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Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

ABSTRACT: Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profiled minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compared to same-patient tumour tissue obtained during invasive surgery. Patient ctDNA abundance was independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduced the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue was 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations were identified across serial ctDNA samples, concordance for serial tumor tissue was below 50%. Overall, our findings demonstrate that ctDNA analysis is a reliable and practical method for genomic profiling of mUC, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

PROVIDER: EGAS00001004615 | EGA |

REPOSITORIES: EGA

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Reliable tumor detection using cerebrospinal fluid cell-free DNA methylomes in pediatric medulloblastoma

Project description:Medulloblastoma (MB) is an embryonal tumor of the cerebellum and a highly malignant childhood brain tumor. Cell-free circulating tumor DNA (ctDNA) from the cerebrospinal fluid (CSF) of patients with brain tumors faithfully represent genomic alterations of brain tumors. Distinct epigenetic signatures among subgroups of MB allow us to detect epigenetic alterations in CSF to aid classify and guide therapy of MB tumors. Here, we evaluate DNA methylation and hydroxymethylation of ctDNA derived from small amount of CSF (200 µL) and matched tumor DNA from 3 MB patients. We find highly concordance of DNA methylation and hydroxymethylation between CSF ctDNA and tumor DNA, especially in CpG islands. Importantly, CSF ctDNA can mostly recapitulate the dynamic changes of DNA methylation and hydroxymehtylation in tumor species compared to healthy cerebellums. Those MB tumor signature CpGs’ DNA methylation status are recovered in CSF ctDNA can clearly distinguish MB subgroups by utilizing public large cohort data. We further identified potential diagnostic and prognostic DNA methylation markers in CSF ctDNA. Our results show that CSF ctNDA methylation and hydroxymethylation can be a minimal invasive method to assess epigenetic alterations of MB, which is complementary to current diagnoses of MB tumors.

2020-10-28 | GSE142241 | GEO

Cerebrospinal fluid cell-free DNA methylomes recapture pediatric medulloblastoma tissue's tumor feature

2024-06-10 | GSE178666 | GEO

Cerebrospinal fluid cell-free DNA methylomes subtyping pediatric medulloblastoma

2023-06-01 | GSE178169 | GEO

Diagnostic accuracy of liquid biopsy in endometrial cancer

Project description:INTRODUCTION. Liquid biopsies are a minimally invasive collection of a patient body fluid sample. In oncology, they offer several advantages compared to traditional tissue biopsies. However, potential of this method in endometrial cancer (EC) remains poorly explored. We studied the utility of tumor educated platelets (TEPs) and circulating tumor DNA (ctDNA) for preoperative EC diagnosis, including histology determination. MATERIALS AND METHODS. TEPs from 297 subjects (53 EC patients, 40 patients with benign gynecologic conditions and 204 healthy women) were RNA-sequenced. DNA sequencing was performed in 519 primary tumor tissue samples and in16 plasma samples. Artificial intelligence was applied to sample classification. RESULTS. Platelet-dedicated classifier yielded AUC of 93.1% in test set when discriminating between healthy subjects and cancer patients. However, the discrimination between endometrial cancer and benign gynecologic conditions was relatively low, with AUC of 60.7%. ctDNA-dedicated classifier discriminated primary tumor tissue samples with AUC of 91.4% and ctDNA blood samples with AUC of 87.5%. CONCLUSIONS Liquid biopsies show potential in EC diagnosis. Both TEPs and ctDNA profiles coupled with artificial intelligence constitute a source of useful information. Further work, involving more cases, is warranted.

2021-12-01 | GSE184904 | GEO

Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: correlation with FDG-PET/CT

Project description:Circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients are still not well-defined. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high PBatial and temporal heterogeneity. Though ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based in total ctDNA quantification, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

2023-12-18 | GSE244989 | GEO

Surgical and blood-based minimal residual disease in patients with ovarian cancer after frontline therapy: Clinical outcomes and translational opportunities [Spatial Transcriptomics]

Project description:Minimal residual disease (MRD) after frontline treatment of advanced stage ovarian cancer remains a longstanding barrier to cure. We investigated the prognostic and translational value of MRD detection by second look laparoscopy (SLL) and circulating tumor DNA (ctDNA) at the completion of frontline therapy. Patients with high-grade epithelial ovarian cancer with complete clinical response to frontline therapy who underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients. Forty of 95 (42.1%) patients had surgically detected MRD, and this was associated with worse PFS (median PFS 7.4 vs 23.8 months; p<0.001) and OS (median OS 33.9 vs not reached; p<0.001). SLL positivity was found to be an independent negative prognostic factor for OS (HR 4.40, 95% CI 1.37-14.21, p=0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs 28.1 months; p<0.001) and OS (32.4 months vs not reached; p=0.008). We demonstrated the feasibility of spatial multi-omics in studying MRD, and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, and ERBB2), and immune exclusion, in the development of MRD lesions. In summary, approximately half of patients in clinical remission after frontline therapy have assessable MRD which can inform prognosis, therapeutic target discovery, and clinical trials.

