Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor prognosis. While chemotherapy remains the conventional treatment approach, its efficacy is limited and often accom...Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor prognosis. While chemotherapy remains the conventional treatment approach, its efficacy is limited and often accompanied by significant toxicity. Advances in precision-targeted therapies have expanded treatment options for TNBC, including immunotherapy, poly (ADP-ribose) polymerase inhibitors, androgen receptor inhibitors, cell cycle-dependent kinase inhibitors, and signaling pathway inhibitors. However, the heterogeneous nature of TNBC contributes to variations in treatment outcomes, underscoring the importance of identifying intrinsic molecular subtypes for personalized therapy. Additionally, due to patient-specific variability, the therapeutic response to targeted treatments is inconsistent. This highlights the need to strategize patients based on potential therapeutic targets for targeted drugs to optimize treatment strategies. This review summarizes the classification strategies and immunohistochemical (IHC) biomarkers for TNBC subtypes, along with potential targets for identifying indications for targeted drug therapy. These insights aim to support the development of personalized treatment approaches for TNBC patients.
Fan L, Guo X, Washington MK
… +11 more, Shi J, Ness RM, Liu Q, Wen W, Huang S, Liu X, Cai Q, Zheng W, Coffey RJ, Shrubsole MJ, Su T
Carcinogenesis
· 2025 Jan · PMID 39977302
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The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of pho...The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r = 0.53, P < .0001) and nuclear β-catenin (r = 0.26, P = .0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P = .05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR = 12.62, 95% CI = 4.57-34.86, P trend < .001), which persisted after adjusting for covariates and biomarkers (OR = 12.31, 95% CI = 3.78-40.10, P trend < .0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced versus nonadvanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR = 16.82, 95% CI = 4.41-64.08, P < .0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.
Resistance to platinum-based chemotherapy agents like oxaliplatin (OXA) poses significant challenges in the treatment of cancers such as hepatocellular carcinoma (HCC). Centrin 2 (CETN2), which functions in nucleotide ex...Resistance to platinum-based chemotherapy agents like oxaliplatin (OXA) poses significant challenges in the treatment of cancers such as hepatocellular carcinoma (HCC). Centrin 2 (CETN2), which functions in nucleotide excision repair (NER) of DNA damage, is overexpressed in HCC. We investigated the potential role of CETN2 in modulating the sensitivity of HCC cells to OXA. CETN2 expression correlated with decreased OXA sensitivity in Huh7 and Hep3B HCC cell lines. CETN2 forms a complex with XPC, which is crucial for the initial DNA damage recognition in NER, thereby enhancing NER and reducing the efficacy of OXA. siRNA-mediated knockdown of CETN2 increased OXA-induced cytotoxicity and apoptosis, confirming its role in chemoresistance. Moreover, overexpression of CETN2 inhibited OXA-induced DNA damage, an effect partially reversed by XPC knockdown. Our findings highlight CETN2 as a potential biomarker and therapeutic target in overcoming OXA resistance in HCC and suggest the possibility for CETN2 inhibitors in enhancing chemotherapeutic efficacy in the treatment of HCC.
High-risk human papillomavirus (HPV) infection is strongly linked to the initiation and progression of cervical cancer (CC), yet the precise molecular mechanisms involved remain partially understood. This investigation e...High-risk human papillomavirus (HPV) infection is strongly linked to the initiation and progression of cervical cancer (CC), yet the precise molecular mechanisms involved remain partially understood. This investigation examined differential protein expression profiles in various cohorts, including healthy controls and HPV-positive CC patients with different expression levels of glucose-6-phosphate dehydrogenase (G6PD), shedding light on the dysregulation of oncogenic proteins by HPV. Proteomic analysis of cervical tissues revealed specific protein signatures, indicating significant upregulation of HPV E6, G6PD, STAT3, phosphorylated STAT3, and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in HPV-infected CC tissues and cell lines. Functional experiments, involving the manipulation of G6PD and STAT3 activities in CC cells with HPV E6 modulation, demonstrated that dysregulated G6PD enhanced cell proliferation, migration, and invasion while suppressing apoptosis, primarily through the STAT3/PLOD2 pathway. Integrating these findings with the existing literature underscores the role of G6PD as an oncogene, potentially under STAT3 regulation, and highlights the role of PLOD2 as a pivotal factor in CC progression. This study also proposed a mechanism in which HPV E6-induced dysregulation of G6PD activates the STAT3-PLOD2 axis to promote CC progression. Understanding the intricate interplay between HPV E6, G6PD, STAT3, and PLOD2 offers valuable insights into the molecular landscape of CC. These findings may pave the way for targeted therapeutic approaches aimed at disrupting this axis to mitigate the progression of CC.
