MicroRNA miR-371a-3p Levels a Promising Biomarker in Testicular Germ Cell Tumors

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Circulating microRNA miR-371a-3p levels appear to be a promising biomarker of tumor bulk in testicular germ cell tumors.
Circulating microRNA miR-371a-3p levels appear to be a promising biomarker of tumor bulk in testicular germ cell tumors.

ORLANDO—Circulating microRNA miR-371a-3p levels appear to be a promising biomarker of tumor bulk in men diagnosed with testicular germ cell tumors (GCTs), according to a study (Abstract 376) presented during the 2015 Genitourinary Cancers Symposium.1

“Serum levels of microRNA miR-371a-3p appear to comprise of all attributes of a valuable serum biomarker of germ cell tumors,” reported lead study author Klaus-Peter Dieckmann, MD, of the Department of Urology, Albertinen-Krankenhaus Hamburg in Hamburg, Germany. “This marker is also expressed in seminoma and it apparently outperforms the classical markers. Evaluation in a large scale multicentric study is warranted.”

The finding shows promise as part of the solution to a key dilemma in managing this type of malignancy, Dr. Dieckmann said. The management of GCT “is largely based on marker monitoring but only 60% of patients express the classical markers AFP and beta HCG,” he explained. “Very clearly, more and better biomarkers are needed.”

MicroRNAs are one avenue of exploration for new prognostic GCT biomarkers, he said. MicroRNAs are approximately 20 base pairs long, and are released from the tumor cell nucleus to enter body fluids, where they can persist and be quantified using polymerase chain reaction (PCR) techniques.

“We measured serum levels of microRNA miR-371a-3p (miR-371) in GCT patients with the aim of establishing a new biomarker,” Dr. Dieckmann said.

He and his coauthors examined serum samples from 84 patients diagnosed with GCT (51 seminoma; 33 nonseminoma) for miR-371a-3p before and after treatment using quantitative PCR. “Over 90% of all patients had higher serum levels of miR-371a-3p than controls,” Dr. Dieckmann reported. “After treatment, all elevated levels decreased to the normal range.”

Unfortunately, 4 patients with teratomas did not express miR-371a-3p, he noted.

Serum levels “appear to correlate with tumor bulk” except in teratomas, he reported. All patients with metastatic disease had significantly higher mean levels of miR-371a-3p than did patients with stage 1 disease.

Furthermore, levels dropped rapidly postoperatively. After orchiectomy in stage 1 cases, serum levels dropped by 90% within 24 hours. Nonseminomas had higher mean levels than seminomas.  “It was a very rapid decline,” Dr. Dieckmann said. “Most patients saw complete clearance after 5 days. Clinically, miR-371 levels correlate with response to treatment.”

Similarly, levels decreased with each cycle of chemotherapy, reflecting tumor bulk, he noted.  “Levels were in the normal range after completion of [chemo-]therapy,” he said.

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To confirm that GCTs are the source of elevated blood levels of miR 371a-3p, the researchers examined fluids surrounding the tumors, from testicular vein blood, and from peripheral blood.

“Many-fold higher” levels in testicular vein blood and tumor-surrounding hydroceles than patients' peripheral blood strongly suggests that tumors are indeed the source of the elevated miR 371 levels seen in patients with GCT, he said.

“miR 371 comprises all the features of a good tumor marker,” he concluded: “it is expressed in more than 90% of GCT patients, and is seen in seminoma but not teratoma. It is specific for GCT. Serum levels correlate with clinical stage (tumor bulk) and we see a rapid decrease after treatment.”

But while miR 371a-3p exhibits sensitivity, specificity, acceptability to patients (because it involves a simple blood draw), and disappears with effective treatment, it has yet to be validated in a prospective large clinical trial, cautioned Darren R. Feldman, MD, of the Memorial Sloan Kettering Cancer Center in New York, NY, who was asked to comment on the study after Dr. Dieckmann's presentation. Nor is it yet clear that it is a standardized, reproducible assay, can provide rapid turn-around at low cost, or reappears early as an indicator of relapse—other important criteria for “ideal biomarkers,” he said.

Describing miRNA 371a-3p as “a promising new biomarker in GCT, particularly for early-stage patients,” Dr. Feldman emphasized that much more work is still needed before this marker is ready for routine clinical use, including evaluation in more patients with advanced-stage tumors and evaluation of its ability to detect relapse. “Further work is warranted,” he concluded.

“Does the rate of decline vary with the degree of treatment response,” Dr. Feldman asked. “Could this test be used to detect poor responders? What is the biological relevance of miRNA 371a-3p? Is it sufficient or optimal itself, or should it be combined with other miRNAs?”

Reference

  1. Dieckmann K-P, Spiekermann M, Ruf CG, et al. Is measuring serum levels of microRNA miR-371a-3p superior to the classical biomarkers of testicular germ cell tumors? 2015 Genitourinary Cancers Symposium. Abstract 376.

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