Role of Biomarkers in Germ Cell Tumors: Focus on microRNA371a-3p
Main Article Content
Abstract
Germ cell tumors (GCTs) are classified into seminomatous and non-seminomatous subtypes and are associated with distinct biomarkers that aid in diagnosis, risk stratification, and monitoring. While traditional serum markers such as AFP, HCG, and LDH have been mainstays in clinical practice, their limitations in sensitivity, especially in small-volume disease, have led to exploration of novel diagnostic tools. Immunohistochemical and molecular markers, including PLAP, OCT3/4, SOX17, SOX2, CD30, GPC3, SALL4, KIT mutations, and I 12p, support histological classification and prognosis. Among emerging biomarkers, microRNA-371a-3p stands out for its superior sensitivity and specificity, rapid serum clearance, and potential to detect minimal residual disease. Although it lacks utility in identifying teratomas, miR371a-3p shows promise in surveillance and early relapse detection, potentially reducing reliance on imaging. Ongoing trials are evaluating its clinical applicability. This review synthesizes current data on established and emerging biomarkers in GCTs, emphasizing the transformative potential of miR-371a-3p in disease management.
Article Details
How to Cite
GIMON, Raul Vera.
Role of Biomarkers in Germ Cell Tumors: Focus on microRNA371a-3p.
Medical Research Archives, [S.l.], v. 13, n. 9, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6833>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i9.6833.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. WHO Classification of Tumors (WHO Blue Book).
2. Bailey D, Marks A, Stratis M, Baumal R. Immunohistochemical staining of germ cell tumors and intratubular malignant germ cells of the testis using antibody to placental alkaline phosphatase and a monoclonal anti-seminoma antibody. Mod Pathol. 1991;4(2):167-171.
3. Cheng L. Establishing germ cell origin for metastatic tumors using OCT4 immunohistochemistry. Cancer. 2004;101(9):2006-2010.
4. Nonaka D. Differential expression of SOX2 and SOX17 in testicular germ cell tumors. Am J Clin Pathol. 2009;131(5):731-736.
5. Zynger DL, Dimov ND, Luan C, Teh BT, Yang XJ. Glypican 3: A novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30(12):1570-1575.
6. Pallesen G, Hamilton-Dutoit SJ. Ki-1 (CD30) antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol. 1988;133(3): 446-450.
7. Cao D, Li J, Guo CC, Allan RW, Humphrey PA. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009;33(7): 1065-1077.
8. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS. SALL4 expression in germ cell and non-germ cell tumors: A systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014;38(3):410-420.
9. Coffey J, Linger R, Pugh J, Dudakia D, et al. Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer. 2008;47(1):34-42.
10. Fichtner A, Richter A, Filmar S, et al. The detection of isochromosome i(12p) in malignant germ cell tumors by quantitative real-time PCR. Histopathology. 2021; 78:593-606.
11. Talerman A, Haije WG, Baggerman L. Serum alpha-fetoprotein in patients with germ cell tumors of the gonads and extragonadal sites. Cancer. 1980; 46(2):380-385.
12. Oldenburg J, Berney DM, Bokemeyer C, et al . ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(4):363-373.
13. Gilligan TD, Seidenfeld J, Basch EM, et al. American Society of Clinical Oncology clinical practice guideline on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol. 2010;28(20):3388-3404.
14. Albany C, Einhorn LH. Pitfalls in management of patients with germ cell tumors and slight elevation of serum -fetoprotein. J Clin Oncol. 2014;32(19): 2114-2115.
15. Myklebust MP, Thor A, Rosenlund B, et al. Serum miR-371a-3p in testicular germ cell cancer before and after orchiectomy. Sci Rep. 2021; 11: 15582.
16. Radtke A, Cremers JF, Kliesch S, et al. The novel biomarker of germ cell tumors, microRNA-371a-3p, has a very rapid decay in patients with clinical stage 1. Urol Int. 2018;100(4):470-475.
17. Dieckmann KP, Radtke A, Spiekermann M, et al Serum levels of microRNA miR-371a-3p: A sensitive and specific new biomarker for germ cell tumors. Eur Urol. 2017;71(2):213-220.
18. Dieckmann KP, Isbarn H, Grobelny F, et al. Primary tumor size in testicular neoplasms is closely related to histology, clinical staging, and tumor marker expression rates. Cancers (Basel). 2022;14 (21):5447.
19. Dieckmann KP, Radtke A, Geczi L, et al. Serum levels of microRNA-371a-3p as a new biomarker of testicular germ cell tumors: Results of a prospective multicenter study. J Clin Oncol. 2019;37(16):1412-1423.
20. Myklebust MP, Thor A, Benedikte R et al. Serum miR371 in testicular germ cell cancer before and after orchiectomy assessed by digital-droplet PCR in a prospective study. Sci Rep 202 Aug 2; 11: 15582.
21. Dieckmann KP, Dumlupinar C, et al. Serum microRNA-371a-3p and classical tumor markers in testicular neoplasms: a statistical analysis. J Cancer Res Clin Oncol. 2023; 149:7079-7090.
22. Laffin JT, Kenigsberg AP, Meng X, et al. Serum small RNA sequencing and miR-375 assay do not identify the presence of pure teratoma at post chemotherapy retroperitoneal lymph node dissection. Eur Urol. Open Sci. 2021; 26:83-87.
