Exploration of <i>CTNNB1</i> ctDNA as a putative biomarker for hepatoblastoma

Kahana-Edwin, Smadar; McCowage, Geoffrey; Cain, Lucy E; Saletta, Federica; Yuksel, Aysen; Graf, Nicole; Karpelowsky, Jonathan

doi:10.1002/pbc.28594

Cited by 8 publications

(21 citation statements)

References 23 publications

(26 reference statements)

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“…While we show that localized neuroblastoma shed higher-than-normal cfDNA amounts, we were not able to analyze any of the four localized cases using SNP array due to low-input cfDNA levels. In addition, although several localized pediatric diseases were found to shed high ctDNA VAF in some cases (e.g., [25]), there was not enough to proceed with SNP CMA, given the assay sensitivity or LOD for identify low levels of MNA (10%) and SCA (20%). Next generation sequencing (NGS) is used routinely to detect DNA somatic variants when VAF ≥ 5% and might offer a better solution in this setting.…”

Section: Discussionmentioning

confidence: 99%

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

Kahana-Edwin

Cain

McCowage

et al. 2021

Cancers

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Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation. Methods: Various pre-analytical conditions tested to optimize circulating-tumor DNA (ctDNA) copy number changes evaluations. Plasma samples from 10 patients diagnosed with neuroblastoma assessed for SCA and MNA using single nucleotide polymorphism (SNP) array approach currently used for neuroblastoma diagnosis, with MNA status assessed independently using digital-droplet PCR (ddPCR). Three patients (one in common with the previous 10) tested for ALK activating mutations p.F1174L and p.F1245I using ddPCR. Results: Copy number detection is highly affected by physical perturbations of the blood sample (mimicking suboptimal sample shipment), which could be overcome using specialized preservative collection tubes. Pre-analytical DNA repair procedures on ctDNA before SNP chromosome microarray processing improved the lower limit of detection for SCA and MNA, defined as 20% and 10%, respectively. We detected SCA in 10/10 (100%) patients using SNP array, 7 of which also presented MNA. Circulating-free DNA (cfDNA) and matched tumor DNA profiles were generally identical. MNA was detected using ddPCR in 7/7 (100%) of MNA and 0/12 (0%) non-MNA cases. MNA and ALK mutation dynamic change was assessed in longitudinal samples from 4 and 3 patients (one patient with both), respectively, accurately reflected response to treatment in 6/6 (100%) and disease recurrence in 5/6 (83%) of cases. Samples taken prior to targeted treatment with the ALK inhibitor Lorlatinib and 6–8 weeks on treatment showed reduction/increase in ALK variants according to response to treatment. Conclusions: These results demonstrate the feasibility of ctDNA profiling for molecular risk-stratification, and treatment monitoring in a clinically relevant time frame and the potential to reduce fresh tissue requirements currently embedded in the management of neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

Kahana-Edwin

Cain

McCowage

et al. 2021

Cancers

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“…Of note, using ddPCR, we were able to find ctDNA molecules, testing DNA purified from whole blood samples collected in EDTA tubes that were left at room temperature for 48 hours before DNA extraction, in two patients diagnosed with a localized hepatoblastoma. 10 Although diagnosed with a localized disease, these patients had very large tumors and mutant allele frequencies of 28%-29% at that time point. The following support our claim that these are true ctDNA observations and not the result of limitations in our assay:…”

Section: Matched Samplesmentioning

confidence: 94%

“…In the localized setting, Shulman and colleagues found EWSR1 ctDNA fusions in 22/50 (44%) patients diagnosed with Ewing sarcoma, analyzing 2 mL of plasma, 9 and we were able to detect an abundant amount of CTNNB1 ctDNA (1095-4585 copies/mL plasma, with mutant allele frequencies of 20%-29%) in 3/3 (100%) infants diagnosed with localized hepatoblastoma, analyzing only 0.5 mL of plasma. 10…”

Section: Pediatric Sampling Restrictionsmentioning

confidence: 99%

Roadmap to Liquid Biopsy Biobanking from Pediatric Cancers–Challenges and Opportunities

Kahana-Edwin

Cain

Karpelowsky

2021

Biopreservation and Biobanking

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Liquid biopsy is rapidly gaining traction for potentially revolutionizing cancer diagnosis and treatment through blood-based utilization of shed biomolecules. This approach can provide a global picture of the cancer in real time, at multiple time points, and with minimal invasiveness. In this review, we familiarize cancer biobanks with the principles used for liquid biopsy work and highlight unique aspects of applying liquid biopsy approaches to pediatric cancers to enable high-quality and efficient translational research.

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“…As renal tumor biopsies are not routinely performed due to risk of rupture, genomic profiling of kidney tumor markers in the blood may be useful for guiding cancer-specific therapies ( Van Paemel et al, 2020 ). Data from a prospective observational study of three patients showed that ctDNA in longitudinal samples could predict treatment response, however, the authors did not conclude whether ctDNA negativity was due to a fully resected disease or eradication of MRD ( Kahana-Edwin et al, 2020 ). Therefore, further prospective studies that include patients who have relapsed or present with low levels of MRD are required to investigate the potential impact of ctDNA analysis for these clinical applications.…”

Section: Clinical Value Of Circulating Tumor Dna Analysis For Pediatr...mentioning

confidence: 98%

Circulating Tumor DNA in Pediatric Cancer

Doculara

Trahair

Bayat

et al. 2022

Front. Mol. Biosci.

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The measurement of circulating tumor DNA (ctDNA) has gained increasing prominence as a minimally invasive tool for the detection of cancer-specific markers in plasma. In adult cancers, ctDNA detection has shown value for disease-monitoring applications including tumor mutation profiling, risk stratification, relapse prediction, and treatment response evaluation. To date, there are ctDNA tests used as companion diagnostics for adult cancers and it is not understood why the same cannot be said about childhood cancer, despite the marked differences between adult and pediatric oncology. In this review, we discuss the current understanding of ctDNA as a disease monitoring biomarker in the context of pediatric malignancies, including the challenges associated with ctDNA detection in liquid biopsies. The data and conclusions from pediatric cancer studies of ctDNA are summarized, highlighting treatment response, disease monitoring and the detection of subclonal disease as applications of ctDNA. While the data from retrospective studies highlight the potential of ctDNA, large clinical trials are required for ctDNA analysis for routine clinical use in pediatric cancers. We outline the requirements for the standardization of ctDNA detection in pediatric cancers, including sample handling and reproducibility of results. With better understanding of the advantages and limitations of ctDNA and improved detection methods, ctDNA analysis may become the standard of care for patient monitoring in childhood cancers.

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Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma

Cited by 8 publications

References 23 publications

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

Roadmap to Liquid Biopsy Biobanking from Pediatric Cancers–Challenges and Opportunities

Circulating Tumor DNA in Pediatric Cancer

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