Clinical utility of circulating microRNAs in malignant germ cell tumours


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Matthew Murray1,Nicholas Coleman1
1University of Cambridge, Cambridge, UK

Abstract

Background

The protein biomarkers AFP/HCG have limited sensitivity/specificity for diagnosing malignant germ-cell-tumours (GCTs). We previously showed that microRNAs from the miR-371-373 and miR-302/367 clusters are universally overexpressed in all malignant GCT tissues, regardless of patient age, tumour site or histological subtype, but are not co-ordinately over-expressed in any other cancer type or disease state. Here we provide an overview of our research studying these microRNAs as GCT biomarkers and consider prospects for future clinical applications.

Method

We have developed a highly sensitive pre-amplified qRT-PCR technique for robust detection of microRNAs from the miR-371-373 and miR-302/367 clusters in biospecimens. Our method has been adopted by multiple other groups internationally and validated in over 2,000 patients. Our pipeline includes quality control checks, use of an exogenous spike-in control and normalisation against the endogenous microRNA miR-30b-5p, prior to data analysis. Cost analysis and patient/public involvement initiatives regarding acceptability of circulating microRNA testing are underway.

Results

Results from our group and others show that a four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) has high sensitivity/specificity for diagnosing malignant GCTs. Individually, miR-371a-3p shows the most utility as it is most dynamic and most accurately reflects disease activity. Levels of these microRNAs are useful for disease-monitoring and early detection of relapse.

Conclusion

Circulating microRNAs should improve future clinical management of patients with malignant GCTs. Potential benefits include: (i) reducing CT scans in follow-up, lowering cumulative radiation exposure to patients and offering cost savings to healthcare systems; (ii) identifying patients with apparent clinical stage I (CSI) seminoma who have persistently elevated serum microRNA levels post-orchidectomy, suggesting micrometastatic disease. Such patients may benefit from adjuvant chemotherapy to prevent subsequent recurrence. This approach will also prevent overtreatment of the majority of CSI patients who are not destined to relapse. Importantly, circulating microRNA testing appears highly acceptable to patients.