Hoos E, Koval LE, Corcoran DL
… +11 more, Eaves LA, Roell K, Rager JE, Tan X, Godfrey S, Keku TO, Bae-Jump V, Olshan AF, Nichols HB, Weissman BE, Fry RC
Carcinogenesis
· 2025 Jan · PMID 39873457
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Endometrial cancer (EC) is the fourth most common cancer in women in the USA. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The...Endometrial cancer (EC) is the fourth most common cancer in women in the USA. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The social and biologic factors that contribute to these disparities are complex and may include racial differences in epigenetic landscapes. To investigate race-specific epigenetic differences in EC tumor characteristics and outcomes, we utilized the most recent data within the Cancer Genome Atlas (TCGA). Genome-wide CpG methylation data for more than 850 000 CpG sites were analyzed across 245 tumor samples, including 52 from Black women and 181 from White women. Race-adjusted and race-stratified associations among CpG methylation in ECs and molecular subtypes and disease-free survival were examined. Race-specific analysis identified subtype-associated CpGs within 9572 genes in tumors from White women and only 10 genes in tumors that were from Black women. Race-specific analyses also identified survival-associated CpGs with 1119 unique genes identified in tumors from White women and none identified in tumors from Black women. Genes identified with differential methylation among subtypes included those involved in oxidative stress (HIF3A), and DNA repair (MLH1). Data from a replication cohort highlighted genes overlapping with those identified within the TCGA, such as G Protein Subunit Beta 1 (GNB1), involved in G-protein signaling, and Interleukin 37 (IL37), involved in cytokine signaling. Identification of these racial differences in EC tumor epigenetic landscapes and associated changes in gene expression may provide insight into strategies to improve outcomes and reduce disparities.
Fang R, Wang X, Wu R
… +10 more, Pan R, Tian M, Zhang R, Wei X, Wang X, Ye S, Li F, Xia Q, Cheng Y, Rao Q
Carcinogenesis
· 2025 Jan · PMID 39851260
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The tumor suppressor gene SMARCA4, a critical component of the SWI/SNF chromatin remodeling complex, is frequently inactivated in various cancers, including clear cell renal cell carcinoma (ccRCC). Despite its significan...The tumor suppressor gene SMARCA4, a critical component of the SWI/SNF chromatin remodeling complex, is frequently inactivated in various cancers, including clear cell renal cell carcinoma (ccRCC). Despite its significance, the role of SMARCA4 in ccRCC development and its potential therapeutic vulnerabilities have not been fully explored. Our research found that SMARCA4 deficiency was associated with poor prognosis and was observed in a subset of high-grade ccRCCs. Through functional assays, we determined that the suppression of SMARCA4 led to an increase in RCC cell proliferation. Further gene expression analysis unveiled that SMARCA4-deficient cells exhibit an upregulation of the oxidative phosphorylation (OXPHOS) pathway. Delving deeper, we combined RNA sequencing (RNA-Seq) and Assay for transposase-accessible chromatin with sequencing (ATAC-Seq) data to uncover that SMARCA4 plays a crucial role in modulating chromatin accessibility and the expression of genes essential for the respiratory electron transport chain. A significant finding from our study is that RCC cells and xenograft tumors lacking SMARCA4 demonstrated an increased sensitivity to the inhibition of the OXPHOS pathway by the novel small molecule IACS-010759. This sensitivity is attributed to the heightened energy demands and susceptibility to energy stress observed in SMARCA4-deficient cells, driven by their amplified biosynthetic requirements. The efficacy of IACS-010759 stems from its ability to induce energy deprivation, pinpointing OXPHOS inhibition as a promising therapeutic approach for targeting SMARCA4-mutant tumors. This strategy offers a novel avenue to address a currently unmet therapeutic need, highlighting the potential of OXPHOS inhibition in the treatment of cancers harboring SMARCA4 mutations.
