Molecular Oncology最新文献

Liquid biopsies containing circulating tumor DNA (ctDNA) are important biomarkers across several forms of cancer. The detection of mutations in cell-free DNA (cfDNA) indicates the presence of ctDNA. However, unsatisfactory ctDNA mutation sensitivities, issues with sequencing errors, and clonal hematopoiesis variants have limited the clinical utility of mutation-based ctDNA assays. Recently, a new avenue of cfDNA assays has been developed, focusing on cfDNA epigenetics. Here, we outline the recent advancements in cfDNA epigenetics, focusing on cfDNA methylation, fragmentomics, and post-translational modifications (PTMs) of circulating nucleosomes. We present various methylation strategies concerning ctDNA detection and tissue of origin (TOO) analyses. cfDNA fragmentomics focuses on cfDNA fragment lengths, fragment end motifs, and nucleosome positioning to infer gene expression and estimate the ctDNA fraction. Lastly, we discuss the development of cell-free chromatin immunoprecipitation of circulating nucleosomes with PTMs. This method has been implemented to detect tumor gene expression, TOO, and treatment resistance. Combining the epigenetic features of cfDNA will expand the utility of liquid biopsies to give a more comprehensive insight into tumor biology, treatment response, and resistance.

Screening heavy smokers by low-dose computed tomography (LDCT) can reduce lung cancer (LC) mortality, but defining the population that benefits most, a prerequisite for cost-effective screening, is challenging. In order to contribute to a more nuanced risk stratification of high-risk target populations, we developed and validated a blood-based protein marker model for LC. A two-stage design was implemented in this study, and the derivation set comprised 18 868 participants from the UK Biobank, which included 200 incident LC cases identified at 6 years of follow-up. The independent validation set included 101 LC cases identified at 6 years of follow-up. A total of 2025 protein markers measured by proximity extension assays available for both datasets were used for analysis. A risk prediction algorithm by least absolute shrinkage and selection operator regression with bootstrap method was developed in the derivation set and then externally evaluated in the independent validation set. The risk discriminatory performance of the protein marker model was compared with the established PLCO_m2012 model, USPSTF 2020 guidelines and trial criteria used in different LDCT trials. The protein marker model comprising of four protein biomarkers-CEACAM5, CXCL17, MMP12, and WFDC2-outperformed the PLCO_m2012 model, and the areas under the receiver operating curve (AUCs) for the protein marker model in the derivation and validation sets were 0.814 [95% confidence interval (95% CI), 0.785-0.843] and 0.814 (95% CI, 0.756-0.873), respectively. The addition of the protein marker model to the PLCO_m2012 model increased the AUCs up to 0.056 and 0.057 and yielded up to 16 and 12 percentage points higher sensitivities to identify future LC cases compared to the LDCT trial criteria, in the derivation and validation sets, respectively. The protein marker model improves the selection of high LC risk individuals for LDCT screening and thereby enhances screening efficacy.

Among the extensive genomic alterations in prostate cancer, phosphatase and tensin homolog (PTEN) deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated with cancer-cell proliferation and survival through the activation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) (PI3K-AKT-mTOR) signaling pathway. However, the use of PTEN as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional and post-translational regulation. In situ protein assessment by immunohistochemistry (IHC) captures PTEN protein status, but it does not report on associated tumor microenvironment remodeling. Here, we undertook an approach that combined PTEN immunoreactivity analysis with high-throughput transcriptional analysis to gain insights into the downstream functional effects of PTEN protein loss in primary tumors. Our extensive bioinformatic analyses highlighted stromal remodeling as a prominent cancer cell-extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to Pten loss-driven murine prostate cancer, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced transforming growth factor beta (TGF-β) signaling and that is compatible with the secretome of PTEN-deficient senescent cancer cells. Finally, our findings enable the sub-stratification of tumors with PTEN loss based on their senescence-associated stroma remodeling program to distinguish indolent from aggressive cases. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss in prostate cancer.

