Molecular Cancer最新文献

{"title":"Metabolic targeting of regulatory T cells in oral squamous cell carcinoma: new horizons in immunotherapy","authors":"Menglai Gan, Nanshu Liu, Wenting Li, Mingwei Chen, Zhongyu Bai, Dongjuan Liu, Sai Liu","doi":"10.1186/s12943-024-02193-7","DOIUrl":"https://doi.org/10.1186/s12943-024-02193-7","url":null,"abstract":"Oral squamous cell carcinoma (OSCC) is a prevalent oral malignancy, which poses significant health risks with a high mortality rate. Regulatory T cells (Tregs), characterized by their immunosuppressive capabilities, are intricately linked to OSCC progression and patient outcomes. The metabolic reprogramming of Tregs within the OSCC tumor microenvironment (TME) underpins their function, with key pathways such as the tryptophan-kynurenine-aryl hydrocarbon receptor, PI3K-Akt-mTOR and nucleotide metabolism significantly contributing to their suppressive activities. Targeting these metabolic pathways offers a novel therapeutic approach to reduce Treg-mediated immunosuppression and enhance anti-tumor responses. This review explores the metabolic dependencies and pathways that sustain Treg function in OSCC, highlighting key metabolic adaptations such as glycolysis, fatty acid oxidation, amino acid metabolism and PI3K-Akt-mTOR signaling pathway that enable Tregs to thrive in the challenging conditions of the TME. Additionally, the review discusses the influence of the oral microbiome on Treg metabolism and evaluates potential therapeutic strategies targeting these metabolic pathways. Despite the promising potential of these interventions, challenges such as selectivity, toxicity, tumor heterogeneity, and resistance mechanisms remain. The review concludes with perspectives on personalized medicine and integrative approaches, emphasizing the need for continued research to translate these findings into effective clinical applications for OSCC treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"38 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer","authors":"Yan Hu, Ze-Rong Cai, Ren-Ze Huang, De-Shen Wang, Huai-Qiang Ju, Dong-Liang Chen","doi":"10.1186/s12943-024-02192-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02192-8","url":null,"abstract":"Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune evasion. circRNA microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with circPHLPP2. circPHLPP2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36γ. This process reduces NK cell infiltration and impairs NK cells’ granzyme B and IFN-γ production, thereby promoting tumor progression. Overall, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"90 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence, risk factors, and epidemiological trends of tracheal cancer: a global analysis","authors":"Junjie Huang, Mingtao Chen, Lin Zhang, Xu Lin, Don Eliseo Lucero-Prisno, Claire Chenwen Zhong, Wanghong Xu, Zhi-Jie Zheng, Mellissa Withers, Martin C. S. Wong","doi":"10.1186/s12943-024-02188-4","DOIUrl":"https://doi.org/10.1186/s12943-024-02188-4","url":null,"abstract":"Tracheal cancer is a rare malignancy with limited research but high mortality rates. This study aims to analyse recent data to understand the global burden, trends, and risk factors for tracheal cancer, facilitating improved prevention and treatment strategies. We conducted a study on tracheal cancer using data from the Global Cancer Observatory and the Cancer Incidence in Five Continents databases. We collected information on the incidence of tracheal cancer, risk factors, and the Human Development Index (HDI) at the country level. The univariate linear regression was used to explore the relationship between tracheal cancer and the various risk factors. We utilised joinpoint regression analysis to calculate the Average Annual Percentage Change (AAPC) in tracheal cancer incidence. The global age-standardised rate of incidence of tracheal cancer was 2.9 per 10 million (3,472 cases in total) in 2022, with the highest regional incidence observed in Central and Eastern Europe (ASR = 9.0) and the highest national incidence in Hungary (12.5). Higher incidence was found among the males (3.8) than females (2.0); among the older adults aged 50-74 (11.9) than the younger population aged 15-49 (1.2). A higher tracheal cancer incidence ratio was associated with higher levels of smoking, alcohol drinking, diabetes, lipid disorders, and HDI. Despite the overall decreasing trends for all population groups (highest decrease in Thailand; AAPC: -15.06, 95% CI: -21.76 to -7.78, p = 0.002), there was an increase in some female populations (highest increase in Colombia, AAPC: 19.28, 95% CI: 16.48 to 22.15, p < 0.001) and younger populations (highest increase in Ireland; AAPC: 29.84, 95% CI: 25.74 to 34.06, p < 0.001). This study provides a comprehensive analysis of tracheal cancer, focusing on risk factors and population-level trends. There has been an overall decreasing trend in the incidence of tracheal cancer, particularly among males and older adults, while the decline is less pronounced in females and younger individuals. Further research is needed to explore the underlying drivers of these epidemiological trends.