophageal, liver, and uterine cancers, but surprisingly correlated with improved outcomes in urothelial carcinoma and cervical squamous cell carcinoma.ConclusionsTogether, this multi-omics analysis reveals the correlation and prognostic values of sirtuins across multiple types of human cancers and suggests that sirtuins may serve as promising biomarkers for different cancers.

Prevalence and clinical significance of CBP deficiency and disturbed CBP expression in human cancer.