Liquid biopsy has transformed molecular oncology by enabling noninvasive, real-time monitoring of cancer progression, treatment responses, and detection of minimal residual disease. Despite technological advances, educational gaps, regarding standardized, comprehensive training for molecular pathologists, remain. To address these, a new educational program, the European Masters in Molecular Pathology (EMMP) developed a dedicated educational module aimed at providing pathologists with specialized competencies in liquid biopsy. In this perspective, we discuss how embedding liquid biopsy training within the integrative pathology framework, linking molecular diagnostics, histopathological findings, and clinical context, enhances diagnostic accuracy and therapeutic decision-making in the clinic. Furthermore, we emphasize the importance of decentralizing liquid biopsy expertise to local pathology units, reducing dependency on external commercial platforms, ensuring data sovereignty, and enabling rapid, cost-effective diagnostics. Finally, integrating health policy and ethical considerations within liquid biopsy education prepares future molecular pathologists to engage meaningfully in shaping policy frameworks that support equitable and sustainable clinical implementation of precision oncology. In summary, we propose the EMMP module as a comprehensive educational strategy for training molecular pathologists in the latest liquid biopsy technologies and advancements.

Pleural mesothelioma (PM) is a rare and aggressive cancer that often requires multiple diagnostic procedures before a definitive diagnosis can be made. To improve diagnostic accuracy, we developed a DNA methylation-based biomarker assay capable of distinguishing PM from healthy pleura and other pleural pathologies. Using Infinium EPIC array data, we identified 744 hypermethylated CpG sites in PM as candidate biomarkers. These were validated in silico using external datasets, yielding a high mean AUC of 0.935. Clinical validation was performed using IMPRESS, a novel bisulfite-free methylation detection technique that enables simultaneous analysis of thousands of CpG sites. A two-step classifier approach was applied: the first model differentiated tumoral from nontumoral pleura with 89.2% sensitivity and 93.5% specificity, while the second model distinguished PM from pleural metastases with 85.2% sensitivity and 100% specificity. These results demonstrate that our methylation-based biomarker panel offers a highly accurate and minimally invasive tool for differentiating PM from other pleural conditions, potentially streamlining the diagnostic process and improving clinical decision-making.

Despite the use of conventional biomarkers and imaging methods for treatment monitoring of colorectal cancer (CRC) patients, limitations remain in detecting minimal residual disease and early relapse. Circulating tumor DNA (ctDNA) offers a promising noninvasive and cost-effective alternative for monitoring disease progression and relapse, potentially improving patient outcomes. In this study, we developed a methylation-specific droplet digital PCR (MS-ddPCR) multiplex assay designed to detect ctDNA through a combination of tumor-specific and tissue-conserved methylation markers. Our objective was to evaluate the performance of this assay in patients with CRC and assess ctDNA dynamics as a prognostic tool in those with metastatic CRC (mCRC). The assay demonstrated high specificity (96.7%) and sensitivity in detecting ctDNA in both patients with localized tumors (64.4%) and mCRC (89.2%). Notably, ctDNA dynamics from baseline to after the first treatment cycle were significantly associated with progression-free survival (PFS) and overall survival (OS) in mCRC. Classifying patients based on ctDNA-RECIST (Response Evaluation Criteria in Solid Tumors) and the percent reduction in ctDNA fraction revealed pronounced differences in PFS and OS. Median PFS and OS were 11.4 and 35.3 months for good responders compared with 7.6 (HR = 1.71, 95% CI 0.9-3.25) and 18.4 (HR = 2.15, 95% CI 1.16-3.99) for poor responders, while patients with progressive disease had a median PFS and OS of 5.1 (HR = 4.36, 95% CI 1.91-9.92) and 6.85 (HR = 4.73, 95% CI 2.09-10.7) months. Our multiplex MS-ddPCR assay provides a sensitive, cost-effective approach for detecting and quantifying ctDNA in CRC patients, especially in metastatic disease. The ability to monitor ctDNA dynamics holds potential for early treatment response assessment, prognosis, and guiding personalized therapeutic strategies, making it a valuable tool for clinical practice.

