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PubMed2026

Artificial intelligence in kidney cancer: a review of clinical applications across the disease spectrum.

PURPOSE OF REVIEW: This review examines recent advances (2024-2025) in the application of artificial intelligence (AI) to kidney cancer diagnosis, prognosis, and treatment planning. It categorizes studies across 13 clinical scenarios to assess where AI offers the most clinical utility. RECENT FINDINGS: AI models have demonstrated strong performance in a range of tasks including tumor grading, subtype classification, survival prediction, and risk stratification. Integration of radiomics, genomics, and histopathology has enabled personalized, noninvasive, and timely decision-making. The highest-performing models used CT-based radiomics, particularly for predicting progression-free and recurrence-free survival. However, performance varies across tasks and tumor subtypes, with lower accuracy in detecting oncocytomas or benign vs. malignant differentiation. AI applications in metastatic and nonresected cases remain underexplored, and ultrasound remains a largely under researched modality. While some models improve diagnostic accuracy and workflow efficiency, broader validation across diverse populations is still needed. SUMMARY: AI is transforming kidney cancer care across multiple clinical stages. Although promising, real-world implementation demands ongoing validation and postdeployment monitoring to prevent performance degradation due to distributional drift. AI's integration with multimodal data offers substantial potential to improve outcomes and reduce overtreatment.

Humans↗

PubMed2026

ARHGAP22 as a Potential Prognostic Biomarker in Clear Cell Renal Cell Carcinoma: Insights into Tumor Immunity and Co-Expression Networks.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by substantial clinical heterogeneity, highlighting the need for reliable prognostic biomarkers. This study evaluated the expression pattern, prognostic relevance, and immune-related associations of ARHGAP22 in ccRCC using transcriptomic and clinical data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) cohort, together with external validation data and protein-expression information from the Human Protein Atlas (HPA). ARHGAP22 expression was compared between tumor and adjacent normal tissues, and its associations with overall survival, clinicopathological characteristics, tumor microenvironment scores, and estimated immune-cell fractions were assessed. Co-expression and functional-enrichment analyses were also performed to characterize potential biological associations. ARHGAP22 was significantly upregulated in ccRCC tissues at the transcriptomic level, with corresponding differences observed in immunohistochemical images. High ARHGAP22 expression was associated with shorter overall survival, advanced clinicopathological features, and higher ImmuneScore, StromalScore, and ESTIMATEScore values. CIBERSORT-based analysis showed that the high-expression group had higher estimated fractions of M2 macrophages and regulatory T cells and lower estimated fractions of naïve B cells, resting mast cells, and activated dendritic cells after false discovery rate correction. Functional-enrichment analyses linked ARHGAP22-associated genes to immune-related processes, cell migration, and chemokine- and cytokine-mediated signaling pathways. These findings suggest that ARHGAP22 may represent a potential prognostic and immune-related biomarker in ccRCC, although further independent clinical and experimental validation is required.

Humans↗

PubMed2026

VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING.

Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in VHL-null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

Humans↗

PubMed2025

Integrated proteomic network analysis reveals PTPRC as a central hub protein orchestrating co-expression modules and metabolic dysregulation in renal carcinoma: PTPRC protein molecular action.

The occurrence of renal carcinoma is closely related to a variety of molecular mechanisms and metabolic disorders. PTPRC (protein tyrosine phosphatase receptor C), as an important regulatory protein, was studied to reveal the role of PTPRC in renal carcinoma through comprehensive proteomic network analysis, especially its core position in the coordination of co-expression modules and metabolic disorders. This study was the first to download and process multiple publicly available renal cancer transcriptome data to conduct differential gene expression analysis across datasets. Functional enrichment and disease ontology analysis were performed on the transcriptome of renal cancer, and weighted gene co-expression network (WGCNA) was constructed. The results showed that comprehensive principal component analysis revealed significant differences in the transcriptome of renal cancer, and functional annotation revealed specific pathways associated with renal cancer. WGCNA analysis identified tumor-associated co-expression modules, while multi-omics analysis further identified core regulatory networks including PTPRC. As a central hub protein, PTPRC plays an important coordinating role in the co-expression module and metabolic dysregulation of renal carcinoma. This discovery provides a new perspective for understanding the molecular mechanism of kidney cancer.

