The Experimental Cancer Medicine Centre (ECMC) Network supports UK-wide access to experimental cancer therapies, many of which require specific genomic alterations. This study aimed to develop expert consensus on essential genes for a pan-cancer sequencing panel, involving subject matter experts (SMEs) from the ECMC Network and the pharmaceutical industry. A pilot with 8 SMEs graded 526 genes, refining the list to 210. A three-round Delphi process was then used, with SMEs iteratively evaluating each gene. In the final round, SMEs also assessed the inclusion of tumour mutational burden (TMB), microsatellite instability (MSI), and mutation types (structural variations, copy number variations, and/or fusions). Consensus was reached on a final panel of 99 genes applicable across multiple cancers. High agreement was also achieved for including TMB, MSI, and screening for structural variations, copy number variants, and fusions. The panel is intended for both adult and paediatric tumour types. This consensus-based gene panel offers a standardised approach to pan-cancer genomic screening. It supports harmonised diagnostics and could improve patient access to personalised therapies and research trials across clinical and NHS settings.

Profilin-2 (PFN2) is implicated in cancer metastasis, yet its significance in oral squamous cell carcinoma (OSCC) is unclear. We quantified PFN2 mRNA and protein in 236 OSCC tumours using qRT-PCR and immunohistochemistry, correlating findings with clinicopathology and survival. Gain- and loss-of-function studies were performed in OSCC cell lines and xenograft mice. RNA sequencing with gene-set enrichment, subcellular fractionation, and immunofluorescence delineated PFN2-dependent pathways. Sensitivity to the histone deacetylase (HDAC) inhibitor SAHA was assessed in vitro. High PFN2 expression correlated with lymph-node metastasis, stage IV disease, and poorer overall and disease-free survival (p < 0.01). PFN2 increased proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and accelerated primary tumour growth plus cervical/lung metastasis in vivo; knockout produced opposite effects. Transcriptomics revealed enrichment of EMT, E2F, G2/M, and hypoxia signatures, with a 44% overlap with HDAC1 targets. PFN2 shifted HDAC1 to the cytoplasm and downregulated NuRD partners MBD3/MTA1 without altering total HDAC1. PFN2-driven EMT was independent of β-catenin nuclear entry. PFN2 overexpression sensitized cells to SAHA, enhancing G2/M arrest, apoptosis, and invasion blockade. PFN2 is an oncogenic driver that promotes OSCC progression through HDAC1-dependent transcriptional reprogramming. PFN2 may serve as a prognostic biomarker and predictor of response to HDAC-targeted therapy.

There is limited evidence on the optimal frequency of mammogram surveillance. At 5-year follow-up, the Mammo-50 trial found that, in patients aged 50+ and 3 years post diagnosis, less frequent mammograms were non-inferior to annual mammograms for breast-cancer-specific-survival, recurrence-free interval and overall survival. A within-trial cost-effectiveness analysis compared annual versus less frequent mammogram surveillance over 5 years from healthcare and societal perspectives. Hospital Episodes Statistics captured hospital-based resource use. Health-related quality of life and other cost data were obtained via questionnaires at surveillance mammograms. A budget impact analysis estimated NHS savings. Less frequent surveillance led to cost savings of -£543.88 (-£1116; £26) and a small reduction in quality-adjusted life years (QALYs) of -0.02 (-0.095; 0.06) per patient. The incremental net monetary benefit at a £20,000/QALY threshold was £187 (-£1574; £2027). Including societal costs increased savings to £1543 per person (-£2416; -£669), and cost-effectiveness. Projected NHS savings were £185.87 million over 6 years. Less frequent mammogram surveillance is cost-effective. Uncertainty remains due to variability in costs and quality of life estimates, and missing data in the less frequent arm due to study design. Given the trial's non-inferiority findings, this strategy is recommended from healthcare and societal perspectives.

