International Journal of Cancer最新文献

Despite significant progress in diagnostic and therapeutic modalities, lung adenocarcinoma (LUAD) still exhibits a high recurrence risk and a low 5-year survival rate. Reliable prognostic signatures are imperative for risk stratification in LUAD patients. This study encompassed 2740 patients from 23 LUAD cohorts, including one single-cell RNA sequencing (scRNA-seq) dataset, five bulk RNA-seq datasets, and 17 microarray datasets. Using scRNA-seq dataset, we defined a group of epithelial-specific transcription factors significantly over-represented in the epithelial-to-mesenchymal transition (EMT) gene set (enrichment ratio [ER] = 5.80, Fisher's exact test p < .001), and the corresponding target genes were significantly enriched in the cancer driver gene set (ER = 2.74, p < .001), indicating of their crucial roles in the EMT process and tumor progression. We constructed a single-cell gene pairs (scGPS) signature, composed of 3521 gene pairs derived from the epithelial cell-specific transcription factor regulatory network, to predict overall survival (OS) of LUAD. High-risk patients identified by scGPS in the discovery cohort exhibited significantly worse OS compared to low-risk patients (Hazard ratio [HR] = 1.78, 95% CI: 1.29-2.46, log-rank p = 1.80 × 10^-4). The scGPS outperformed other established gene signatures and demonstrated robust prognostic stratification across various independent datasets, including microarray data and even early-stage LUAD patients. It remained an independent prognostic factor after adjusting for clinical and pathologic factors. In addition, combining scGPS with tumor stage further enhanced prognostic accuracy compared to using stage alone. The scGPS signature offers individualized prognosis estimations, showing significant potential for practical application in clinical settings.

This study aims to assess the influence of colorectal cancer screening on the incidence of synchronous colorectal peritoneal metastases (CPM). Patients diagnosed with CPM between 2009 and 2022 were selected from the Netherlands Cancer Registry. Crude rates of the observed and expected CPM incidence were calculated per 100,000 individuals and compared. Expected incidence was extrapolated from the incidence in the years prior to screening invitation. In total, 9,238 patients with CPM were included. For the screen-eligible population (55-75 years), the observed CPM incidence increased from 5.1 (2009) to 7.0 before screening initiation (2013) (Annual percent change [APC] 8.2%, p = .014). Since the start of screening, the observed CPM incidence stabilized: 8.8 (2014) to 8.9 (2022) (APC -1.0%, p = .159). Within the total population, the observed CPM incidence before screening showed an increase from 3.6 (2009) to 4.0 (2013) (APC 3.4%, p = .050). Since screening, a decrease in CPM incidence was observed from 4.4 (2014) to 3.5 (2022) (APC -2.2%, p = .010). The observed and expected number of CPM differed significantly in the screen-eligible population (6,437 observed vs. 7,992 expected individuals; p < .001) and in the overall Dutch population (9,238 observed vs. 10,440 expected individuals; p < .001). In conclusion, a declining trend was observed in the incidence of CPM in the Dutch population since the start of colorectal cancer screening. The observed incidence was lower compared to the expected incidence, both in the screen-eligible population and in the overall population. These findings suggest that screening results in a decrease of patients diagnosed with CPM possibly resulting in an improved survival of colorectal cancer patients.

High-risk human papillomavirus (hrHPV) genotype is needed for adequate cervical cancer screening and HPV vaccination program evaluation as recommended by different guidelines. We aimed to assess the rate of HPV infection and HPV genotype distribution using vaginal self-sampling in a cohort of unscreened reproductive-age women in Ethiopia. A community-based cohort study was conducted with women aged 23-46 living in Adama, Ethiopia. A total of 885 self-collected vaginal swabs were obtained and tested for hrHPV genotypes with the real-time polymerase chain reaction technique. The overall hrHPV prevalence was 21.1% (187/885, 95% confidence interval [CI]: 18.5-24.0). Among women living with human immunodeficiency virus, 46% (30/56) (95% CI: 33.7-59) were hrHPV positive compared with 19% (157/820) (95% CI: 16.2-22) of human immunodeficiency virus-negative women. The most frequent genotypes were HPV16 (3.1%), HPV51 (3.1%), HPV35 (2.6%), HPV56 (2.6%), HPV52 (2.4%), HPV31 (2.5%), and HPV39 (2.5%). Among the 187 HPV-positive women in self-samples, HPV 16/18 was found in 21% (39), HPV 16/18/45 was found in 24% (44), and HPV 16/18/31/33/45/52/58 was prevalent in 56% (104). Out of 116 biopsies, 7% (8) had cervical intraepithelial lesions and worse identified. Of these eight cervical intraepithelial lesions and worse patients, only 25% tested positive for HPV-16; none tested positive for HPV-18 or 45. One out of five women tested positive for hrHPV genotypes. Other HPV genotypes not covered by the quadrivalent HPV vaccine but associated with clinically significant cervical high-grade lesions or cancer were detected in 75%. It is more effective to prevent cervical cancer by switching to the nine-valent HPV vaccine.

