International Journal of Cancer最新文献

Benefits and harms of breast cancer (BC) screening with mammography have been debated and, although most studies reported positive effects, some studies found a negative effect in terms of net quality-adjusted life years (QALYs). We aimed to estimate net QALYs associated with biennial mammographic screening for women aged 50-69 years offered to 100,000 women followed until age 85, using various assumptions on BC mortality reduction, overdiagnosis and mortality transfer (the extent to which a reduction in BC mortality results in a reduction in all-cause mortality). Individual-level data from women invited to BreastScreen Norway during 1996-2020 were used to perform the calculations. The three baseline scenarios included (1) Model Microsimulation Screening Analysis (MISCAN): MISCAN prediction for mortality reduction and overdiagnosis proportion; (2) Model A: 40% BC mortality reduction and 15% overdiagnosis; and (3) Model B: 20% BC mortality reduction and 50% overdiagnosis. For all scenarios, an 80% mortality transfer was assumed. An online tool was developed to illustrate the impact of alternative assumptions. Biennial organized mammographic screening for women aged 50-69 years who were followed until the age of 85 years was associated with 6819, 7444 and 2446 net QALYs gained per 100,000 women for Model MISCAN, A and B, respectively. Assumptions on BC mortality reduction exhibited the largest impact on net QALYs. To conclude, even when assuming a high overdiagnosis proportion and low BC mortality reduction, net QALYs remained positive, reinforcing the value of offering BC screening with mammography to Norwegian women and showing its potential to improve health outcomes.

Exercise protects against colon cancer progression, but the underlying biological mechanisms remain unclear. One proposed mechanism is the release of bioactive molecules into the systemic circulation during exercise, which may act directly on tumour cells to suppress DNA damage, inhibit proliferation, and preserve genomic stability. Here, we profiled the serum proteomic response to acute exercise and evaluated the effects of exercise-conditioned human serum on DNA damage kinetics and transcriptomic signatures in colon cancer cells. Blood samples were collected from 30 overweight/obese adults before and immediately after a maximal incremental cycling test. LoVo cells were exposed to pre- or post-exercise serum, treated with 2 Gy irradiation, and assessed for γ-H2AX foci over 24 h. Acute exercise increased the relative abundance of 13 proteins in serum (p < 0.05), including interleukin-6 (IL-6) and its soluble receptor IL-6R, reflecting systemic activation of acute-phase immune and vascular signalling. Compared to pre-exercise serum, post-exercise serum significantly reduced γ-H2AX foci in LoVo cells at 6 h (p = 0.010) and decreased the area under the curve (p = 0.014), indicating accelerated DNA repair. Post-exercise serum also increased expression of the DNA repair gene PNKP, with and without irradiation (p = 0.007 and p = 0.029, respectively). Transcriptomic analysis revealed upregulation of mitochondrial energy metabolism and downregulation of cell cycle and proteasome-related pathways. These findings suggest that acute exercise elicits systemic responses that enhance DNA repair and shift colon cancer cells towards a less proliferative transcriptomic state under sublethal genotoxic stress, offering a potential mechanistic explanation for the protective effects of exercise against colorectal carcinogenesis.

Lynch syndrome is a germline cancer predisposition syndrome caused by a variant in one of four genes. Lynch syndrome places individuals at significantly higher risk for a range of cancers, especially colorectal and endometrial. Depending on which gene is affected, the risk of ovarian, gastric, small bowel, pancreatic, biliary urothelial, brain, and certain skin tumors is also increased. Tailored treatment, cancer surveillance, and consideration of primary prevention measures are critical for at-risk individuals. Despite advancements in genetic testing, Lynch syndrome remains underdiagnosed, with only a small proportion of those affected aware of their genetic predisposition. This article explores the patient experience of living with Lynch syndrome, focusing on the challenges surrounding diagnosis, risk-adjusted prevention, healthcare coordination, and information dissemination. Stages of the patient journey are explored, from awareness and suspicion to diagnosis, treatment and surveillance, psychosocial adaptation, and ongoing management. The need for more comprehensive healthcare strategies and better communication to enhance the quality of care for Lynch syndrome patients is emphasized. We recommend improvements to better meet patient needs.

The immunosuppressive tumor microenvironment, characterized by limited immune cell infiltration, represents a major challenge for effective immunotherapy in hepatocellular carcinoma (HCC). Epigenetic dysregulation has emerged as a critical mechanism underlying tumorigenesis and progression; however, the specific epigenetic mechanisms governing immune infiltration remain poorly understood. Here, we investigated the role of G9a, a histone methyltransferase catalyzing H3K9 methylation, in modulating anti-tumor immunity in HCC. Bioinformatic analysis of human HCC datasets revealed a significant inverse correlation between G9a expression and T cell infiltration. Genetic ablation of G9a in hepatoma cells markedly enhanced CD8⁺ T cell recruitment and activation in immunocompetent mouse models. Through RNA sequencing and functional validation, we identified CXCL10 as the key chemokine directly repressed by G9a. Mechanistically, G9a mediates H3K9 dimethylation at the CXCL10 promoter, and G9a deletion or inhibition significantly reduced this repressive mark, resulting in increased CXCL10 expression and secretion. Importantly, neutralization of CXCL10 abolished G9a inhibition-induced enhancement of CD8⁺ T cell migration. In preclinical models, pharmacological inhibition of G9a with UNC0642 not only suppressed tumor growth by promoting T cell infiltration but also synergized with anti-PD1 therapy to achieve superior therapeutic efficacy. These findings establish G9a as an epigenetic regulator of anti-tumor immunity in HCC and provide evidence for combining G9a inhibitors with immune checkpoint blockade to improve outcomes for HCC patients who are receiving immunotherapy.