This study characterised the proteins from EVs in the serum from high-grade serous ovarian cancer (HGSOC) compared to healthy controls. Serum EVs were isolated, followed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. We validated the expression of 4 EV proteins increased in cancer serum (KRT4, MARCKS, SPP1/OPN, and UCHL1) in HGSOC tissues and normal ovarian tissues using online databases and independent HGSOC patient tissue cohorts. We additionally investigated the effects of the UCHL1 inhibitor, LDN-57444, on HGSOC cell metabolic activity, motility, invasion, and apoptosis in HGSOC tissues using patient-derived explant assays. Proteomics analysis identified 28 EV proteins that were upregulated in HGSOC compared to healthy controls. We confirmed that UCHL1 protein levels were increased in HGSOC tissues compared to normal (OSE and FT) and benign epithelium. High stromal UCHL1 levels were associated with reduced progression-free survival in HGSOC. The UCHL1 inhibitor, LDN-57444, reduced the cell metabolic activity of ovarian cancer cell lines and primary ovarian cancer cells with high UCHL1 levels. LDN-57444 blocked the motility and invasion of OVCAR3 cells and promoted apoptosis in the HGSOC patient explant tissue assay. UCHL1 has the potential to be used as a novel prognostic and therapeutic target for HGSOC.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant cancer predisposition syndrome, caused by pathogenic variants in FLCN, characterized by benign fibrofolliculomas, pulmonary cysts, pneumothorax, and increased risk for kidney tumors. To date, the risk of other solid tumors in individuals with BHDS remains unclear. We performed a register-based matched cohort study of 353 Swedish born individuals with verified pathogenic variants in FLCN to study the association between BHDS and other cancer types than kidney tumors. Each patient was matched to 50 comparisons, matched by birth year, birth county and sex. Associations were estimated using Cox Proportional Hazard models, expressed as Hazard Ratios with 95% Confidence Intervals. Patients with BHDS exhibited a significantly elevated risk of adult cancer (adjusted HR 2.25, 95% CI 1.76-2.87), primarily driven by kidney tumors. Colorectal cancer and malignant melanoma were more prevalent in the BHDS cohort, reflected by a fivefold increase in risk of colorectal cancer (adjusted HR 5.44, 95% CI 2.74-10.81) and an almost threefold risk of malignant melanoma (adjusted HR 2.67, 95% CI 1.17-6.07). This study confirms the high risk of kidney tumors in BHDS and identifies increased risks for colorectal cancer and malignant melanoma, though the absolute risks remain low. Further research is needed to validate the colorectal cancer association and assess its implications for screening and management.

Chronic inflammation and inflammatory-related exposures have been implicated in epithelial ovarian cancer (EOC) prognosis. However, no studies have evaluated whether analgesic medication use impacts survival in Black women with EOC, an understudied population with poor survival. Leveraging data from the African American Cancer Epidemiology Study, we examined the association of pre-diagnostic analgesic medication use (aspirin, non-aspirin non-steroidal anti-inflammatory drugs [naNSAIDs], and acetaminophen) with survival among self-identified Black women diagnosed with EOC (N = 541) using multivariable Cox proportional hazards regression. Stratified analyses were conducted by comorbidities and histotype. Acetaminophen use was associated with a higher risk of mortality overall (HR = 1.40; 95% CI = 1.00-1.97) and for frequent and chronic use (≥30 days per month: HR = 1.62; 95% CI = 1.12-2.34; >5 years: HR = 1.57; 95% CI = 1.03-2.39). These associations were more pronounced among women with high-grade serous carcinoma (HGSC)/carcinosarcoma and those with comorbidities. Among women with comorbidities, naNSAID use was associated with a decreased risk of mortality (HR = 0.71; 95% CI = 0.51-0.99), but no association was observed among women without comorbidities (HR = 0.99; 95% CI = 0.56-1.75). No associations with survival were observed for aspirin. Chronic use of acetaminophen negatively impacted survival among Black women with EOC, while naNSAID use conferred a survival advantage only among women with comorbidities.