Muñoz-Bravo C, Marín-Burdallo I, González-Herrera L
… +4 more, González-Palacios Torres C, Lozano-Lorca M, Jiménez-Moleón JJ, Olmedo-Requena R
Carcinogenesis
· 2025 Jan · PMID 39847508
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Several clinical studies have evaluated the relationship between copper on colorectal cancer (CRC), but the results are contradictory. This study aimed to conduct a systematic review and meta-analysis to investigate copp...Several clinical studies have evaluated the relationship between copper on colorectal cancer (CRC), but the results are contradictory. This study aimed to conduct a systematic review and meta-analysis to investigate copper measured in two biological matrices (serum/plasma/blood and tissue) and dietary intake in CRC patients compared to healthy controls. We conducted a comprehensive and systematic search in PubMed, Scopus, Embase, and Web of Science. We included studies that reported copper levels in serum/plasma/blood, tissue, or from the diet, with an observational study design (cohort and case-control studies). Study quality was assessed with the Newcastle-Ottawa scale and potential causes of heterogeneity were evaluated. Standardized mean differences (SMD) with 95% confidence interval (CI) were pooled using random-effect models. Overall pooled odds ratio and 95% CI for the risk of CRC were calculated. Twenty-six studies (23 case-control and 3 cohort studies) with a total of 227 354 participants were included. Most of the studies presented low (50%) or moderate quality (42.3%). No differences in serum/plasma/blood copper levels (SMD = 0.23; 95% CI: -0.23, 0.70; I2 = 97.3%, 19 studies), tissue copper levels (SMD = -1.69; 95% CI: -3.41, 0.03; I2 = 85.6%, 2 studies), or copper/zinc ratio (SMD = 1.19; 95% CI: 0.54, 1.84; I2 = 95.3%, 6 studies) were found between CRC patients and healthy controls. Regarding dietary copper, CRC patients had a lower intake (SMD = -0.27; 95% CI: -0.51, -0.03; I2 = 0.0%, 2 studies). No differences were found in copper levels between CRC patients and healthy controls. However, evidence shows mostly low or moderate quality, and results were heterogeneous. More prospective studies with an adequate methodological approach are needed.
Garay MI, Mazo T, Ferrero V
… +10 more, Barotto NN, Lagares C, Granton MF, Moreira-Espinoza MJ, Cremonezzi DC, Comba A, Brunotto MN, Tolosa EJ, Fernandez-Zapico ME, Pasqualini ME
Carcinogenesis
· 2025 Jan · PMID 39742417
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Pancreatic cancer is a devastating malignancy in great need of new and more effective treatment approaches. In recent years, studies have indicated that nutritional interventions, particularly nutraceuticals, may provide...Pancreatic cancer is a devastating malignancy in great need of new and more effective treatment approaches. In recent years, studies have indicated that nutritional interventions, particularly nutraceuticals, may provide novel avenues to modulate cancer progression. Here, our study characterizes the impact of ω-3 polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, as a nutraceutical intervention in pancreatic cancer using a genetically engineered mouse model driven by KrasG12D and Trp53R172H. This model closely resembles human pancreatic carcinogenesis, offering a disease relevant platform for translational research. Our findings showed that ω-3 polyunsaturated fatty acids intervention (using a diet supplemented with 6% cod liver oil) significantly reduced tumor volume as well as lung and liver metastasis and a trend toward improved survival rate compared with control treated mice. This antitumoral effect was accompanied by distinct changes in tumor membrane fatty acid profile and eicosanoids release. Furthermore, the eicosapentaenoic acid and docosahexaenoic acid intervention also reduced malignant histological parameters and induced apoptosis without affecting cell proliferation. Of note is the significant reduction in tumor fibrosis that was associated with decreased levels of Sonic Hedgehog, a major ligand controlling this cellular compartment in pancreatic cancer. All together our results demonstrate the impact of eicosapentaenoic acid and docosahexaenoic acid as antitumor regulators in pancreatic cancer, suggesting potential for ω-3 polyunsaturated fatty acids as a possible antitumoral dietary intervention. This research opens new avenues for integrating nutraceutical strategies in pancreatic cancer management.