Breast cancer's global prevalence underscores a critical need for novel biomarkers to guide treatment and improve patient outcomes. Biomarker discovery historically focused on mutations in protein coding regions, comprising merely 1% of the genome. However, with advances in whole-genome sequencing, the functional significance of the noncoding genome-comprising the remaining 99%-has become increasingly evident. Noncoding regions play a vital role in regulating gene expression, and mutations within these regions have been associated with cancer risk, progression, and treatment response. This Review compiles and synthesizes current knowledge on cis-regulatory alterations (promoters/enhancers) and long noncoding RNAs (lncRNAs) in breast cancer. Key examples include promoter mutations [e.g., rs2279744 (Mouse double minute 2 homolog gene; MDM2)], enhancer mutations [e.g., rs4784227 (thymocyte selection-associated high mobility group box family member 3 gene; TOX3)], and lncRNAs [e.g., HOX transcript antisense intergenic RNA (HOTAIR)] linked to progression, metastasis, and poor survival. Integrating preclinical (in vitro, in vivo) and clinical findings, we emphasize the biomarker and therapeutic potential of these noncoding alterations. This Review also critically identifies the pressing need for more specific functional validation studies to fully elucidate their mechanistic roles. This emerging field offers promising opportunities to advance personalized medicine and refine prognostic/predictive strategies for breast cancer patients.

Advanced urothelial carcinoma (UC) requires new therapeutics beyond chemo- and immunotherapies. Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin-treated UC, yielded limited response. Biomarker-based patient selection (apart from BRCAness) or combination treatment may increase efficacy. To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. RNA sequencing of PARPi-treated UC lines revealed few common targets and a different impact on immune response. By analysis of experimental and public clinical data, we identified new UC-specific PARPi response predictors SLFN5, SLFN11, and OAS1. We investigated a new combination treatment using PLX51107, an epigenetic BET protein inhibitor, to increase PARPi efficacy. The Talazoparib + PLX51107 combination had a strong synergistic impact on UC cells and organoids, including Cisplatin-resistant cells, allowing dose reduction to spare benign cells. Mechanisms of synergism targeted homologous recombination repair, DNA replication, and apoptosis regulation. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.

Low-dose computed tomography (LDCT) screening is increasingly used for early lung cancer detection targeted to high-risk populations. Quantifying overdiagnosis, its potential harms, and economic consequences is important. We assessed the magnitude, harms, and economic impact of lung cancer overdiagnosis from LDCT screening in high-risk populations. We synthesized evidence from eight randomized trials involving 84,660 participants. LDCT may increase overdiagnosis compared to no screening (relative risk [RR] 1.05; 222 additional cases per 100 000 people screened; low certainty). Compared to chest x-ray (CXR), LDCT likely slightly increases overdiagnosis (RR 1.01; 63 additional cases per 100 000 people screened; moderate certainty). The proportion of overdiagnosed cancers is 0.07 (7000 more lung cancers overdiagnosed per 100 000 lung cancers detected; low certainty) when compared to no screening, and 0.01 compared to CXR (1000 more lung cancers overdiagnosed per 100 000 lung cancers detected; moderate certainty). In terms of cost, LDCT resulted in an additional societal burden of €2,026,422.00 per 100 000 individuals screened compared to no screening. The magnitude of overdiagnosis in LDCT screening is likely low compared to CXR.

Cancer is a highly heterogeneous disease, with many cancers containing multiple distinct subclones. While subclones are often seen as competitors (survival of the fittest), intratumor heterogeneity can also offer direct benefits to the tumor through cooperation between different clones. This has important clinical implications, as interdependent populations may present therapeutic vulnerabilities. Here, we review existing evidence for clonal cooperativity to address key questions and outline future developments based on six overarching principles: (a) secreted factors are important mediators of clonal cooperation; (b) (very) small subclones can significantly affect tumor behavior; (c) both genetic and nongenetic heterogeneity are substrates for cooperation; (d) nonmalignant cells from the tumor microenvironment can act as cooperating partners; (e) clonal cooperation occurs throughout different stages of cancer, from premalignancy to metastasis; and (f) clonal cooperation can promote therapy resistance by protecting otherwise sensitive populations. Together, these principles suggest clonal cooperation as an important mechanism in cancer. Lastly, we discuss how novel technological developments could address remaining gaps to open up new therapeutic strategies that exploit clonal cooperativity by targeting the tumor's weakest link.