2025-06-20 | GSE284100 | GEO

Molecular subtypes are associated with clinical benefit in cisplatin-treated metastatic urothelial cancer patients

Project description:Cisplatin-based combination chemotherapy (CHT) is standard of care in locally advanced and metastatic urothelial cancer (mUC). No predictive biological biomarkers are available for clinical use. Here, we investigate the impact of molecular subtypes in relation to response and survival in mUC patients treated with first-line CHT. Molecular subtype classification according to Lund taxonomy was performed by tumour transcriptomic profiling and immunostaining in a retrospective cohort with mUC patients treated with CHT. We analyze overall response rate (ORR) and secondary endpoint overall survival (OS) in comparison to prespecified molecular subtypes. Differential gene expression and association to treatment response was explored. Ninety-five patients with mUC were classified into urothelial (Uro, 43%), genomically unstable (GU, 26%), basal/squamous (Ba/Sq, 20%), mesenchymal like (Mes-like, 8%) and small-cell/neuroendocrine-like (Sc/NE, 3%) subtypes. Gene expression data is available for 86 patients. Patients with Mes-like tumours had significantly lower ORR (14%), compared to Uro (70%), GU (77%), Ba/Sq (75%) and Sc/NE, 67%), p = 0.020. Further, patients with the Mes-like subtype had significantly shorter mOS (HR 3.13, 95% CI: 1.37-7.13, p = 0.007), with Uro as reference. An enrichment of down-regulated stromal- and immune-related genes was seen in responders. Down-regulation of interferon-induced transmembrane protein 2 (IFITM2), an inflammation related gene, was associated with increased ORR and improved OS. In patients treated with CHT for mUC, the Mes-like subtype showed significantly lower response rate and shorter overall survival. Down-regulation of IFITM2 was associated with clinical benefit, suggesting the presence of IFITM2 to be a possible unfavourable prognostic marker in mUC.

2024-10-09 | GSE250194 | GEO

Evolutionary pressures shape undifferentiated pleomorphic sarcoma development and radiotherapy response.

Project description:Although radiotherapy plays a crucial role in treating many cancers, the effect of radiation on tumor evolution remains unclear. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA (ctDNA) analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPS displayed initial linear evolution followed by subsequent branching evolution with distinct mutational processes during early and late development. Using metrics of genetic divergence between regions, we demonstrated evidence of strong selection pressures during UPS development that further increased during radiotherapy. We observed changes in subclone abundance following radiotherapy with subclone contraction tied to alterations in calcium signaling and demonstrated that inhibiting calcium transporters can radiosensitize sarcoma cells. Finally, ctDNA analysis accurately measured subclone abundance and enabled non-invasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPS and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy.

2024-12-13 | GSE279683 | GEO

A genomic ruler to assess oncogenic transition between breast tumor and stroma

Project description:Genome-wide gene expression changes were determined in histopathologically normal breast tissue in 33 women undergoing mastectomy for stage II and III primary invasive ductal carcinoma at serial distances in three dimensions from the tumor. Gene expression was determined by genome-wide mRNA analysis and subjected to metagene mRNA characterization

2018-09-19 | GSE120129 | GEO

Cytokine, cfDNA levels and tumoral DNA profiling in plasma as biomarkers of response to immunotherapy in hepatocellular carcinoma

Project description:Background: Immunotherapy has increased the expected survival of patients with advanced HCC. However, objective radiological response to these therapies has been reported to occur in around 20% of patients. Our aim was to identify potential serological markers of response to ICIs. Methods: 25 patients with advanced HCC treated with immunotherapy were prospectively in-cluded. Cytokine and cfDNA/ctDNA levels were measured prior to first treatment administration (basal) and after 3 months of treatment. Basal ctDNA profiling was also analyzed. Results: Basal levels of CTLA-4, cfDNA and ctDNA were significantly different in patients presenting progres-sive disease as best radiological response. The percentage of patients with basal mutations in CDKN2A was significantly higher in patients presenting progressive disease and they have a significantly lower number of CNV. Levels at 3 months of starting the treatment of MCP-1, TNF-alpha, cfDNA and ctDNA were also significantly different between patients with and without progressive disease. Higher cfDNA and ctDNA levels were associated with a poorer overall survival. Conclusion: Analysis of cfDNA and cytokines could help to stratify patients according to expected response to immunotherapies.

2025-04-02 | GSE237791 | GEO

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