Humans↗

PubMed2026

Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.

Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.

Basic Helix-Loop-Helix Proteins↗

PubMed2025

Study on the mechanism of BGN in progression and metastasis of ccRCC.

PURPOSE: To investigate the role of Biglycan(BGN) in the progression and metastasis of clear cell renal cell carcinoma(ccRCC). METHODS: Based on multiple public databases, we investigated the expression level of BGN in ccRCC, its clinical significance, and its association with immune cells. Real-time fluorescence quantitative polymerase chain reaction(PCR) was employed to validate BGN expression in tumor and adjacent normal tissues from ten patients. We utilized RNA sequencing results for further analysis, including differential gene analysis, GO-KEGG analysis, and GSEA analysis, to identify the signaling pathways through which BGN exerts its effects. BGN knockdown cells(786-0 and Caki-1) were generated through lentiviral transfection to examine the impact of BGN on ccRCC. Cell proliferation, migration, and invasion were assessed using CCK8, colony formation, wound healing, Transwell migration, and invasion assays, respectively. RESULTS: Our findings from database analysis and PCR revealed a significant upregulation of BGN expression in kidney cancer tissues compared to normal tissues. Further analysis demonstrated a correlation between high BGN expression and ccRCC progression and immune infiltration. In vitro experiments confirmed that BGN silencing effectively inhibited cell proliferation, migration, and invasion of ccRCC. Mechanistically, these effects may be mediated through the MAPK signaling pathway. CONCLUSION: BGN potentially plays a pivotal role in the progression and metastasis of ccRCC, possibly acting through the MAPK signaling pathway. Therefore, BGN holds promise as a potential therapeutic target for ccRCC.

Humans↗

PubMed2025

miR-9-5p/HMMR regulates the tumorigenesis and progression of clear cell renal cell carcinoma through EMT and JAK1/STAT1 signaling pathway.

BACKGROUND: The most common malignant type of kidney cancer is clear cell renal cell carcinoma (ccRCC). The expression levels of hyaluronan-mediated motility receptor (HMMR) in many tumor types are significantly elevated. HMMR is closely associated with tumor-related progression, treatment resistance, and poor prognosis, and has yet to be fully investigated in terms of its expression patterns and molecular mechanisms of action in ccRCC. Further research is imperative to elucidate these aspects. METHODS: We used The Cancer Genome Atlas (TCGA) database to preliminarily investigate HMMR expression and function in ccRCC and the data for 19 samples from the NCBI GEO database (GSE207493) for single-cell analysis. We assessed the differential expression level of HMMR between ccRCC cancerous tissues and their matched non-tumor tissues. Subsequently, a series of in vivo and in vitro experiments were designed to elucidate the biological function of HMMR in ccRCC, including Transwell assays, CCK-8 assays, clone formation assays and subcutaneous xenograft experiments in nude mice. Through bioinformatics analysis, we identified potential microRNAs (miRNAs) that may regulate HMMR, as well as the possible signaling pathways involved. Finally, we conducted a series of cellular functional experiments to validate our hypotheses regarding the HMMR axis. RESULTS: HMMR expression was significantly up-regulated in tumor tissues of ccRCC patients, and elevated HMMR expression level showed a strong correlation with ccRCC progression and adverse prognoses of patients. Knocking down HMMR inhibited the proliferative and migratory abilities of ccRCC cells, while its overexpression amplified these oncogenic properties. In nude mice model, reduced HMMR expression inhibited ccRCC tumor proliferation in vivo. Furthermore, overexpression of an upstream transcriptional regulator, miR-9-5p, effectively downregulated HMMR expression and thus impeded ccRCC cells proliferation and migration. HMMR might influence ccRCC growth via the Epithelial-Mesenchymal Transition (EMT) pathway and the Janus Kinase 1/Signal Transducer and Activator of Transcription 1 (JAK1/STAT1) pathway. CONCLUSIONS: HMMR is overexpressed in ccRCC, and there is a significant link between high HMMR expression and tumor progression, as well as poor patient prognosis. Specifically, HMMR could be targeted and inhibited by miR-9-5p and might modulate the tumorigenesis and progression of ccRCC through both EMT and JAK1/STAT1 signaling pathway.

