British Journal of Cancer最新文献

Background: The high mutational burden in microsatellite unstable colorectal cancers (MSI CRCs) results in high immunogenicity, yet response rates to immunotherapy vary, suggesting underlying heterogeneity of the tumour immune landscape. Here, our aims were (1) to characterise the immune cell infiltrate and immune evasion in MSI CRCs, (2) to correlate these with clinical and genomic features, and (3) to compare these between Lynch syndrome (LS) and sporadic MSI CRCs.

Method: Immunohistochemistry was utilised to detect T cell and myeloid cell subsets. Whole-genome and RNA sequencing were utilised to analyse somatic variants, tumour clonality, neoantigen burden, antigen presentation, immune checkpoint expression, and consensus molecular subtypes.

Results: Our results revealed higher immune cell scores in LS tumours, depicting higher T cell infiltration, compared to sporadic tumours. Conversely, sporadic tumours displayed increased infiltration of protumorigenic M2-like macrophages and increased expression of immune checkpoints PDCD1LG2 and CD40LG. Across our MSI CRC cohort, high neoantigen burden was associated with low tumour clonality.

Conclusions: Our findings reveal differences between sporadic MSI and LS tumours in T cell and myeloid immune cell landscapes, and in immune evasion. These differences may contribute to the variable immunotherapy responses among MSI CRC patients and are targetable by emerging therapeutic approaches.

Background: Airborne particulate matter (PM) is a complex mixture of particles thought to be associated with a range of adverse health effects, including female breast cancer. Current evidence on the association between PM and female breast cancer risk is inconsistent.

Methods: This study investigated the association between long-term exposure to PM and breast cancer risk in a nested case-control study within the French E3N-Generation cohort including 5222 breast cancer cases identified over the 1990-2011 follow-up period and 5222 individually matched controls. Annual mean concentrations of PM₁₀ and PM_2.5 at participants' residential addresses, were estimated using a land use regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models.

Results: ORs for each 10 µg/m³ increase in the average of PM_2.5 and PM₁₀ were 1.14 (95% CI: 0.99-1.30) and 1.08 (95% CI: 0.98-1.18), respectively. When restricted to invasive ductal and lobular carcinomas, ORs were 2.74 (95% CI: 1.05-7.15) for PM_2.5 and 2.05 (95% CI: 1.11-3.78) for PM₁₀. Comparable effects of PM exposure estimated by a chemistry transport model reinforces these findings.

Conclusion: This study suggests a potential association between PM_2.5 and PM₁₀ exposure and breast cancer risk.

Background: Oxaliplatin resistance continues to undermine therapeutic outcomes in colon cancer (CC). Recent investigations point to unc-51 like kinase 1 (ULK1)-mediated disruption of apoptotic pathways as a potential driver of chemoresistance, though the exact mechanisms remain incompletely characterized.

Methods: Using established CC cell lines, we developed oxaliplatin-resistant models through stepwise dose escalation. ULK1 expression was modulated through targeted siRNA knockdown and stable overexpression. Protein interactions were examined via co-immunoprecipitation coupled with mass spectrometry, supplemented by kinase activity assays. Functional impact was assessed through proliferation kinetics, apoptosis profiling, and tumor xenograft studies. Clinical correlations were derived from TCGA analysis and immunohistochemical evaluation of patient tumor specimens.

Results: ULK1 overexpression consistently correlated with oxaliplatin resistance and adverse clinical parameters. At the molecular level, ULK1 catalyzed Bcl-2 associated X protein (Bax) phosphorylation at Ser184, creating a recognition motif for Parkin-mediated ubiquitination and proteasomal targeting. Disruption of this axis through ULK1 inhibition restored Bax protein levels, enhanced apoptotic response, and reversed oxaliplatin resistance in both cellular and animal models.

Conclusion: These findings identify ULK1-dependent phosphorylation as a novel regulatory mechanism governing Bax stability in CC. The study provides preclinical rationale for targeting the ULK1-Bax interface to overcome oxaliplatin resistance, while highlighting the need for further investigation into optimal therapeutic strategies.

The urgent need for drug development for cancer patients and the complexity of novel therapies have led to the increasing importance of expansion cohorts (EC) within phase 1 trial design. We conducted a systematic review of oncology phase 1 trials with EC published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of EC. A mixed-effects meta-regression model was conducted to analyse response rates. 479 published phase 1 trials with EC were included (median number of EC patients per trial: 27). The EC objective was stated in 55.7% of studies (76.8% safety, 16.5% dosing, 25.8% pharmacokinetics, 22.1% pharmacodynamics, 77.5% preliminary efficacy). 117 trials (24.4%) included a statistical justification plan. The mean Overall Response Rate (ORR) was 20.2% in solid tumours and 46.8% in haematological malignancies. Among drug classes, Antibody-drug conjugates showed the highest ORR (32.1%). Higher ORR was significantly associated with combination therapies, haematological trials, trials with statistical justification for EC sample size and trials not containing Immunotherapy. EC have evolved to become large dynamic studies assessing both preliminary efficacy and safety. This study highlights the importance of clearly stated EC objectives and sample size justification to enhance the rigour and interpretability of early-phase evidence.

Background: Despite significant advances in diagnosis and therapy, the prognosis of late-stage lung adenocarcinoma (LUAD) remains poor, underscoring the urgent need for effective biomarkers to enable early detection. Epigenetic alterations, particularly DNA methylation, is essential for controlling gene expression, and its abnormality plays critical roles in promoting carcinogenesis.