Steroid hormones influence breast morphology and cellular proliferation and are associated with breast carcinogenesis. However, their associations with mammographic breast density (MBD) are less studied, particularly in premenopausal women. We, therefore, investigated the associations of steroid hormone metabolites with MBD in premenopausal women. Our study included 700 premenopausal women scheduled for screening mammograms. We analyzed 54 steroid hormone metabolites (Metabolon®) and assessed volumetric measures of MBD including volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV) using Volpara. We investigated associations using linear regression modeling to estimate the covariate-adjusted means of VPD, NDV, and DV, corresponding to each steroid hormone metabolite tertile and on a continuous scale. Models were adjusted for age, body fat percentage, age at menarche, race, alcohol consumption, family history of breast cancer, oral contraceptive use, body shape at age 10, and parity/age at first birth. We applied false discovery rate (FDR) to control multiple testing and determined significance at FDR-adjusted p-value ≤ 0.05. One corticosteroid (cortolone glucuronide (1)) and four androgenic steroid metabolites (androstenediol (3beta,17beta) monosulfate (2), androstenediol (3beta,17beta) disulfate (1), 5alpha-androstan-3alpha,17beta-diol monosulfate (2), and 5alpha-androstan-3alpha,17beta-diol disulfate) were inversely associated with VPD. For instance, VPD was lower monotonically across tertiles (T) of cortolone glucuronide (1) (T1 = 8.9%, T2 = 8.3%, and T3 = 7.3%; p-trend=7.55 × 10-5, FDR p-value = 0.01); androstenediol (3beta,17beta) monosulfate (2), (T1 = 8.8%, T2 = 8.6% and T3 = 7.5%; p-trend=8.89 × 10-4, FDR p-value = 0.03), and androstenediol (3beta,17beta) disulfate (1) (T1 = 9.0%, T2 = 8.4% and T3 = 7.6%; p-trend=8.41 × 10-4, FDR p-value = 0.03). Five progestin steroid metabolites were positively associated with VPD, but only 5alpha-pregnan-3beta,20alpha-diol monosulfate (2) was marginally significant after FDR correction (T1 = 7.5%, T2 = 8.2%, T3 = 8.8%; p-trend=4.56 × 10-3, FDR p-value = 0.06). Two corticosteroid metabolites, tetrahydrocortisol glucuronide and cortolone glucuronide (1), were positively associated with NDV. For instance, NDV was higher across tertiles of cortolone glucuronide (1) (T1 = 744.3 cm3, T2 = 829.0 cm3, and T3 = 931.8 cm3; p-trend=4.64 × 10-6, FDR p-value = 7.51 × 10-4). No metabolites were associated with DV. We identified novel inverse associations of cortolone glucuronide (1) and four androgenic steroid metabolites with VPD, underscoring the importance of steroid hormone metabolites in MBD and the potential for modulating these in reducing MBD.

MYBL2, a member of the MYB transcription factor family, promotes the advancement of certain types of malignancies. However, the involvement of MYBL2 in endometrial cancer (EC) remains uncertain, and its investigation at the pan-cancer level is ongoing. In order to conduct an analysis and visualisation of The Cancer Genome Atlas and Genotype-Tissue Expression databases, along with transcriptomic data, we employed the use of R software and various online tools. Additionally, the effects of MYBL2 downregulation on the functional capabilities of EC cells were investigated using a range of methods, including the CCK8 assay, Transwell assay, flow cytometry assay, and western blot analysis. Furthermore, the expression of MYBL2 was evaluated in clinical EC tissues and tumour sections of nude mice through the utilisation of an immunohistochemical assay. We identified MYBL2 as a potential target for the impact of icariside II on EC progression. Meanwhile, we successfully developed a prognostic model for MYBL2 expression in patients with EC. Moreover, a notable decrease in EC cell growth and migration was observed when MYBL2 expression was suppressed. Our pan-cancer examination revealed that MYBL2 was significantly upregulated in most malignancies and was associated with poor prognosis in these cases. Moreover, there was an important connection between high MYBL2 expression and immune cell infiltration as well as immune checkpoint genes. These outcomes emphasise the notable relationship between cancer progression and the expression of MYBL2, indicating that MYBL2 could function as a potential biomarker for the prognosis and immunotherapy of malignancies. These results provide a new perspective for cancer treatment, particularly for EC.

Microsatellite instable (MSI) colorectal cancer (CRC) has distinct features that distinguish it from microsatellite stable CRC. While ferroptosis may play a role in the development of MSI CRC, its mechanisms remain unclear. Ferroptosis was assessed via the detection of lipid peroxidation, malondialdehyde, 4-hydroxy-2-nonenal, and intracellular Fe2+, etc. Phosphoproteomic analysis, cytokine array, and flow cytometry were performed to explore the regulation of CD8+ T cell infiltration. Dual specificity phosphatase 4 (DUSP4) suppressed ferroptosis in MSI CRC cells by reducing lipid peroxidation and inhibiting intracellular Fe2+ accumulation. Mechanistic studies showed that DUSP4 downregulated the expression of transferrin receptor (TFRC), which was transcriptionally regulated by c-MYC. In addition, a positive correlation was observed between the infiltration of CD8+ T cells in CRC tissues and the expression of DUSP4 in cancer cells. Mechanistically, DUSP4 dephosphorylated cyclin-dependent kinase 7 (CDK7) and promoted C-X-C Motif chemokine ligand 16 (CXCL16) expression, resulting in an increased infiltration of CD8+ T cells. Importantly, the combination of a CDK7 inhibitor and anti-programmed cell death protein-1 therapy demonstrated a synergistic therapeutic effect in MSI CRC. DUSP4 acts as a negative regulator of ferroptosis and a positive regulator of CD8+ T cell infiltration in MSI CRC.