New molecular approaches are being developed to detect endometrial cancer using minimally invasive sampling methods. This study aims to evaluate the acceptability of self-collected cervicovaginal samples among women with Lynch syndrome, a group at high risk for developing endometrial cancer. Participants collected cervicovaginal self-samples and answered an at-home acceptability questionnaire in a cross-sectional study. Self-samples from a subset of these women were analyzed for somatic mutations using next-generation sequencing (NGS), targeting a panel of 47 genes. A total of 61 (88.4%) out of 69 eligible women participated in the study. The overall self-sampling experience was rated good or very good (N = 55, 90.2%). Most of the women were confident about correctly sampling (N = 58, 95.1%), and most reported no or mild pain (N = 56, 91.8%). During self-sample collection, most women reported feeling calm and comfortable and experiencing safety, privacy, and normality. In a pilot study using a subset of 15 samples, five somatic variants were identified in four self-samples (4/15, 26.7%) in ACVR2A, ARID1A, APC, and KMT2D. During follow-up, three out of four women with variants detected in the self-sample underwent prophylactic hysterectomy at a median of 9.1 months, while one out of four developed endometrial cancer after 3.9 years since the collection of the sample. Self-sampling is well-accepted and well-tolerated in women with Lynch syndrome and could potentially reduce some barriers associated with gynaecological surveillance. Further research is needed to evaluate the feasibility of implementing cervicovaginal self-collection and the accuracy of molecular testing for gynaecological surveillance in women with Lynch syndrome.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous. Young children are commonly exposed to these chemicals via ingestion of settled dust. Several PFAS have been associated with cancers in adults, yet little is known about the risk in children. We investigated whether PFAS concentrations in residential dust were associated with childhood acute lymphoblastic leukemia (ALL). Vacuum bags were collected in homes of 178 children diagnosed with ALL and 204 healthy controls (age 0-7 years) residing in California (2001-2007). Dust samples were sieved and analyzed for 19 PFAS using targeted liquid chromatography mass spectrometry analysis. The effects of individual PFAS and PFAS mixtures were estimated for eight PFAS with at least 50% above the limit of quantification (LOQ) using logistic regression, G-computation, and generalized additive modeling (GAM). In the model mutually adjusting for eight PFAS, a statistically significant association was seen only for N-ethyl perfluorooctane sulfonamido acetic acid (EtFOSAA) (OR_continuous = 1.40, 95% CI = 1.05-1.86 and ${\text{OR}}_{4\mathrm{th}\mathrm{vs}.1\mathrm{st}\text{quartile}}=2.58$ , 95% CI = 1.16-5.71). Using G-computation, the eight PFAS mixture was positively associated with childhood ALL (OR = 1.60, 95% CI = 1.15-2.24), with positive weights for EtFOSAA, perfluoro-n-hexanoic acid (PFHxA), perfluoro-1-decanesulfonate (PFDS), and perfluoro-1-octanesulfonate (PFOS), and negative weights for perfluoro-1-hexanesulfonate (PFHxS) and bis(1H,1H,2H,2H-perfluorooctyl)phosphate (6:2 diPAP). Using GAM, the OR for the mixture reached a maximum of 2.24, at the highest value of log10 EtFOSAA and lowest value of log10 PFHxS. Exposure to a mixture of PFAS in settled dust was associated with an overall elevated risk of childhood ALL, with EtFOSAA and PFHxS being the main contributors to the positive and negative weights, respectively.