Carcinogenesis
· 2025 Jan · PMID 39742416
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Antibody-drug conjugates (ADCs) have garnered significant attention as an innovative therapeutic strategy in cancer treatment. The mechanism of action for ADCs involves the targeted delivery of antibodies to specific rec...Antibody-drug conjugates (ADCs) have garnered significant attention as an innovative therapeutic strategy in cancer treatment. The mechanism of action for ADCs involves the targeted delivery of antibodies to specific receptors, followed by the release of cytotoxic payloads directly into tumor cells. In recent years, ADCs have made substantial progress in the treatment of breast cancer (BC), particularly demonstrating significant efficacy in the human epidermal growth factor receptor-2 (HER-2)-positive subgroup. Clinical evidence indicates that ADCs have notably improved treatment efficacy and survival outcomes for BC patients. However, challenges such as drug toxicities and the emergence of drug resistance necessitate further research and discussion. In this paper, we will summarize the advances in ADCs targeting various receptors in BC patients and explore the challenges and future directions in this field. We anticipate that the increasing availability of ADCs will lead to more effective and personalized treatment options for BC patients.
Carcinogenesis
· 2025 Jan · PMID 39714081
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Chronic myeloid leukemia (CML) is a malignant hyperplastic tumor that originates from pluripotent hematopoietic stem cells in the bone marrow. The introduction of tyrosine kinase inhibitors has significantly improved the...Chronic myeloid leukemia (CML) is a malignant hyperplastic tumor that originates from pluripotent hematopoietic stem cells in the bone marrow. The introduction of tyrosine kinase inhibitors has significantly improved the survival rates of CML patients. This study aimed to identify immune-related genes associated with the response to imatinib (IM) therapy in CML. Gene expression profiles from IM-treated CML patients were obtained from the Gene Expression Omnibus database and categorized into high- and low-score groups based on immune scores calculated using the ESTIMATE algorithm. Subsequent bioinformatics analysis identified 428 differentially expressed immune-related genes in the CML context. Functional enrichment analysis revealed that these genes were involved in immune-related pathways, including T-cell receptor signaling and cytokine-cytokine receptor interaction. Finally, based on five modules in weighted gene co-expression network analysis and the top-ranked degree, 10 hub genes were identified. Receiver operating characteristic analysis in two Gene Expression Omnibus datasets identified IL10RA, SCN9A, and SLC26A11 as potential biomarkers for predicting IM response. We further validated these biomarkers in an independent clinical cohort of 60 CML patients treated with IM. Results from quantitative real-time polymerase chain reaction (qRT-PCR) revealed high expression of IL10RA and SLC26A11 in responders, while SCN9A showed low expression. All three genes had an area under the curve greater than 0.75, confirming their potential as predictive biomarkers. These findings deepen our understanding of functional characteristics and immune-related molecular mechanisms underlying IM response and offer promising predictive biomarkers.
Li B, Wu M, Geng H
… +15 more, Li Y, Chen Z, Lu Z, Chen X, Wang Q, Song S, Li X, Zhu X, Wei Y, Zhu Y, Miao X, Tian J, Liu J, Huang C, Yang X
Carcinogenesis
· 2025 Jan · PMID 39680067
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Although genome-wide association studies have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often rem...Although genome-wide association studies have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often remain elusive. Recently, the genomic locus 12p13.32, with the tag single-nucleotide polymorphism rs10774214, was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here, we applied a high-throughput RNA interference approach in CRC cell lines to interrogate the function of genes in this genomic region. Multiple genes were found to affect cell functions, with CCND2 having the most significant effect as an oncogene. Moreover, overexpressed CCND2 could promote CRC cell proliferation. Subsequently, by integrating a fine-mapping analysis and multi-ancestry large-scale population cohorts consisting of 14 358 CRC cases and 34 251 healthy controls, we identified a regulatory variant rs4477507-T that contributed to an increased CRC risk in populations from China (odds ratio = 1.16, 95% confidence interval = 1.11-1.22, P = 4.45 × 10-10) and Europe (odds ratio = 1.17, 95% confidence interval = 1.12-1.21, P = 1.65 × 10-14). Functional characterization of the variant demonstrated that it could act as an allele-specific enhancer to distally facilitate the expression of CCND2 mediated by the transcription factor TEAD4. Overall, our study underscores the essential role of CCND2 in CRC development and delineates its regulatory mechanism mediated by rs4477507, establishing an epidemiological and biological link between genetic variation and CRC pathogenesis.
