MicroRNA-371a-3p as a serum biomarker for the early detection of recurrences in patients with testicular germ cell tumors

Abstract

Testicular cancer represents a relatively rare neoplasia, accounting for 1.6% of all male cancer cases. However, it is one of the most common malignant diseases among young men aged between 15 and 40 years. Currently, about more than 4,000 men are diagnosed with testicular cancer in Germany each year. The first-line treatment for stage I GCT patients is surgical removal of the affected testicle, followed by active surveillance, which is often preferred over adjuvant chemotherapy to avoid overtreatment and minimize long-term side effects. After treatment is completed, follow-up care is crucial to detect cancer recurrence early. The recurrence rate during surveillance ranges from 15% to 20% for CSI seminoma, whereas for non-seminomas, the recurrence rate varies depending on risk factors, ranging from 15% to 50%. Tumor markers play an essential role in both diagnosis and follow-up. However, classical tumor markers face limitations due to their low sensitivity and specificity, with only 60% of all patients showing elevated levels of these markers at initial diagnosis. Thus, additional imaging modalities such as CT or MRI a required during follow-up. However, the use of CT scans is associated with radiation exposure in this young patient population. Therefore, additional markers are urgently needed for the early detection of recurrences in TGCT patients. Recently, microRNAs of the miR-371~373 cluster have been proposed as reliable serum markers for GCTs. MicroRNAs are short, single-stranded, non-coding RNAs between 18 and 24 nucleotides long. Among the three microRNAs of the miR-371~373 cluster (miR-371a-3p, miR-372-3p, and miR-373-3p), miR-371a-3p (M371) demonstrated the most favorable performance with higher specificity and sensitivity compared to traditional serum tumor markers. The aim of this study was to evaluate the utility of M371 as a serum biomarker for the early detection of recurrences in CS1 patients with GCTs during active surveillance in a prospective long-term study. The results of the miRNA expression studies that were conducted to answer this question were published in five scientific reports, which are presented within this thesis. In the last and main study, the utility of M371 in detecting relapses in patients with clinical stage I TGCTs was evaluated, with a focus on accuracy and earlier relapse detection than traditional methods. Results showed that among the 258 GCT patients, 39 relapsed during the follow-up period of up to 48 months. All of these relapses were detected using the M371 test, emphasizing its potential as a highly sensitive biomarker for recurrence detection. The M371 test revealed impressive diagnostic characteristics with an area under the ROC curve of 0.993, sensitivity of 100% and specificity of 96.3%, thus outperforming the classical serum markers for TGCTs. Findings also demonstrated that relapses were detected earlier with the M371 test in 28% of cases. The M371 test showed superior sensitivity and specificity for detecting relapses in CSI GCTs compared to classical tumor markers. Overall, the results show, that the M371 test holds promise for integration into clinical follow-up protocols, potentially leading to more effective and cost-efficient approaches, by reducing the need for frequent imaging scans and minimizing ionizing radiation exposure in young patient population.