Identification of genomic methylation markers for colorectal cancer diagnosis and toxicity of capecitabine-based chemotherapy
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PROVIDER: PRJNA670787 | ENA |
REPOSITORIES: ENA
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Project description:Genome-wide maps of colorectal cancer diagnosis and toxicity of capecitabine-based chemotherapy.
| PRJNA719747 | ENA
Project description:Genome-wide maps of colorectal cancer diagnosis and toxicity of capecitabine-based chemotherapy [methylation array]
| PRJNA720055 | ENA
Project description:Background: Capecitabine-based adjuvant chemotherapy is the first-line treatment for patients with colorectal cancer (CRC). Although this therapy generally reduces the incidence of CRC recurrence and mortality, it can cause various chemotherapy-related adverse events (CRAEs), one of the most frequent of which is hand-foot syndrome (HFS). Most of the currently available HFS prediction markers focus on the pharmacokinetic parameters of drugs or their metabolites, yet our understanding of the biomolecular mechanism of HFS remains limited. Methods: We conducted an integrated multi-omics analysis of 63 Chinese patients with colorectal cancer (CRC) who had chemotherapy related adcerse effect (CRAE) records during adjuvant chemotherapy. The metabolomic profiles for each of plasma, urine, and colorectal tissue as well as profiles for colorectal-tissue transcriptomics and genome methylation were analyzed based on samples collected before and during surgery. Results: Susceptibility to HFS was found to be associated with profibrotic changes in several aspects of cellular biochemistry and physiology, characterized by reduced nucleotide salvage (indicating potential tissue damage, elevated spermine release, increased M2 macrophage polarization, and hypermethylation of genes for collagen formation. All these aspects were found to promote fibrosis, even before patients received chemotherapeutic drugs or developed any HFS symptoms. Additionally, we developed and validated relevant biomarkers with reasonably good discrimination performance and a high AUROC (area under the receiver operating characteristic curve) value, i.e., from 0.848 to 1.000. Conclusions: Our results demonstrate that a profibrotic phenotype characterized by multi-omics variation in colorectal tissue, plasma, and urine is closely related to the susceptibility to chemotherapy-induced HFS. Our findings provide a better understanding of the molecular mechanism underlying HFS.
2021-08-27 | GSE171468 | GEO
Project description:Background: Colorectal cancer (CRC) remains a major concern with high morbidity and mortality worldwide. DNA methylation alteration plays a pivotal role in cancer development. We aimed to screen novel biomarkers for CRC diagnosis and chemotherapy-related adverse event (CRAE) prediction using the advanced Illumina Infinium MethylationEPIC (850K) BeadChip. Methods: We analyzed the methylation profiles of paired tumor and normal tissues from 21 Chinese CRC patients. After normalization by potential confounders, three types of methylation profiles (differentially methylated probes, differentially methylated regions, and gene-function-differentially methylated regions) were further studied by functional annotation and pathway enrichment analysis. At last, integrated-methylation-marker systems for CRC diagnosis and CRAE prediction were developed based on genes within the mostly related pathways and LASSO regression. Findings: Tumor-related methylation was characterized with hypermethylated promoter islands and hypomethylated intragenic openseas. CRAE-related methylation was characterized with hyper- (or hypo-) methylated intragenic (or intergenic) regions. The two most important susceptible factors for various types of CARE were inactive regeneration functions and active immune response. Differentially methylated genes were significantly enriched in neuronal system, metabolism of RNA, and extracellular matrix organization. All of the integrated-methylation-marker systems demonstrated high discriminative accuracy in both CRC diagnosis (AUROC = 1) and CRAE prediction (AUROC = 0.817-1). Interpretation: In this study, we provided new insights on the formation of CRC diagnosis and CRAE based on three types of methylation profile. The integrated-methylation-marker systems combining multiple DMPs were found to have potentially diagnostic and predictive values. Hence, our findings have important clinical implications, and further validation is warranted.
2021-08-01 | GSE159898 | GEO
Project description:Background: Capecitabine-based adjuvant chemotherapy is the first-line treatment for patients with colorectal cancer (CRC). Although this therapy generally reduces the incidence of CRC recurrence and mortality, it can cause various chemotherapy-related adverse events (CRAEs), one of the most frequent of which is hand-foot syndrome (HFS). Most of the currently available HFS prediction markers focus on the pharmacokinetic parameters of drugs or their metabolites, yet our understanding of the biomolecular mechanism of HFS remains limited. Methods: We conducted an integrated multi-omics analysis of 63 Chinese patients with colorectal cancer (CRC) who had chemotherapy related adverse effect (CRAE) records during adjuvant chemotherapy. The metabolomic profiles for each of plasma, urine, and colorectal tissue as well as profiles for colorectal-tissue transcriptomics and genome methylation were analyzed based on samples collected before and during surgery. Results: Susceptibility to HFS was found to be associated with profibrotic changes in several aspects of cellular biochemistry and physiology, characterized by reduced nucleotide salvage (indicating potential tissue damage, elevated spermine release, increased M2 macrophage polarization, and hypermethylation of genes for collagen formation. All these aspects were found to promote fibrosis, even before patients received chemotherapeutic drugs or developed any HFS symptoms. Additionally, we developed and validated relevant biomarkers with reasonably good discrimination performance and a high AUROC (area under the receiver operating characteristic curve) value, i.e., from 0.848 to 1.000. Conclusions: Our results demonstrate that a profibrotic phenotype characterized by multi-omics variation in colorectal tissue, plasma, and urine is closely related to the susceptibility to chemotherapy-induced HFS. Our findings provide a better understanding of the molecular mechanism underlying HFS.
2021-08-27 | GSE171550 | GEO
Project description:Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m2 weekly) or flat-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n=4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n=6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.
2023-02-17 | GSE225078 | GEO
Project description:To develop diagnostic and prognostic biomarkers, we compared methylation profiles of HCC tissues and normal blood by analyzing 485,000 CpG markers and identified a HCC enriched methylation marker panel compared to that of normal blood. We found there was a highly correlation of methylation profiles between DNA from HCC cancer tissue and matched plasma ctDNA within the same patient. We then selected 10 markers from this panel and created a combined diagnosis score (cd-score) which showed high diagnostic specificity and sensitivity in both a training cohort and an independent validation cohort. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. Additional, we generated 8 markers from unicox and LASSO-cox analysis and created a combined prognosis score (cp-score) which could predict prognosis and survival. Together, these findings demonstrated the utility of ctDNA methylation markers in the diagnosis, treatment evaluation and prognosis of HCC.
2019-01-01 | GSE93203 | GEO
Project description:The impact of gut microbiota on chemotherapy-induced gastrointestinal toxicity in children with leukemia
| PRJEB35526 | ENA
Project description:The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.
2024-06-01 | GSE266932 | GEO
Project description:We found that ERY974 shows only moderate antitumor efficacy in MKN45 non-inflamed tumor in huNOG mice. We also observed that ERY974 + capecitabine increases antitumour efficacy in non-inflamed MKN45 tumours. To identify a mechanism of combination effect, we compared RNA expression of MKN45 tumors treated with ERY974, capecitabine, or combination.
2022-08-21 | GSE211373 | GEO