High-grade serous ovarian carcinoma (HGSC) is the most lethal form of ovarian carcinoma, often diagnosed at advanced stages due to non-specific symptoms and the lack of reliable screening methods. This proof-of-concept study aimed to develop a robust TP53 mutation panel for detecting HGSC through targeted DNA sequencing in both liquid and solid biopsies. We constructed a custom TP53 gene panel and utilized a PCR-based unique molecular identifier approach for next-generation sequencing to analyze 94 samples from 11 patients diagnosed with HGSC, including primary tumor, plasma, ascites, ovarian cyst fluid, vaginal, endocervical and endometrial samples. Detected TP53 mutations were analyzed, categorized, and their frequencies calculated. Pathogenic TP53 mutations were identified in all patients, with 91% of the patients exhibiting one unique paired mutation across three or more sample types. The panel demonstrated high sensitivity and technical reproducibility, successfully detecting TP53 mutations across all sample types, with as little as 2.6 ng of DNA. TP53 mutations were consistently found in ascites, ovarian cyst fluid, and plasma samples, confirming the presence of pathogenic mutations in each sample type across all patients. This study underscores the potential of liquid biopsies in clinical molecular diagnostics. The TP53 mutation panel presented in this proof-of-concept study offers a promising approach for differential diagnostics and detection of HGSC, informative data prior to extended investigation and first-line treatment guidance.

To assess the effectiveness and safety of 5-aminolevulinic acid-based photodynamic therapy (5-ALA PDT) for cervical low-grade squamous intraepithelial lesions (LSIL) patients with high-risk human papillomavirus (HR-HPV) infection and to investigate independent factors that influence the efficacy of PDT treatment. A retrospective analysis was conducted on 530 patients with pathologically confirmed LSIL and HR-HPV infection, treated between March 2017 and January 2024. All patients underwent 5-ALA PDT at an interval of 7-14 days, for a total of 3 to 6 sessions. Follow-ups were conducted 3 and 12 months post-treatment. The efficacy was assessed using HPV genotyping, ThinPrep cytology test (TCT) and colposcopy-directed biopsy. The HPV remission rate was 52.08% at 3 months' follow-up and increased to 69.84% at 12-month follow-up, surpassing the rate at 3-month follow-up (p < 0.001). The LSIL regression rate was 75.85% at 3 months' follow-up and rose to 86.77% at 12-month follow-up, exceeding the rate at 3-months' follow-up (p < 0.001). Multivariate analysis revealed that single HPV infection (OR 2.296 [95%CI 1.550-3.402]) was an independent predictor of HPV remission after 5-ALA PDT treatment. Single HPV infection (OR 1.690 [95% CI 1.077-2.652]), type III transformation zone (OR 3.094 [95% CI 1.899-5.041]), HPV remission after PDT treatment (OR 4.938 [95% CI 3.099-7.870]) were independent predictors of LSIL participants receiving total lesion regression after PDT treatment. Adverse reactions were all mild. 5-ALA PDT is an effective and non-invasive therapy for LSIL patients with HR-HPV infection. Identifying predictors of treatment success may optimize patient selection, ultimately improving clinical outcomes.

Acute lymphoblastic leukemia (ALL) driven by KMT2A rearrangements (KMT2A-r) is an aggressive hematologic malignancy with poor prognosis and a high incidence in infants. While KMT2A fusion proteins drive leukemogenesis through transcriptional dysregulation, recent discoveries have highlighted the pivotal role of non-coding RNAs (ncRNAs) in shaping the molecular and epigenetic landscape of this disease. These key regulators of gene expression influence chromatin dynamics, transcriptional activation, and post-transcriptional control. Circular RNAs (circRNAs) contribute to genome instability and facilitate chromosomal translocations, while some fusion-derived circRNAs (f-circRNAs) sustain oncogenic signaling and promote chemoresistance. Long non-coding RNAs (lncRNAs) orchestrate transcriptional programs that maintain leukemic stem cell properties and reinforce aberrant self-renewal pathways. MicroRNAs (miRNAs) modulate critical oncogenic networks by regulating KMT2A fusion transcripts and downstream effectors, thereby impacting drug resistance, apoptosis, and proliferation. Meanwhile, enhancer RNAs (eRNAs) fine-tune transcriptional activity and epigenetic regulation, influencing KMT2A target gene expression and chromatin accessibility. Collectively, these ncRNAs integrate into the complex regulatory circuits of KMT2A-r ALL, revealing their potential as biomarkers for disease classification, risk stratification, and treatment response prediction. Understanding their interplay with KMT2A fusion proteins not only provides new insights into leukemogenesis but also highlights promising opportunities for therapeutic intervention and precision medicine in this high-risk leukemia subtype.