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"4 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chimeric antigen receptor macrophages targeting c-MET(CAR-M-c-MET) inhibit pancreatic cancer progression and improve cytotoxic chemotherapeutic efficacy","authors":"Huaijin Zheng, Xinzhe Yang, Nan Huang, Shangqin Yuan, Jiayi Li, Xudong Liu, Qing Jiang, Shanshan Wu, Yue Ju, Jorg Kleeff, Xiushan Yin, Quan Liao, Qiaofei Liu, Yupei Zhao","doi":"10.1186/s12943-024-02184-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02184-8","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Macrophages are abundant in the tumor microenvironment, making them an attractive target for therapeutic intervention. While current immunotherapies, including immune checkpoint inhibition (ICI) and chimeric antigen receptor T (CAR-T) cells, have shown limited efficacy in pancreatic cancer, a novel approach involving chimeric antigen receptor macrophages (CAR-M) has, although promising, not been explored in pancreatic cancer. In this study, we first investigated the role of CAR-M cells targeting c-MET in pancreatic cancer. The effectiveness and rationality of c-MET as a target for CAR-M in pancreatic cancer were validated through bioinformatic analyses and immunohistochemical staining of samples from pancreatic cancer patients. We utilized flow cytometry and bioluminescence detection methods to demonstrate the specific binding and phagocytic killing effect of CAR-M on pancreatic cancer cells. Additionally, we observed the process of CAR-M engulfing pancreatic cancer cells using confocal microscopy and a long-term fluorescence live cell imaging system. In an in situ tumor model transplanted into NOD/SCID mice, we administered intraperitoneal injections of CAR-M to confirm its inhibitory function on pancreatic cancer. Furthermore, we validated these findings in human monocyte-derived macrophages (hMDM). Bioinformatics and tumor tissue microarray analyses revealed significantly higher expression levels of c-MET in tumor tissues, compared to the paired peritumoral tissues, and higher c-MET expression correlated with worse patient survival. CAR-M cells were engineered using human monocytic THP-1 cell line and hMDM targeting c-MET (CAR-M-c-MET). The CAR-M-c-MET cells demonstrated highly specific binding to pancreatic cancer cells and exhibited more phagocytosis and killing abilities than the pro-inflammatory polarized control macrophages. In addition, CAR-M-c-MET cells synergized with various cytotoxic chemotherapeutic drugs. In a NOD/SCID murine model, intraperitoneally injected CAR-M-c-MET cells rapidly migrated to tumor tissue and substantially inhibited tumor growth, which did not lead to obvious side effects. Cytokine arrays and mRNA sequencing showed that CAR-M-c-MET produced higher levels of immune activators than control macrophages. This study provides compelling evidence for the safety and efficacy of CAR-M therapy in treating pancreatic cancer. The results demonstrate that CAR-M-c-MET significantly suppresses pancreatic cancer progression and enhances the effectiveness of cytotoxic chemotherapy. Remarkably, no discernible side effects occur. Further clinical trials are warranted in human pancreatic cancer patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent response to combination therapy of pemigatinib and chemotherapy in a child of combined hepatocellular-cholangiocarcinoma with FGFR2 fusion","authors":"Guo-qian He, Qing Li, Xiao-yu Jing, Jian Li, Ju Gao, Xia Guo","doi":"10.1186/s12943-024-02190-w","DOIUrl":"https://doi.org/10.1186/s12943-024-02190-w","url":null,"abstract":"Combined hepatocellular-cholangiocarcinoma (cHCC-CCA), an extremely rare and underinvestigated subtype of primary liver cancer in children, generally has a poor prognosis and greater aggressiveness. Histological diagnosis of cHCC-CCA is difficult because of its diverse components, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). cHCC-CCA shares some genetic alterations with HCC and CCA. However, only a few studies on genetic alterations in fibroblast growth factor receptor 2 (FGFR2) in cHCC-CCAs have been reported in adults. Therapeutic strategies for cHCC-CCAs are limited, and surgical resection is the only standard of care. No standard systemic treatment has been established for unresectable cHCC-CCAs. Herein, we report a rare case of a 14-year-old female patient diagnosed with unresectable cHCC-CCA with multiple liver masses and metastases to the lungs, lymph nodes and peritoneum. Next-generation sequencing (NGS) has identified an FGFR2-PRDM16 fusion, which has not been previously reported as a common FGFR2 fusion. The blood tumour markers alpha-fetoprotein (AFP) and carbohydrate antigen 19 - 9 (CA19 - 9) were both elevated. The patient was treated with pemigatinib (a selective FGFR inhibitor) in combination with Gemcitabine and Cisplatin at our hospital. After three cycles of the combination therapy, the patient achieved a partial response and normalization of tumor markers. After seven cycles of combination therapy, the patient achieved stable disease with the best response. Subsequently, the patient was administered received pemigatinib and gemcitabine. As of the last follow-up date, the patient has survived for 26 months. To the best of our knowledge, this is the first reported rare case of unresectable cHCC-CCA with FGFR2-PRDM16 fusion in a child successfully treated with a combination of pemigatinib and chemotherapy as a first-line regimen. This treatment combination may be effective and safe for patients with unresectable cHCC-CCAs.