Carcinoma, Renal Cell↗

PubMed2026

Cellular Recovery and Therapeutic Rechallenge After Cancer Therapy-Induced Kidney Injury: Mechanistic Insights and Clinical Implications.

Cancer therapy-related acute kidney injury has become an increasingly common challenge as modern treatments prolong survival and increase exposure to potentially nephrotoxic therapies. Decisions regarding therapeutic rechallenge have relied on normalizing serum creatinine and recovering estimated glomerular filtration rate, despite growing evidence that biochemical recovery does not necessarily indicate restoration of kidney integrity or resilience. In this review, we propose biological kidney recovery as a conceptual framework that integrates mechanisms of kidney injury and repair (adaptive and maladaptive) with emerging biomarkers and therapeutic rechallenge. We first summarize the distinct mechanisms of kidney injury induced by platinum-based chemotherapy, immune checkpoint inhibitors, and vascular endothelial growth factor pathway inhibitors, highlighting how these differences influence subsequent repair. We then discuss the cellular and metabolic processes underlying adaptive repair, the transition to maladaptive remodeling, and current approaches for assessing biological recovery through pathology, biomarkers, and multi-omics technologies. Finally, we present a practical framework for individualized therapeutic rechallenge based on an integrated assessment of kidney-, tumor-, and patient-related factors and outline future directions for precision onco-nephrology. By shifting the focus from filtration alone to biological recovery, this framework enables more informed therapeutic rechallenge aimed at preserving both oncologic efficacy and long-term kidney health.

Humans↗

PubMed2025

Dual-specific phosphatases-8: a new target for clinical disease intervention.

Dual-specific phosphatase-8 (DUSP8), identified as the first gene in a genome-wide association study (GWAS), is implicated in cellular oxidative stress, proliferation, apoptosis, and drug resistance through its negative regulation of the dephosphorylation activities of JNK, ERK, and p38 within the MAPK pathway. Recent studies have shown that DUSP8 plays a pivotal role in the progression of several human diseases, notably colorectal cancer, diabetic kidney disease, and breast cancer. This suggests that DUSP8 may represent a novel target for clinical intervention in these diseases. This review first introduces the biological structure and function of DUSP8, with a focus on its relationship with a series of diseases and the regulatory mechanisms involved. Furthermore, we concentrate on unresolved scientific questions in the current research, aiming to establish a new theoretical foundation for the diagnosis and treatment of related diseases.

Humans↗

PubMed2026

[Moxibustion combined with Jianpi Wenshen formula for cancer-related anorexia of spleen-kidney yang deficiency: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of moxibustion combined with Jianpi Wenshen formula in treating cancer-related anorexia of spleen-kidney yang deficiency. METHODS: A total of 80 patients with cancer-related anorexia of spleen-kidney yang deficiency were randomized into an observation group and a control group, with 40 cases in each group.Jianpi Wenshen formula was given orally in the control group. On the basis of the treatment in the control group, moxibustion was applied at bilateral Zusanli (ST36), Neiguan (PC6) and Zhongwan (CV12), Guanyuan (CV4), Mingmen (GV4) in the observation group, once daily for the first 15 days, then once every other day. Both groups were treated for 4 weeks. The scores of appetite, Karnofsky performance status (KPS), nutritional risk screening 2002 (NRS-2002), and patient-generated subjective global assessment (PG-SGA), as well as the serum levels of interferon-γ (IFN-γ) and C-reactive protein (CRP)were observed before and after treatment, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: After treatment, the scores of appetite, NRS-2002, PG-SGA, and the serum levels of IFN-γ and CRP were decreased compared with those before treatment in the two groups (P<0.001, P<0.05, P<0.01), and the above indexes in the observation group were lower than those in the control group (P<0.05, P<0.001); the KPS scores were increased in the two groups compared with those before treatment (P<0.001, P<0.05), and the KPS score in the observation group was higher than that in the control group (P<0.001). The marked response rate was 57.5% (23/40) in the observation group, which was higher than 30.0% (12/40) in the control group (P<0.05). CONCLUSION: Moxibustion combined with Jianpi Wenshen formula can effectively improve appetite and overall status, and reduce the levels of IFN-γ and CRP in patients with cancer-related anorexia of spleen-kidney yang deficiency.