Seventeen years after the licensure of prophylactic human papillomavirus (HPV) L1 virus-like-particle vaccines, a defined antibody level that correlates with vaccine-induced protection against HPV infections and associated neoplasia is missing. In contrast, correlates of protection have been defined for many viral vaccines, including for the hepatitis B virus (HBV) vaccine. This review includes lessons learned from vaccination against HBV and the use of an established protective HBV surface antigen antibody level: 10 mIU/mL, an overview of HPV infection-induced and HPV vaccine-induced antibody responses, successful efforts to establish international standardization of serological reagents and associated tools, and 15-year vigilance of HPV vaccine-induced antibody levels in a vaccination cohort against breakthrough infections. This report identifies progress but also gaps on the journey toward the definition of a HPV vaccine-induced correlate of protection.

Human papillomavirus (HPV)-associated high-grade vulvar intraepithelial lesion (HSIL) is a precursor of vulvar squamous cell carcinoma (VSCC). Because of the 8% cancer risk, many vulvar HSIL patients undergo aggressive and mutilating treatments. Characterizing HSIL by their progression risk can help individualize treatment strategies. Accordingly, copy number alterations (CNAs) and DNA methylation have been identified as biomarkers for cancer risk stratification of HSIL. Here, we assessed their potential correlation, and relation to HPV16 (sub)lineages and progression to vulvar cancer. Eighty-two vulvar formalin-fixed paraffin-embedded (FFPE) samples, including controls, HSIL, HSIL adjacent to VSCC and VSCC, with previously determined DNA methylation profiles, were analysed for CNAs using mFAST-SeqS. Genome-wide z-scores were calculated to determine overall aneuploidy (aneuploidy scores), and compared to the methylation levels and status of marker panel ZNF582/SST/miR124-2. For 52 HPV16-positive cases, HPV (sub)lineages were determined by Sanger sequencing. HPV16 lineage A was predominant (86.4%), followed equally by lineages B, C, and D. Frequent chromosomal alterations included chr1pq, chr3q, chr9q gains, and chr2q, chr4q losses. Median aneuploidy scores increased across disease categories, from 0 in controls, to 3 in HSIL, 16 in HSIL adjacent to VSCC and 29 in VSCC. A positive relationship between aneuploidy scores and DNA methylation levels was found (ρ = 0.61, Spearman's rank correlation test). Aneuploidy scores were significantly higher in methylation-positive samples (p < .001). In conclusion, we showed that DNA methylation and CNAs both rise with increasing severity of disease, indicating their prognostic value for cancer risk stratification of HSIL, while no relation to HPV16 (sub)lineages was found.

Carbonic anhydrase-9 (CA9) is highly expressed in clear cell renal cell carcinoma (ccRCC) cells despite no expression in normal kidney tissues. Thus, CA9 has been proposed as a theranostic target for radioligand therapy (RLT). However, ccRCC tends to be radioresistant and may not effectively respond to RLT. Alternatively, CA9 can be targeted for near-infrared photoimmunotherapy (NIR-PIT) of ccRCC. Here, we sought to test NIR-PIT using CA9 in a preclinical model of ccRCC to determine its potential as a therapeutic strategy. Tissue microarray analysis showed that membrane CA9 was expressed in the majority of ccRCC cases. In vitro, CA9-targeted NIR-PIT induced cell membrane damage and cell killing in all CA9-expressing ccRCC cell lines specifically, UOK154, UOK220, and UOK122. In vivo, CA9-targeted NIR-PIT significantly inhibited tumor growth and prolonged survival in UOK154 and UOK220 subcutaneous xenograft models. Notably, 70%-80% of mice achieved complete remission after a single treatment of NIR-PIT. Additionally, remaining tumors after the first NIR-PIT persistently expressed CA9, suggesting that remaining tumors can be treated with repeated NIR-PIT. Furthermore, CA9-targeted NIR-PIT induced significant cytoplasmic damages on ccRCC cells in UOK154 orthotopic xenograft models. In conclusion, CA9-targeted NIR-PIT, which allow for safe and repeated application on the same lesion, is a promising treatment for ccRCC, especially in the management of multiple primary ccRCC (e.g., von Hippel-Lindau syndrome) and oligometastatic ccRCC.