Carcinogenesis
· 2025 Jan · PMID 39673782
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Interleukin 17 (IL17) is a cytokine involved in immune regulation and has been increasingly recognized for its role in cancer progression. This systematic review aims to integrate data on IL17's role in various tumors to...Interleukin 17 (IL17) is a cytokine involved in immune regulation and has been increasingly recognized for its role in cancer progression. This systematic review aims to integrate data on IL17's role in various tumors to better understand its implications for cancer prognosis and treatment. The review included 105 studies (27.6% experimental and 72.4% clinical). Clinical studies involved 9266 patients: 31.2% males, 60.0% females, and 8.8% with undefined gender. IL17A and IL17 were the most studied subtypes (36.2% and 33.3%, respectively). Breast cancer (26.7%), colorectal carcinoma (13.3%), and hematologic malignancies (10.5%) were the most researched neoplasms. IL17A promoted tumor growth in breast cancer and correlated with poor outcomes in colorectal, breast, and lung cancers. IL17 also played a significant role in immune modulation in gliomas and other tumors. IL17A significantly influences tumor growth and prognosis across various cancers, with notable roles in immune modulation and poor outcomes in multiple cancer types.
Dinevska M, McAloney L, Widodo SS
… +6 more, Filiz G, Anderson J, Dworkin S, Windley SP, Wilhelm D, Mantamadiotis T
Carcinogenesis
· 2025 Jan · PMID 39672957
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Testicular tumors are the most common malignancy of young men, and tumors affecting the testis are caused by somatic mutations in germ or germ-like cells. The PI3K pathway is constitutively activated in about one-third o...Testicular tumors are the most common malignancy of young men, and tumors affecting the testis are caused by somatic mutations in germ or germ-like cells. The PI3K pathway is constitutively activated in about one-third of testicular cancers. To investigate the role of the PI3K pathway in transforming stem-like cells in the testis, we investigated tumors derived from mice with post-natal, constitutive activation of PI3K signaling and homozygous deletion of tumor suppressor Pten, targeted to Nestin-expressing cells. Mice developed aggressive tumors, exhibiting heterogeneous histopathology and hemorrhaging. The tumors resemble the rare testis tumor type, testicular sex cord-stromal Leydig cell tumors. Single-cell resolution spatial tissue analysis demonstrated that T-cells are the dominant tumor-infiltrating immune cell type, with very few infiltrating macrophages observed in the tumor tissue, with CD8+ T-cells predominating. Further analysis showed that immune cells preferentially localize to, or accumulate within stromal regions.