Methods: Reduced representation bisulfite sequencing (RRBS) technique was used to establish the DNA methylation profile in early-stage LUAD in comparison to normal tissues. The epigenetic abnormalities and expression, as well as the functions of ArfGAP with coiled-coil, ankyrin repeat and PH domains 3 (ACAP3) in LUAD carcinogenesis were further investigated.

Results: we investigated the DNA methylation dysregulation during tumorigenesis in the early-stage LUAD, and identified that Myc-mediated DNA hypermethylation and deacetylation as key mechanisms suppressing ACAP3 expression. ACAP3 significantly suppresses the proliferation of LUAD cells in vitro and in vivo. Mechanically, ACAP3 inhibits epidermal growth factor receptor (EGFR) signalling via impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GTPase-activating protein (GAP) activity-dependent manner.

Conclusion: Our finding reveals that ACAP3, suppressed by Myc-mediated epigenetic abnormality in early-stage LUAD, acts as a tumour suppressor by inhibiting EGFR signalling and cells proliferation, suggesting its potential as a diagnostic and therapeutic target.

Background: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associations between circulating metabolites with overall and clinically significant PCa risk has not been quantitively aggregated.

Methods: We performed a systematic review and meta-analysis of untargeted pre-diagnostic circulating metabolomic studies across four clinically distinct outcomes: overall, low- to intermediate-risk, high- to very high-risk, and lethal PCa, each compared to controls.

Results: Twelve studies were identified in the systematic review, and up to 408 metabolites were meta-analysed across the four PCa outcomes. Three, eleven, and nineteen metabolites were significantly associated with risk of overall, high- to very high-risk, and lethal PCa, respectively. Metabolites associated with high- to very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. In follow-up analyses, 13 of the significant metabolites were found to be modifiable by drugs and/or diet.

Conclusions: These findings suggest a strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.

Background: Long-term alcohol use is a recognised risk factor for liver, upper aerodigestive tract (UADT), colorectal, and female breast cancers, yet aggregate-level evidence linking alcohol consumption to mortality from these cancers remains limited. This study examined the potential preventive impact of reducing population drinking on cancer mortality in Australia, accounting for tobacco use and health expenditure.

Methods: Annual per capita alcohol and tobacco consumption data (aged 15+) from 1910-2018, and mortality data for UADT, liver, breast, and colorectal cancers from the 1950s-2018, were collected from national registries. Time series models were used to estimate sex- and age-specific associations and long-term lagged effects of alcohol and tobacco consumption.

Results: A one-litre per capita annual reduction in alcohol consumption was significantly associated with decreases in mortality: 3.6% (95% CI: 1.0-6.2%) in male and 3.4% (1.8-4.9%) in female UADT cancer; 3.9% (0.2-7.7%) in male liver cancer; 1.2% (0.7-1.7%) in male and 0.7% (0.2-1.4%) in female colorectal cancer; and 2.3% (1.7-3.0%) in female breast cancer over a 20-year period.

Conclusion: Reducing population-level alcohol consumption in Australia could substantially lower mortality from UADT, colorectal, male liver, and female breast cancers, particularly among older adults.

Background: Homologous recombination deficiency (HRD) is a predictive biomarker for response to PARP inhibitors and platinum-based therapies in prostate cancer (PCa). However, current diagnostic approaches, often limited to BRCA1/2 mutation testing or genomic scars, fail to capture the full spectrum of HRD. Tissue-based testing is further hampered by tumour heterogeneity and biopsy limitations in patients with metastatic bone disease. This study aimed to develop a noninvasive, multimodal ctDNA-based strategy for comprehensive HRD profiling in advanced PCa.

Methods: We analysed plasma-derived ctDNA from 106 patients with metastatic PCa. The approach integrated targeted sequencing of homologous recombination repair (HRR) genes, low-pass whole genome sequencing for genomic instability scores (GIS), whole-exome sequencing for mutational signature analysis, and cfDNA fragmentomics, including chromatin accessibility profiling.

Results: BRCA2 was the most frequently altered HRR gene, frequently co-occurring with PTEN loss. High GIS was associated with BRCA2/RB1 loss, increased somatic copy number alterations, and poor overall survival. HRD tumours were enriched for mutational signatures SBS3 and ID6, displayed increased dinucleosome-length fragments, and showed reduced accessibility at zinc finger transcription factor binding sites. A fragmentomics-based classifier identified HRD-positive cases with high accuracy.

Conclusions: Our findings support the use of multimodal ctDNA profiling as a non-invasive approach to identify HRD in prostate cancer. The integration of mutation, genomic instability, and fragmentomic features provides a broader functional view of HRD and may enhance patient stratification for targeted therapies.

Background: Risk-stratified lung cancer screening programs identify high-risk individuals who use tobacco but do not account for underlying genetic susceptibility. Many polygenic scores (PGS) have been developed for lung cancer, but it is unclear which, if any, are suitable for identifying high-risk individuals in the general population.

Methods: We used a systematic review to identify published lung cancer PGS, which were implemented and validated in the UK Biobank (UKB) cohort. Performance (discrimination and accuracy) was compared. Subgroup analyses by sex, ethnicity, and smoking status identified differences across the population.

Results: We identified 60 lung cancer PGS published since 2012. Most scores were associated with lung cancer risk in UKB. Of the 39 evaluated PGS, 33 had a hazard ratio per standard deviation greater than 1.1 and 22 had a C-index greater than 0.55. Most PGS perform better in individuals who use tobacco than those who do not, although for a small number of scores (n = 8) the reverse is true.

Discussion: Performance of lung cancer PGS is weak compared to scores for other cancers; the potential benefit of combining genetics with other risk factors for lung cancer remains unclear. Selection of a suitable score is context dependent and requires consideration of the characteristics of the target population (such as ethnicity and tobacco usage).