International Journal of Cancer最新文献

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes, most notably associated with colorectal cancer. Although LS patients face high risk of CRC, risk can vary even among those with the same pathogenic MMR germline mutations. We suggest a functional assay platform for assessing mutation risk using patient-derived organoid (PDOs). We measured organoid response to the cytotoxic effects of a methylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) based on DNA damage-induced apoptosis. When normal (non-LS) colon organoids were used, treatment with MNNG and four passages of organoid culture led to decreased total growth (organoid area), but there was no significant change in number. To increase the effect of MNNG and induce apoptosis in normal colon organoids, we added O⁶BG (an MGMT inhibitor) and an ATR inhibitor. The cytotoxic effects of combined treatment with MNNG, O⁶BG and ATR inhibitor on non-LS-PDOs were significantly higher than in PDOs of LS patients. To detect the difference at an earlier phase, we examined DNA damage response by analyzing γH2AX expression after treatment with MNNG and O6BG for 24 h. Then, we found higher expression of γH2AX in non-LS-PDOs than in PDOs of LS patients, suggesting continued cell survival with mutation accumulation in LS-PDOs. In conclusion, treatment with MNNG and O6BG using PDOs and measurement of resulting DNA damage response could be used as a preclinical platform for risk stratification in LS patients.

MET is an actionable receptor tyrosine kinase, and MET-directed antibody-drug conjugates (ADCs) have recently entered clinical practice with FDA approval in non-small cell lung cancer and are now being evaluated across gastrointestinal malignancies, with patient selection based on MET immunohistochemistry (IHC) 3+ membranous staining at varying percentage thresholds. However, robust real-world data on MET protein expression and clinically relevant ADC-aligned thresholds in upper GI adenocarcinomas remain limited. We profiled 1532 upper GI adenocarcinomas using the clinically validated VENTANA MET (SP44) IHC assay. MET was stratified by (i) 3+ membranous staining fractions (any, ≥ 10%, ≥ 50%) reflecting contemporary ADC eligibility concepts and (ii) H-score (0-300; high ≥ 150). Overall survival analyses and multivariable Cox regression analyses were performed. High MET expression was uncommon (H-score ≥ 150: 2.3%; any 3+: 1.6%; ≥ 10% 3+: 1.3%; ≥ 50% 3+: 1.0%) and enriched in advanced T stage. MET IHC strongly predicted MET amplification (H-score ≥ 150: 63.6% amplified vs. 2.4% in negatives; any 3+: 75.0% vs. 2.6%; all p < 0.001). Any MET 3+ staining was independently associated with inferior overall survival (adjusted HR 2.22, 95% CI 1.29-3.83). Most MET 3+ tumors lacked concurrent HER2 positivity, Claudin-18.2 expression, or dMMR/MSI. In the largest real-world cohort to date, MET overexpression identifies a rare, biologically aggressive subset with poor outcomes. By applying the latest MET-ADC-relevant IHC criteria (including the ≥ 10% 3+ threshold), this study provides clinically translatable prevalence estimates and supports standardized MET testing to inform prospective MET-directed ADC trials in upper GI adenocarcinoma.

Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male-to-female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry-based proteomics, comprising 47 female and 45 male tumors from treatment-naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex-associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in EAC. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y-chromosome-encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune-related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival specifically in male patients, with no significant association detected in the combined or female-only cohort. Proteome-wide survival analyses further demonstrated distinct sex-specific prognostic landscapes. Our study provides the first comprehensive characterization of sex-associated proteomic differences in EAC. Sex shapes immune-related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex-differential, complement-associated protein with adverse prognostic significance in male patients, highlighting sex as a biologically and clinically relevant variable in EAC.

The incidence of human papillomavirus-positive (HPV+) oropharyngeal cancer (OPC) has increased rapidly, and HPV early antigen serology has been proposed as a scalable and cost-effective early detection test. HPV seropositivity can precede clinical presentation of OPC by several years, so additional surveillance procedures may be necessary to optimize early cancer detection. The potential for HPV circulating tumor DNA (ctDNA) to confirm a diagnosis of OPC in seropositive individuals is poorly understood. Here, we assess the relationship between HPV serology and HPV ctDNA with disease burden in a large cohort of HPV+ OPC. We analyzed baseline blood samples from 262 patients using a multiplex serology assay and an HPV-targeted deep sequencing assay (HPV-seq), and HPV-seq results were validated by an orthogonal droplet digital PCR assay. Both assays identified HPV16 as the most prevalent genotype (84%), with serology results indicating a total of 4 HPV genotypes and HPV ctDNA results indicating a total of 6 HPV genotypes. HPV ctDNA results demonstrated higher sensitivity and lower cross-reactivity between HPV types compared with HPV serology results. Furthermore, HPV ctDNA but not HPV16 E6 antibody levels were positively associated with disease burden as determined by N-category, overall stage, and by tumor volume (ctDNA vs. volume, r = 0.48 p = 6.4e-12; E6 vs. volume, r = -0.079 p = 0.26). Overall, this is the largest cohort to compare HPV serology and HPV ctDNA results in OPC, and these findings highlight the potential for ctDNA to augment future strategies for blood-based early detection of HPV+ OPC.

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) infection predominantly affects males, yet few studies have investigated the association between sex hormones and HBV integrations, and their involvement in HCC prognosis. We assessed estrogen receptor alpha (ERα) and androgen receptor (AR) expression via immunohistochemistry on tissue microarrays constructed from 426 HBV-related HCC samples. HBV integration features were determined using HBV-captured sequencing data. Logistic regression models were utilized to evaluate the association between sex hormone receptor expression level and HBV integration features. Cox regression models, combined with machine learning (ML) methods, were implemented to investigate the prognostic value of sex hormone receptors and HBV integrations concerning overall survival. We found high AR expression level was significantly associated with higher HBV integration levels (adjusted odds ratio [aOR] = 1.84, 95% confidence interval [CI]: 1.09-3.11, P for trend = 0.012), TERT integration (aOR = 2.34, 95% CI: 1.16-4.74, P for trend = 0.047), intergenic integration (aOR = 2.25, 95% CI: 1.20-4.24, P for trend = 0.021), and promoter integration (aOR = 1.81, 95% CI: 1.00-3.31, P for trend = 0.034). The inclusion of sex hormone receptors and HBV integrations in the predictive models led to improvements across all performance metrics in the Cox regression analyses (AUC improvement: 0.014 [Training], 0.026 [Validation]) and the ML (AUC improvement: 0.022 [Training]), although a slight deterioration in performance was noted in the ML validation set. The results suggested a relationship between AR expression level and HBV integration events, as well as the potential utility of HBV integration biomarkers and sex hormone receptor profiles in assessing post-surgical prognosis among HCC patients.