Humans↗

PubMed2026

Prostate Cancer, Genetic Susceptibility, and Risk of Chronic Non-Urological Complications.

BACKGROUND: Chronic nonurological complications are common among prostate cancer (PCa) survivors; however, their spectrum, magnitude, and genetic contribution remain poorly characterized. METHODS: We evaluated 15 commonly reported nonurological complications and tested their associations with exposure to PCa and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N = 219,133). Analyses were conducted using cause-specific Cox proportional-hazards models within a full-cohort framework with time-updated PCa status, delayed entry at study recruitment, and age as the underlying time scale. RESULTS: After recruitment, incident PCa was diagnosed in 13,780 men, of which 1,656 (12.02%) had metastatic PCa (mPCa). Risks for seven complications were higher among men with PCa, adjusting for genetic background (all p < 0.05), including osteoporosis, venous thromboembolism, depression, and four primary cancers (bladder, kidney, colorectal, and pancreatic). Risks were consistently stronger among men exposed to mPCa than non-mPCa; for example, the hazard ratio (HR) (95% confidence interval) for osteoporosis was 1.88 (1.63-2.18) for any PCa, 4.67 (3.11-7.01) for mPCa, and 1.75 (1.50-2.04) for non-mPCa. Elevated risks for three additional complications (coronary artery disease, type 2 diabetes and chronic obstructive pulmonary disease) were observed only among men with mPCa. The risks for these ten complications were further increased among men with higher disease-specific PRS; for example, the HR for osteoperosis in mPCa patients in the top PRS quartile was 13.57 (8.24-22.34) compared with men without PCa (p < 0.001). CONCLUSION: PCa diagnosis and inherited genetic susceptibility jointly contribute to increased risks of multiple chronic non-urological complications among survivors.

Humans↗

PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗

PubMed2025

DNA Methylation-Based Classification of Kidney Neoplasms.

Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immunohistochemical, mutation, and cytogenetic-based diagnostic workup. Through examination of the genome-wide DNA methylation signatures of over 2000 renal neoplasms, we identified 23 coherent groups that correlate with known neoplasm types and identified novel clinically relevant subtypes of existing neoplasm types. We used machine learning models to develop and validate a classifier trained on DNA methylation profiles of 1284 samples. The classifier was tested on an external data set of 287 renal neoplasms with >90% concordance between expected neoplasm type and high-score DNA methylation-based classification. Discordance between the original histologic label and methylation class led to potential reclassification of some cases. This work demonstrates proof of principle for the feasibility of a DNA methylation classifier as a clinically useful tool to assist in the diagnosis of renal neoplasms.

Humans↗

PubMed2025

Role of lncRNA PVT1 in the progression of urological cancers: Novel insights into signaling pathways and clinical opportunities.

Urologic malignancies, encompassing cancers of the kidney, bladder, and prostate, represent approximately 25 % of all cancer cases. Recent advances have enhanced our understanding of PVT1's crucial functions. Long noncoding RNAs influence both the onset and development of cancer, as well as epigenetic alterations. Recent findings have focused on PVT1's mechanism of action across several malignancies, particularly urologic cancers. Understanding the various functions of PVT1 linked to cancer is necessary for the development of cancer detection and treatment when PVT1 is dysregulated. Furthermore, recent advancements in genomic and epigenetic research have elucidated the complex regulatory networks that control PVT1 expression. Comprehending the intricate role of PVT1 Understanding the complex function of PVT1 in urologic cancers has substantial clinical implications. Here, we summarize some of the most recent findings about the carcinogenic effects of PVT1 signaling pathways and the possible treatment strategies for urological malignancies that target these pathways.