Li J, Li Y, Wang X
… +6 more, Zhou Z, Li X, Yue S, Wang H, Yang M, Zhang G
Carcinogenesis
· 2025 Jan · PMID 39574310
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Multiple primary lung tumors are garnering attention from clinicians, with adenocarcinoma emerging as the predominant histological type. Because of the heterogeneity and diffuse distribution of lesions in the same patien...Multiple primary lung tumors are garnering attention from clinicians, with adenocarcinoma emerging as the predominant histological type. Because of the heterogeneity and diffuse distribution of lesions in the same patient, the treatment of multiple primary lung adenocarcinoma (MPLA) is a significant challenge. As a kind of variation unaffected by tumor heterogeneity, germline alterations may play a key role in the development of MPLA. Here, whole-exome sequencing of peripheral blood was employed to obtain germline alteration data. Intergroup comparative analyses on rare and deleterious alterations of MPLA, solitary lung adenocarcinoma, and healthy individuals in an MPLA family were performed to clarify the candidate alterations. Whole-exome sequencing and targeted Sanger sequencing were performed in 27 disseminated MPLA patients to detect the mutation site that had been screened. A rare and deleterious germline alteration, EPHB4R91H, was found in all of the patients of an MPLA family and a patient with disseminated MPLA. It was revealed that EPHB4R91H was able to enhance the proliferation, migration, and invasion ability of A549 cells through increased binding affinity to ephrinB2, which in turn activated the EPHB4/ERK/JNK/MAPK pathway. Our findings corroborate that germline alterations are involved in the development of MPLA. And it was found for the first time that the EPHB4R91H mutation promotes the development of MPLA by enhancing its affinity for ephrinB2 and thereby active EPHB4/ERK/JNK/MAPK pathway.
Sogbe M, Aliseda D, Sangro P
… +3 more, de la Torre-Aláez M, Sangro B, Argemi J
Carcinogenesis
· 2025 Jan · PMID 39549302
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Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5 × coverage) of plasma cell-free DNA (cfDNA) has emerged as a low-cost, promising tool to assess the circulating tumor DNA (ctDNA) fraction. This meta-analysis aims t...Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5 × coverage) of plasma cell-free DNA (cfDNA) has emerged as a low-cost, promising tool to assess the circulating tumor DNA (ctDNA) fraction. This meta-analysis aims to summarize the current findings and comprehensively investigate the prognostic value of baseline ctDNA detected by ULP-WGS in solid tumors. A systematic review was carried out by searching PubMed/MEDLINE and Scopus databases to identify eligible studies conducted between January 2014 and January 2024. Inclusion criteria comprised studies with reported overall survival and progression-free survival outcomes across therapy-naïve patients with different solid tumors. All patients underwent baseline ULP-WGS of plasma cfDNA and were categorized as ctDNA positive (tumor fraction ≥10%) or negative (tumor fraction <10%). A one-stage meta-analysis was performed using patient-level survival data reconstructed from published articles. A Cox proportional hazards model with shared frailty was used to assess the difference in survival between arms. A total of six studies, comprising 620 patients (367 negative ctDNA and 253 positive ctDNA), were included in the overall survival analysis, while five studies, involving 349 patients (212 negative ctDNA and 137 positive ctDNA), were included in the progression-free survival analysis. The meta-analysis showed that patients with baseline positive ctDNA had a significantly higher risk of death (HR = 2.60, 95% CI: 2.01-3.36) and disease progression (HR = 2.28, 95% CI: 1.71-3.05) compared to those with negative ctDNA. The presence of a positive ctDNA at baseline is associated with increased risk of death and progression in patients with same-stage cancer.
Yang Y, Liu L, Cui H
… +11 more, Cheng B, Peng W, Wang R, Wang J, Chen W, Cao M, Li Y, Liang J, Chen S, Bai S, Zhao Y
Carcinogenesis
· 2025 Apr · PMID 39526455
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New-onset diabetes (NOD) is a common condition among patients with pancreatic adenocarcinoma (PAAD) and is related to poor clinical outcomes. The potential impact of NOD on PAAD progression and the tumor microenvironment...New-onset diabetes (NOD) is a common condition among patients with pancreatic adenocarcinoma (PAAD) and is related to poor clinical outcomes. The potential impact of NOD on PAAD progression and the tumor microenvironment remains unclear. Here, we revealed that NOD in PAAD was associated with metabolic disorders. Utilizing three machine-learning algorithms, an NOD-related metabolism signature (NRMS) was established. Validated in three independent cohorts, patients with a high NRMS score exhibited a worse prognosis. Moreover, an elevated NRMS score was associated with an immunosuppressive microenvironment and diminished response to immunotherapy. Further experiments demonstrated that ALDH3A1, a key feature in NRMS, was significantly upregulated in tissues from PAAD patients with NOD and played a crucial role in tumor progression and immune suppression. Our findings highlight the potential of NRMS as a prognostic biomarker and an indicator of immunotherapy response for patients with PAAD.