International Journal of Cancer最新文献

Genetic mutations are well known to influence tumorigenesis, tumor progression, treatment response and relapse, but the role of epigenetic variation in cancer progression is still largely unexplored. The lack of epigenetic understanding in cancer evolution is in part due to the limited availability of methods to examine such a heterogeneous disease. However, in the last decade the development of several single-cell methods to profile diverse chromatin features (chromatin accessibility, histone modifications, DNA methylation, etc.) has propelled the study of cancer epigenomics. In this review, we detail the current landscape of single-omic and multi-omic single-cell methods with a particular focus on the examination of histone modifications. Furthermore, we provide recommendations on both the application of these methods to cancer research and how to perform initial computational analyses. Together, this review serves as a referential framework for incorporating single-cell methods as an important tool for tumor biology.

Fibroblasts are important components in the tumor microenvironment and can affect tumor progression and metastasis. However, the roles of genetic variants of the fibroblast-related genes (FRGs) in the prognosis of non-small-cell lung cancer (NSCLC) patients have not been reported. Therefore, we investigated the associations between 26,544 single nucleotide polymorphisms (SNPs) in 291 FRGs and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In Cox regression multivariable analysis, we found that 661 SNPs were associated with NSCLC overall survival (OS). Then we validated these SNPs in another independent replication dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, we identified two independent SNPs (i.e., FER rs7716388 A>G and SULF1 rs11785839 G>C) that remained significantly associated with NSCLC survival with hazards ratios (HRs) of 0.87 (95% confidence interval [CI] = 0.77-0.98, p = 0.018) and 0.88 (95% CI = 0.79-0.99, p = 0.033), respectively. Combined analysis for these two SNPs showed that the number of protective alleles was associated with better OS and disease-specific survival. Expression quantitative trait loci analysis indicated that the FER rs7716388 G allele was associated with the up-regulation of FER mRNA expression levels in lung tissue. Our results indicated that these two functional SNPs in the FRGs may be prognostic biomarkers for the prognosis of NSCLC patients, and the possible mechanism may be through modulating the expression of their corresponding genes.

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cancer subtype but has no indicated targeted treatments. MET inhibition may be a treatment for MET-driven pRCC, but there is a large group of non-MET-driven pRCC without targeted therapy. Activation of NRF2-ARE pathway has been suggested to be involved in pRCC. To study the relevance of the NRF2-ARE pathway, we characterized 60 pRCCs by copy number analysis and Whole Exome Sequencing. Because stabilisation of NRF2 results in enhanced expression of NQO1, a reductase that prevents production of reactive oxygen species, protein expression of NQO1 was analysed by immunohistochemistry (IHC) from tissue microarrays (TMAs) and by enzymatic activity assay. Finally, patient-derived pRCC cells (PDCs) were applied for drug profiling with 18 NRF2-ARE pathway inhibitors. We identified MET mutations in 5%, and mutations in four genes of NRF2-ARE pathway (NFE2L2, KEAP1, CUL3 and BACH1) in 10% of 60 pRCC samples. IHC analysis of TMAs of 638 renal cancers showed the correlation of the expression of NQO1 with poor survival outcome (p < .001) and high tumour grade (p < .001) and stage (p < .001) in pRCC. NQO1 mRNA, protein levels and enzymatic activity were increased in 56% of matched pRCC tissue samples and patient-derived cells (PDCs, n = 9). Drug screening revealed that Brusatol and Convallatoxin are potential novel drugs for pRCC. Inhibition of NRF2 represents a novel therapeutic approach for MET-independent pRCC patients.

This study evaluates the H2AX/γ-H2AX expression in soft tissue sarcomas (STS), its implications for biological behavior and immune environment, and its potential as a prognostic biomarker. RNA-Seq data from 237 STS were obtained from The Cancer Genome Atlas project. Patients were stratified by H2AX mRNA expression using a survival-associated cutoff. Differentially expressed genes and pathways as well as immune signatures between H2AX^high- and H2AX^low tumors were identified with DESeq2 analysis, gene set enrichment analyses (GSEA), Enrichr pathway analysis and CIBERSORTx. Tissue microarrays of a different cohort of 291 STS were generated for immunohistochemical staining to assess γ-H2AX protein expression, followed by statistical evaluation. High H2AX mRNA expression was associated with shorter overall survival (OS) in STS (p = 0.02), particularly in leiomyosarcomas (LMS) (p < 0.001), and was a negative prognostic factor in LMS (HR 11.15, p < 0.001). H2AX^high LMS tumors showed upregulation of cell cycle-related pathways, while H2AX^low LMS exhibited increased inflammatory activity, including elevated M1 macrophage signatures and resting mast cell signatures (both p < 0.001). High γ-H2AX protein levels were an independent negative prognostic factor in the total LMS cohort (HR 12.12, p = 0.025) and in the subgroup of non-uterine LMS (HR 153.80, p = 0.013). Consistent with CIBERSORTx analysis, γ-H2AX^low LMS showed higher mast cell infiltration than γ-H2AX^high LMS (p = 0.038). In conclusion, H2AX mRNA and γ-H2AX protein expression are associated with distinct biological behavior, differences in the immune cell environment, and might serve as useful prognostic biomarkers in LMS.