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication","authors":"Hua Wang, Tao Wang, Shuxiang Yan, Jinxin Tang, Yibo Zhang, Liming Wang, Haodong Xu, Chao Tu","doi":"10.1186/s12943-024-02183-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02183-9","url":null,"abstract":"In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"26 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression","authors":"Ruimin He, Yifan Liu, Weijie Fu, Xuan He, Shuang Liu, Desheng Xiao, Yongguang Tao","doi":"10.1186/s12943-024-02172-y","DOIUrl":"https://doi.org/10.1186/s12943-024-02172-y","url":null,"abstract":"Cell death is a fundamental part of life for metazoans. To maintain the balance between cell proliferation and metabolism of human bodies, a certain number of cells need to be removed regularly. Hence, the mechanisms of cell death have been preserved during the evolution of multicellular organisms. Tumorigenesis is closely related with exceptional inhibition of cell death. Mutations or defects in cell death-related genes block the elimination of abnormal cells and enhance the resistance of malignant cells to chemotherapy. Therefore, the investigation of cell death mechanisms enables the development of drugs that directly induce tumor cell death. In the guidelines updated by the Cell Death Nomenclature Committee (NCCD) in 2018, cell death was classified into 12 types according to morphological, biochemical and functional classification, including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, PARP-1 parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence and mitotic catastrophe. The mechanistic relationships between epigenetic controls and cell death in cancer progression were previously unclear. In this review, we will summarize the mechanisms of cell death pathways and corresponding epigenetic regulations. Also, we will explore the extensive interactions between these pathways and discuss the mechanisms of cell death in epigenetics which bring benefits to tumor therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"260 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1/PD-L1 immune checkpoint blockade in breast cancer: research insights and sensitization strategies","authors":"Menglei Jin, Jun Fang, Junwen Peng, Xintian Wang, Ping Xing, Kunpeng Jia, Jianming Hu, Danting Wang, Yuxin Ding, Xinyu Wang, Wenlu Li, Zhigang Chen","doi":"10.1186/s12943-024-02176-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02176-8","url":null,"abstract":"Immunotherapy targeting programmed cell death-1 (PD-1) and PD-L1 immune checkpoints has reshaped treatment paradigms across several cancers, including breast cancer. Combining PD-1/PD-L1 immune checkpoint blockade (ICB) with chemotherapy has shown promising efficacy in both early and metastatic triple-negative breast cancer, although only a subset of patients experiences durable responses. Identifying responders and optimizing immune drug selection are therefore critical. The effectiveness of PD-1/PD-L1 immunotherapy depends on both tumor-intrinsic factors and the extrinsic cell-cell interactions within the tumor microenvironment (TME). This review systematically summarizes the key findings from clinical trials of ICBs in breast cancer and examines the mechanisms underlying PD-L1 expression regulation. We also highlight recent advances in identifying potential biomarkers for PD-1/PD-L1 therapy and emerging evidence of TME alterations following treatment. Among these, the quantity, immunophenotype, and spatial distribution of tumor-infiltrating lymphocytes stand out as promising biomarkers. Additionally, we explore strategies to enhance the effectiveness of ICBs in breast cancer, aiming to support the development of personalized treatment approaches tailored to the unique characteristics of each patient’s tumor.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"37 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications","authors":"Hua-Qi Si, Peng Wang, Fei Long, Wei Zhong, Yuan-Dong Meng, Yuan Rong, Xiang-Yu Meng, Fu-Bing Wang","doi":"10.1186/s12943-024-02178-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02178-6","url":null,"abstract":"Liquid biopsies, in particular, analysis of cell-free DNA, are expected to revolutionize the current landscape of cancer diagnostics and treatment. However, the existing methods for cfDNA-based liquid biopsies for cancer have certain limitations, such as fragment interruption and GC bias, which are likely to be resolved by the emerging Oxford Nanopore Technologies (ONT), characterized by long read-length, fast read-times, high throughput, and polymerase chain reaction-free. In this review, we summarized the current literatures regarding the feasibility and applications of cfDNA-based liquid biopsies using ONT for cancer management, a possible game-changer that we believe is promising in detecting multimodal biomarkers and can be applied in a wide range of oncology utilities including early screening, diagnosis, and treatment monitoring. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"69 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-occurring mutations identify prognostic subgroups of microsatellite stable colorectal cancer","authors":"Luís Nunes, Jakob Mørkved Stenersen, Kushtrim Kryeziu, Tobias Sjöblom, Bengt Glimelius, Ragnhild A. Lothe, Anita Sveen","doi":"10.1186/s12943-024-02173-x","DOIUrl":"https://doi.org/10.1186/s12943-024-02173-x","url":null,"abstract":"Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling. Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately. Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively). We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"80 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}