Molecular Oncology最新文献

The relevant role of LINE-1 (L1) retrotransposition in cancer has been recurrently demonstrated in recent years. However, the repetitive nature of retrotransposons makes their identification and detection inaccessible for clinical practice. Also, its clinical relevance for cancer patients is still limited. Here, we developed RetroTest, a new efficient method to quantify L1 activation based on targeted sequencing and a sophisticated bioinformatic pipeline, allowing its application in tumor biopsies. Firstly, we performed RetroTest benchmarking to confirm its high specificity and reliability. Then, we unraveled L1 activation in head-and-neck squamous cell carcinoma (HNSCC) according to an extensive patient cohort including all tumor stages. L1 retrotransposition estimation revealed a surprisingly early activation in HNSCC progression, contrary to its classical association with advanced stages. In addition, L1 activation together with genomic mutational profiling in normal adjacent tissues supported a field cancerization process, a phenomenon where a tissue develops multiple patches of cells with genetic and/or epigenetic alterations, increasing the risk of cancer development in that area. Overall, our results underline an early L1 activation in HNSCC and field characterization, raising L1 as a promising early diagnostic biomarker and supporting the importance of estimating L1 retrotransposition in clinical practice toward a more efficient diagnosis in HNSCC.

Mismatch repair-proficient (pMMR) colorectal cancers (CRC) have long been considered nonresponsive to immune checkpoint blockade (ICB), in contrast to their mismatch repair-deficient (dMMR) counterparts. Recent evidence indicates that neoadjuvant immunotherapy can be used to treat pMMR CRC before surgery, potentially reducing postoperative relapse. Tan et al. report results from the NICHE-2 trial, which achieved a 26% response rate in early-stage pMMR colon cancer (CC) patients. Molecular studies show that despite low tumor mutational burden (TMB), responders exhibit higher chromosomal instability (CIN), TP53 mutations, and enrichment of proliferative and cell-cycle signatures, associated with higher density of Ki-67⁺ tumor and CD8⁺ T cells. In contrast, nonresponders display metabolic and stromal reprogramming, enhanced TGF-β signaling, and immune exclusion. Circulating tumor DNA (ctDNA) clearance correlated with pathological response and long-term disease-free survival postsurgery. While the biological and molecular determinants underlying the response rates observed in the NICHE-2 trial remain to be fully elucidated, the work by Tan et al. suggests that biomarker-guided neoadjuvant immunotherapy could represent a valuable strategy to achieve pathological responses in early-stage pMMR CC, despite its clinical relevance requiring further evaluation.

Chordoma, a rare primary bone malignancy, currently lacks effective targeted therapies. Despite surgical resection and adjuvant radiotherapy, prognosis remains poor. Recent preclinical studies have highlighted potential therapeutic targets, including the transcription factor T-box transcription factor T (TBXT). However, clinical outcomes associated with therapies targeting TBXT remain underexplored or have been modest, warranting further investigation. In this study, we investigated the therapeutic potential of transfer RNA (tRNA) synthetase inhibitors in chordoma treatment. Focused compound screening identified distinct chemotypes targeting human glutamyl-prolyl-tRNA synthetase (EPRS) as being effective in reducing cell viability in chordoma cell lines through a cyclic AMP-dependent transcription factor (ATF4)-mediated stress response rather than through TBXT regulation. Mechanistically significant upregulation of ATF4 and associated stress response genes was identified with consecutive pro-apoptotic DNA damage-inducible transcript 3 protein (DDIT3)-mediated cell death. The prototypic EPRS inhibitor halofuginone demonstrated significant tumour growth inhibition in an in vivo patient-derived xenograft model. These results suggest that targeting metabolic stress pathways via ATF4 activation presents a novel therapeutic approach for chordoma, warranting further clinical investigation.

Breast cancer is known for late recurrences, yet current follow-up lacks radiological or blood-based monitoring for systemic relapse. This study evaluated circulating tumor DNA (ctDNA) monitoring for early detection of systemic relapse after curative treatment. In this case-control study of 70 patients with operable breast cancer (35 with relapse and 35 without relapse), blood samples were collected every 6-12 months during a median 8.3-year follow-up. ctDNA was analyzed by targeted DNA sequencing using Oncomine™ Breast cfDNA Research Assay v2, and results were compared to genetic analysis of tumor and metastasis biopsies. ctDNA was detected at relapse in 19 of 35 (54%) patients with disease relapse and preceded clinical or radiological relapse detection in 17, with a median lead time of 10.3 months. In 13 (68%) patients, there was concordance with tumor mutations, and in seven patients, there was also concordance with metastasis. Among the relapse-free patients, seven were ctDNA-positive postsurgery, and only one of them had a match among the tumor variants. These findings suggest serial ctDNA analysis may enable earlier detection of systemic relapse in patients with operable breast cancer.

Penile carcinoma is a rare malignancy in developed countries but is more common in South America and East Africa. The small number of cases means there are limited resources to investigate disease pathogenesis. This report describes a method of generating primary cell lines from freshly isolated human penile tissue using a clonal expansion approach on mitotically inactivated fibroblasts. Matched normal and penile cancer cell lines from two patients were generated and characterised. Molecular karyotyping and targeted sequencing were performed to compare their genomic landscape. Gains in 8q13.3, 10q23.2, 10q25.1, 10q26.13,12p13.33, 20q13.33, Xq21.1 or losses in Yq11.23 were consistent in both tumour cell lines. Gains in 8q13.3 and Xq21.1 cytobands positively correlated with changes in the expression of nearby genes. The top 20 differentially expressed genes are involved in immune responses like interferon alpha/beta signalling. Additionally, there was an increase in integrin β1, transglutaminase 1, keratins 5, 10, 14 and 16, and a decrease in involucrin protein expression. The cell lines described in this study can provide an invaluable platform for new insights and testing of therapies for penile carcinoma.

Immunotherapy has revolutionized cancer treatment; yet, a subset of patients with microsatellite instability-high (MSI-H) tumors fails to respond to treatment despite their elevated tumor mutational burden and immunogenic potential. In a recent study, Xu et al. uncover a key mechanism of immune evasion in MSI-H tumors mediated by the exonuclease TREX1, which degrades cytosolic DNA and suppresses activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-type I interferon pathway. Loss of TREX1 restores cytosolic DNA sensing, promotes CD8⁺ T and NK cell infiltration, and enhances antitumor immunity. These findings highlight TREX1 as a potential therapeutic target to overcome resistance to immune checkpoint blockade.

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.

Several medical therapies modify the risk of developing certain cancers in an individual. The aim of this paper was to provide the scientific justification for the 5th edition of the European Code Against Cancer (ECAC5) recommendation on the use of hormone replacement therapy (HRT) and other drugs used at population scale, such as hormonal contraceptives and aspirin. HRT modifies the risk of developing certain cancers in an individual. Except for vaginal oestrogens, all forms of HRT are associated with an increased breast cancer risk; the risk of serous ovarian cancer and endometrial cancer may also be increased. Despite such an increase in cancer risk, HRT often remains the only option for the management of certain menopausal symptoms for the restoration of quality of life and mental health. Therefore, the ECAC5 recommends using HRT for bothersome menopausal symptoms only after a thorough discussion with a healthcare professional and limiting its use for as short a duration as possible. On review of up-to-date evidence for hormonal contraceptives and aspirin, the ECAC5 Working Group elected not to make a recommendation for the average-risk general population regarding the use of these therapies.