Molecular Oncology最新文献

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.

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.

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.

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.

Rearranged during transfection (RET) fusions drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs), resistance usually occurs and is often driven by RET-independent bypass mechanisms. Previous studies have implied crosstalk between RET and proto-oncogene tyrosine-protein kinase SRC, but the anticancer effects of targeting SRC combined with selective RET TKIs, and the underlying molecular mechanisms involved, are not fully understood. Our results show that the multitargeted SRC TKI dasatinib significantly enhanced the efficacy of RET TKIs in RET fusion-positive (RET⁺) NSCLC and PTC cells. Genetic rescue experiments validated that the combination effects between RET TKIs and dasatinib were indeed SRC-dependent. Phosphoproteomics analysis and validation using selective inhibitors and small interfering RNAs (siRNAs) determined that synergy was primarily mediated by suppression of downstream serine/threonine-protein kinase PAK signaling, with contributions from AKT and ribosomal protein S6. Importantly, synergy was also observed with eCF506 (NXP900), a next-generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib-resistant RET⁺ PTC cells. These results elucidate RET and SRC signaling crosstalk in RET⁺ NSCLC and PTC, suggesting that co-inhibiting SRC has clinical potential in TKI-naïve and -resistant RET⁺ cancers.

Metastatic colorectal cancer (mCRC), particularly microsatellite stable (MSS) cases, often exhibits limited responsiveness to immunotherapy, leaving chemotherapy as the primary treatment option. While chemotherapy effectively targets tumor cells, its impact on the broader mutational landscape, including passenger mutations in large genes such as Titin (TTN), remains poorly understood. Passenger mutations, traditionally deemed biologically inert, may reflect tumor mutational burden (TMB) and influence treatment outcomes. In our study involving whole exome sequencing of paired primary and metastatic tumor samples from 22 mCRC patients, recurrent driver mutations in APC, KRAS, and TP53 were consistently observed. However, passenger mutations in large genes, particularly TTN, were notably enriched in chemonaïve specimens and associated with higher TMB. Chemotherapy-treated samples exhibited a significant reduction in these mutations, suggesting selective depletion of hypermutated subclones. Our findings demonstrate that chemotherapy may selectively reduce passenger mutations in mCRC, potentially influencing the persistence of hypermutated subclones. This highlights the potential role of passenger mutation patterns and TMB as biomarkers for treatment response and raises the hypothesis that they could help guide immunotherapy considerations for patients with MSS mCRC.