Brain metastases (BrMs) may present with intralesional or intracranial hemorrhage (ICH), yet risk factors and outcomes remain unclear. This monocentric cohort study at Germany's largest neurosurgical clinic included 973 adults undergoing BrM resection (2010-2024), with histopathologically confirmed etiologies and known tumor burden. Based on pre-operative CT or MRI, 880 patients were categorized as non-hemorrhagic (non-hBrM), presenting with intralesional hemorrhage (hBrM), or with ICH of ≥30 mm diameter (ICH-BrM). Risk factors for hBrM and ICH-BrM were assessed, and overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meyer methods. Of 880 patients, 560 (63.6%) were non-hBrM, 243 (27.6%) hBrM, and 77 (8.8%) ICH-BrM. ICH-BrM had larger tumor volume (21 cm³, IQR 13-34) than hBrM (14 cm³, IQR 6-28) and non-hBrM (12 cm³, IQR 6-21) (p_adjust = .017), correlated with lower post-op Karnofsky index (p_adjust = .047), dsGPA score (p_adjust = .032), and more BrMs (p_adjust = .004). Pre-operative antithrombotic use did not differ between groups (p_adjust = .32). Melanoma was more common in hBrM (27.8%) and ICH-BrM (38.0%), predicting ICH (OR 2.95, p < .001) along with NSCLC (OR 1.64, p < .001). ICH did not independently predict worse OS (HR 1.23, p = .38). Worse OS was linked to larger tumor volume (HR 1.35, p = .002), extracranial metastases (HR 1.77, p < .001), and older age (HR 1.53, p < .001), while KPS >80% (HR 0.77, p < .01), solitary BrM (HR 0.62, p = .002), and adjuvant treatments (p < .001) predicted improved OS. ICH is associated with larger tumors and melanoma but is not an independent OS predictor. Tumor burden, extracranial metastases, and adjuvant treatments drive BrM survival.

Breast cancer (BC) is the most common malignancy in women worldwide and has a significant impact on younger populations. This study analyses incidence and survival by grade of histological differentiation, molecular subtype, stage at diagnosis and socioeconomic deprivation in young women diagnosed with BC in 2018 in the Community of Madrid (CM) followed up to 2023. Data from invasive BC cases in women aged 20-49 were obtained from the Population-Based Cancer Registry of the CM. Descriptive analyses were conducted for sociodemographic and tumour characteristics. Crude, age-specific and age-standardised incidence rates were calculated. For survival analysis, observed, net and age-standardised net survival using the international cancer survival standard weights were estimated at 1, 3, and 5 years. Flexible parametric models were adjusted to determine differences in the risk of death by molecular subtype. In 2018, 1049 invasive BC cases were registered among 1,432,392 women aged 20-49. The age-standardised BC incidence rate computed was 66 cases/100,000 women-year. Luminal B was the most frequent subtype with 22.9 cases/100,000 (95% CI: 20.6-25.4). Stages I and II had the highest age-standardised incidence rates. Women in less deprived areas showed the highest crude incidence rate: 100.3 cases/100,000 women-year. The 5-year observed survival was 94.8% (95%CI: 93.2-95.9). Poorly differentiated tumours (grade III), triple negative subtype and stage IV at diagnosis had the lowest survival estimates. No significant differences in survival were observed across deprivation status. This study offers comprehensive epidemiological insights into BC incidence and survival in young women in Madrid, offering support for clinical decision-making and prognosis assessment.

Progression from minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IA) in lung adenocarcinoma (LUAD) is associated with a significantly worse prognosis and lacks predictive markers. The genomic molecular mechanisms of progression and genetic signatures mediating the MIA to IA transition in early-stage LUAD are still largely uncharacterized. In our study, a genomic signature driving MIA to IA was developed by 243 MIA and 532 IA stage I LUAD patients, and its ability to predict outcomes was validated in multiple cohorts. Among patients with stage I LUAD, 19 genes exhibited significant differences in frequency between MIA and IA groups, with notable enrichment in the MAPK, PI3K-Akt and ErbB pathways. A genomic signature of 11 genes associated with LUAD invasion progression, with TP53 and CDKN2A playing key functional roles, was developed and correlated with poor prognosis by internal and external cohorts (p < 0.05). The high-risk group exhibited elevated tumor mutational burden, mutation-allele tumor heterogeneity, and variant allele frequency values both in train and validation cohorts (p < 0.001). Mixed ground-glass opacity and solid nodules, predominantly larger than 1 cm, were more common in the high-risk population (p < 0.001), while the low-risk group exhibited a higher proportion of high-medium differentiated LUAD (p < 0.001). Our results reveal an 11-gene genomic signature driving invasive progression from MIA to IA associated with poor outcome in stage I LUAD patients by validating internal and external cohorts, radiological, pathological and tumor size, with potential future implications for disease monitoring, prognosis, and future therapeutic interventions.