Cyclin-dependent kinase 4/6 inhibitors (CDKIs) in combination with endocrine therapy (ET) are the standard-of-care in the first-line treatment of HR-positive, HER2-negative metastatic breast cancer. In the absence of direct head-to-head trials comparing the efficacy and safety of the different CDKIs, the individual choice of treatment in everyday practice is complex. Inverse probability of treatment weighting was used to emulate a head-to-head comparison of palbociclib +ET (PALBO) and ribociclib +ET (RIBO) in patients recruited into the prospective, observational, multicenter registry platform OPAL (NCT03417115). Progression-free survival (PFS), overall survival (OS) and quality of life surveys were analyzed, also for subgroups stratified by treatment-free interval (TFI). A total of 623 patients with HR-positive, HER2-negative metastatic breast cancer received PALBO (n = 388) or RIBO (n = 235) in their first line of treatment. No difference between PALBO and RIBO was found for PFS (median 26.7 months [23.6, 30.7] vs. 27.0 months [21.1, 30.4], HR 1.01 [0.80, 1.27]) and OS (median 42.4 months [38.8, 50.3] vs. 49.3 months [36.9, NA], HR 0.96 [0.71, 1.28]). There was a trend for longer PFS and OS in patients with TFI <12 months receiving RIBO. Patients reported comparable side effects for both CDKIs. This head-to-head comparison revealed no difference in PFS and OS between PALBO and RIBO, however, a trend to longer PFS and OS with RIBO was observed in the subgroup of patients with TFI <12 months. Side effects experienced with PALBO and RIBO highlight the important toxicities to be addressed during treatment decision.

Upper age limits are currently fixed for all fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening programs. A risk-stratified upper age limit may be beneficial. Therefore, we assessed differences in interval CRC risk among individuals who had reached the upper age limit of screening (75 years). Individuals with a negative FIT (<47 μg Hb/g feces) in the final round of the Dutch CRC screening program were selected from the national screening database and linked to the national cancer registry to identify CRCs diagnosed within 24 months (interval CRCs). Survival analyses assessed whether sex and last fecal hemoglobin (f-Hb) concentration were associated with interval CRC risk. A multivariable logistic regression assessed whether sex, last f-Hb concentration and screening round were associated with stage distribution (early vs. late). Last f-Hb concentrations were considered detectable when they were >0 μg Hb/g feces. Among 305,761 individuals with a complete follow-up (24 months), 661 were diagnosed with interval CRC (21.6 per 10,000 negative FITs). Individuals with detectable f-Hb (15%) were 5 times more likely to be diagnosed with interval CRC than those without (HR 4.87, 95%CI: 4.19–5.65). Moreover, their cancers were more often detected at a late stage compared to individuals without detectable f-Hb (OR 1.45, 95%CI: 1.06–2.01). Our results show that interval CRC risk among individuals aged ≥75 differs substantially by last f-Hb concentration, indicating a uniform age to stop screening is suboptimal. Future research, taking into account multiple screening rounds and FIT results, should determine the optimal risk-stratified screening strategy.

Circulating tumour DNA (ctDNA) is an emerging biomarker for monitoring cancers. The personalised disease monitoring in metastatic breast cancer (PDM-MBC) study is an ongoing study instigated to evaluate ctDNA as a biomarker to individualise imaging requirements in patients with MBC. Patients receiving first-line endocrine therapy (aromatase inhibitor + cyclin-dependent kinase 4/6 inhibitor) had plasma samples collected pre-treatment, weeks 2 and 4, and concurrently with imaging until progressive disease (PD). Here, we apply an experimental analytical workflow for ultrasensitive ctDNA analysis, utilising personalised ctDNA panels designed from mutations identified in tumour tissue, and present results for 24 patients. Twenty patients (83%) had detectable ctDNA pre-treatment. The median progression-free survival was 25.6 months, and 13 patients experienced PD, with rising ctDNA detected at or prior to PD in 12 patients (92%). If imaging had been omitted until the detection of rising ctDNA for at least one mutation, 68% (n = 71) of the scans performed amongst ctDNA-positive patients would have been avoided. Our results demonstrate that integration of personalised ctDNA monitoring of patients with MBC has potential to substantially reduce the imaging needs in patients showing ctDNA response to treatment.

Animal models of N-butyl-N-(4-hydroxy butyl) nitrosamine (BBN)-induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN-induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi-omics analyses, including whole-exome, whole-transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi-omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf-related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf-related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non-engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.

The data sources and methods used to develop global cancer incidence and mortality statistics—the GLOBOCAN estimates—for the year 2022 are documented in this article, alongside a brief overview of the global cancer burden. The estimates, made available in 185 countries or territories worldwide for 36 cancer sites by sex and age, are based on the best available local data sources, namely population-based cancer registries (for incidence) and national vital statistics (for mortality). In males, lung cancer was the most commonly diagnosed cancer worldwide in 2022 (1.57 million new cases [95% UI: 1.56–1.58]), followed by prostate cancer (1.47 million [1.46–1.48]). With 2.30 million (2.28–2.30) new cases estimated in 2022, breast cancer was the most diagnosed cancer in females, followed by lung cancer (0.91 million [0.90–0.91 million]) and cervical cancer (0.66 million [0.66–0.67]). The most common causes of cancer death in males and females were lung cancer (1.23 million [1.22–1.24]) and breast cancer (0.67 million [0.66–0.67]), respectively.