Humans↗

PubMed2026

Reduced VEPH1 expression is associated with an invasive phenotype and poor prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) remains a clinically heterogeneous urologic malignancy, and improved biomarkers are needed to refine prognostic stratification. VEPH1 has been implicated in cancer biology, but its role in ccRCC is incompletely defined. This study aimed to investigate the expression, prognostic relevance, and functional effects of VEPH1 in ccRCC. METHODS: VEPH1 transcript expression and prognostic relevance were evaluated using The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) and validated in paired ccRCC and adjacent normal renal tissues. The ability of VEPH1 transcript expression to distinguish tumor from normal tissues within the TCGA-KIRC dataset was assessed by receiver operating characteristic analysis. Gain- and loss-of-function experiments were performed in 786-O and 769-P ccRCC cells to determine the effects of VEPH1 on epithelial-mesenchymal transition (EMT)-related markers, migration, and invasion. AKT and ERK phosphorylation was evaluated by western blotting. RESULTS: VEPH1 transcript expression was significantly lower in ccRCC tissues than in normal renal tissues and distinguished tumor from normal samples within the TCGA-KIRC dataset. Low VEPH1 transcript expression was associated with poorer overall survival. Validation in 11 paired clinical specimens confirmed reduced VEPH1 messenger RNA (mRNA) and VEPH1 protein expression in tumor tissues. Functionally, VEPH1 overexpression increased E-cadherin, decreased N-cadherin, and suppressed migration and invasion, whereas partial VEPH1 knockdown produced the opposite changes. In exploratory signaling analyses, VEPH1 overexpression was associated with reduced AKT and ERK phosphorylation without altering total AKT or ERK levels. CONCLUSIONS: Reduced VEPH1 transcript expression was associated with poorer overall survival, whereas experimental VEPH1 depletion was associated with invasive and EMT-related features in ccRCC cells. VEPH1 may represent a candidate prognostic indicator in ccRCC; however, its relationship with AKT and ERK signaling and its clinical relevance require further mechanistic and independent-cohort validation.

Clear cell renal cell carcinoma (ccRCC)↗

PubMed2026

Glycoinformatic Profiling of Label-Free Intact Heparan Sulfate Oligosaccharides.

Heparan sulfates (HSs) are a group of heterogenous linear, sulfated polysaccharides that play a role in health and many diseases, including cancer, cardiovascular, and kidney diseases. The structural variety of HS has greatly challenged the development and utility of HS analytics, particularly for native (nondepolymerized) structures, leaving a significant gap in HS technologies for clinical application. Mass spectrometry-based profiling with bioinformatics offers an approach that can retain variety in large datasets. Using healthy human plasmas, we developed a mass spectrometry glycoprofiling approach for native HS oligosaccharides, which retains the structural complexity of each individual HS chain and generates an HS "index" (or Heparan-ome) for each patient. As a proof of concept, analysis of 53 plasma samples ranging from four groups of kidney disease patients revealed a new subset cluster (21%, 4/19) of membranous glomerulopathy patients with distinct HS profiles, highlighting the potential of HS glycoprofiling as a powerful new approach to clinical practice, which warrants future development into quantitative oligosaccharide glycosaminoglycanomics and clinical diagnostics of kidney and other diseases.

Humans↗

PubMed2025

Genomic testing for RET in the clinic: UK and global perspective.

RET is a key oncogene in neuroendocrine cancer. Pathogenic germline variants lead to multiple different phenotypes, including multiple endocrine neoplasia type 2, medullary thyroid cancer (MTC), Hirschsprung disease and kidney malformations. Pathogenic somatic variants are also associated with MTC, and RET rearrangements are observed in papillary thyroid cancer, non-small cell lung cancer and pan-cancer syndromes. Testing for both germline and somatic variants is now feasible in everyday clinical practice, and their identification has important clinical consequences, both for affected individuals and their families. This mini-review will discuss current germline and somatic testing strategies in the UK and worldwide, as well as reporting and test outcomes (including variants of uncertain significance or incidental findings). It will explore actions following identification of a pathogenic germline variant, including predictive, reproductive and childhood testing, and somatic testing of RET variants in solid tumours informing personalised cancer treatment. Finally, it will discuss the challenge of delivering rapid and equitable access to genomic testing to ensure that all individuals can benefit promptly and appropriately to improve clinical outcomes.

Humans↗

PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