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Extracellular vesicle miRNA predict FDG-PET status in patients with classical Hodgkin Lymphoma
Esther E E Drees1, Margaretha G M Roemer1, Nils J Groenewegen1,2
1Department of Pathology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands.
Abstract:
Minimally-invasive tools to assess tumour presence and burden may improve clinical management. FDG-PET (metabolic) imaging is the current gold standard for interim response assessment in patients with classical Hodgkin Lymphoma (cHL), but this technique cannot be repeated frequently. Here we show that microRNAs (miRNA) associated with tumour-secreted extracellular vesicles (EVs) in the circulation of cHL patients may improve response assessment. Small RNA sequencing and qRT-PCR reveal that the relative abundance of cHL-expressed miRNAs, miR-127-3p, miR-155-5p, miR-21-5p, miR-24-3p and let-7a-5p is up to hundred-fold increased in plasma EVs of cHL patients pre-treatment when compared to complete metabolic responders (CMR). Notably, in partial responders (PR) or treatment-refractory cases (n = 10) the EV-miRNA levels remain elevated. In comparison, tumour specific copy number variations (CNV) were detected in cell-free DNA of 8 out of 10 newly diagnosed cHL patients but not in patients with PR. Combining EV-miR-127-3p and/or EV-let-7a-5p levels, with serum TARC (a validated protein cHL biomarker), increases the accuracy for predicting PET-status (n = 129) to an area under the curve of 0.93 (CI: 0.87-0.99), 93.5% sensitivity, 83.8/85.0% specificity and a negative predictive value of 96%. Thus the level of tumour-associated miRNAs in plasma EVs is predictive of metabolic tumour activity in cHL patients. Our findings suggest that plasma EV-miRNA are useful for detection of small residual lesions and may be applied as serial response prediction tool.
Insights
New minimally-invasive tests using microRNAs (miRNAs) from extracellular vesicles (EVs) in blood show promise for monitoring classical Hodgkin Lymphoma (cHL) treatment response. These EV-miRNAs can help detect residual disease and predict treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Assessing treatment response in classical Hodgkin Lymphoma (cHL) is crucial for patient management.
- Current methods like FDG-PET scans are effective but cannot be frequently repeated.
- There is a need for minimally-invasive, serial monitoring tools for cHL.
Purpose of the Study:
- To investigate the potential of circulating tumor-secreted microRNAs (miRNAs) within extracellular vesicles (EVs) as biomarkers for assessing treatment response in cHL.
- To evaluate the diagnostic and predictive accuracy of EV-miRNAs, alone and in combination with other biomarkers, for predicting metabolic tumor activity.
Main Methods:
- Small RNA sequencing and quantitative reverse transcription PCR (qRT-PCR) were used to analyze miRNA abundance in plasma EVs from cHL patients.
- Levels of specific miRNAs (miR-127-3p, miR-155-5p, miR-21-5p, miR-24-3p, let-7a-5p) were compared between pre-treatment, complete metabolic responders (CMR), partial responders (PR), and treatment-refractory cHL patients.
- Tumor-specific copy number variations (CNVs) in cell-free DNA were also assessed.
- The predictive accuracy of EV-miRNA levels, combined with serum TARC, for PET-status was determined using ROC analysis.
Main Results:
- Pre-treatment plasma EV levels of specific cHL-associated miRNAs were significantly elevated (up to 100-fold) in cHL patients compared to CMR.
- Elevated EV-miRNA levels persisted in PR or treatment-refractory cases.
- Tumor-specific CNVs were detected in most newly diagnosed cHL patients but not in PR.
- Combining EV-miR-127-3p and/or EV-let-7a-5p with serum TARC achieved high accuracy (AUC 0.93) in predicting PET-status.
Conclusions:
- Circulating tumor-associated miRNAs within plasma EVs are indicative of metabolic tumor activity in cHL patients.
- Plasma EV-miRNAs show potential for detecting small residual lesions and can serve as a serial response prediction tool.
- This approach may enhance the clinical management of cHL by providing a non-invasive method for monitoring treatment efficacy.
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