23. Belge G, Grobelny F, Matthies C, et al. Serum level of microRNA-375-3p is not a reliable biomarker of teratoma. In Vivo. 2020;34(1):163-168.
24. Nappi L, Thi M, Adra N, et al. Integrated expression of circulating miR-375 and miR-371 to identify teratoma and active germ cell malignancy components. Eur Urol. 2021;79(1):16-19.
25. Lobo J, Leo R, Gillis AJM, et al. Utility of serum miR-371a-3p in predicting relapses on surveillance in patients with clinical stage I testicular germ cell cancer. Eur Urol. Oncol. 2021;4(3):483-491.
26. Fankhauser CD, Christiansen AJ, Rothermundt C, et al. Detection of recurrences using serum miR-371a-3p during active surveillance in men with stage I testicular germ cell tumors. Br J Cancer. 2022;126(8):1140-1144.
27. Nappi L, Saxena N, Pautasso S, et al. Long-term follow-up analysis of plasma miR-371 expression to detect early relapses in patients with clinical stage I testicular germ cell tumors on surveillance. J Clin Oncol. 2023;41(16_suppl):5006.
28. Parizi M, Singla M, Daneshmand S, et al. Diagnostic efficacy of serum microRNAs in predicting pathology of retroperitoneal lymph node dissection in patients with testicular germ cell tumors: A systematic review and meta-analysis. World J Urol. 2025; 43:192.
29. Morup N, Rajpert-De Meyts E, Juul A, et al. Evaluation of circulating miRNA biomarkers of testicular tumors during therapy and follow-up: A Copenhagen experience. Cancers (Basel). 2020;12 (3):759.
30. Weiten R, Engler T, Schorle H, et al. The tumor biomarker miRNA-371a-3p influences cisplatin sensitivity of testicular germ cell tumor cell lines. J Mol Cell Med. 2024;28(24).
31. Ozgun G, Abdalvand N, Ozcan G, et al. Predicting teratoma histology in post chemotherapy residual lesions of non-seminoma testicular cancer (NSTC) patients using integrated CT radiomics and circulating MicroRNAs modelling. J Clin Oncol. 2025;43(16_suppl):5035. ASCO Annual Meeting Poster Session.
2. Bailey D, Marks A, Stratis M, Baumal R. Immunohistochemical staining of germ cell tumors and intratubular malignant germ cells of the testis using antibody to placental alkaline phosphatase and a monoclonal anti-seminoma antibody. Mod Pathol. 1991;4(2):167-171.
3. Cheng L. Establishing germ cell origin for metastatic tumors using OCT4 immunohistochemistry. Cancer. 2004;101(9):2006-2010.
4. Nonaka D. Differential expression of SOX2 and SOX17 in testicular germ cell tumors. Am J Clin Pathol. 2009;131(5):731-736.
5. Zynger DL, Dimov ND, Luan C, Teh BT, Yang XJ. Glypican 3: A novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30(12):1570-1575.
6. Pallesen G, Hamilton-Dutoit SJ. Ki-1 (CD30) antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol. 1988;133(3): 446-450.
7. Cao D, Li J, Guo CC, Allan RW, Humphrey PA. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009;33(7): 1065-1077.
8. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS. SALL4 expression in germ cell and non-germ cell tumors: A systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014;38(3):410-420.
9. Coffey J, Linger R, Pugh J, Dudakia D, et al. Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer. 2008;47(1):34-42.
10. Fichtner A, Richter A, Filmar S, et al. The detection of isochromosome i(12p) in malignant germ cell tumors by quantitative real-time PCR. Histopathology. 2021; 78:593-606.
11. Talerman A, Haije WG, Baggerman L. Serum alpha-fetoprotein in patients with germ cell tumors of the gonads and extragonadal sites. Cancer. 1980; 46(2):380-385.
12. Oldenburg J, Berney DM, Bokemeyer C, et al . ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(4):363-373.
13. Gilligan TD, Seidenfeld J, Basch EM, et al. American Society of Clinical Oncology clinical practice guideline on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol. 2010;28(20):3388-3404.
14. Albany C, Einhorn LH. Pitfalls in management of patients with germ cell tumors and slight elevation of serum -fetoprotein. J Clin Oncol. 2014;32(19): 2114-2115.
15. Myklebust MP, Thor A, Rosenlund B, et al. Serum miR-371a-3p in testicular germ cell cancer before and after orchiectomy. Sci Rep. 2021; 11: 15582.
16. Radtke A, Cremers JF, Kliesch S, et al. The novel biomarker of germ cell tumors, microRNA-371a-3p, has a very rapid decay in patients with clinical stage 1. Urol Int. 2018;100(4):470-475.
17. Dieckmann KP, Radtke A, Spiekermann M, et al Serum levels of microRNA miR-371a-3p: A sensitive and specific new biomarker for germ cell tumors. Eur Urol. 2017;71(2):213-220.
18. Dieckmann KP, Isbarn H, Grobelny F, et al. Primary tumor size in testicular neoplasms is closely related to histology, clinical staging, and tumor marker expression rates. Cancers (Basel). 2022;14 (21):5447.
19. Dieckmann KP, Radtke A, Geczi L, et al. Serum levels of microRNA-371a-3p as a new biomarker of testicular germ cell tumors: Results of a prospective multicenter study. J Clin Oncol. 2019;37(16):1412-1423.
20. Myklebust MP, Thor A, Benedikte R et al. Serum miR371 in testicular germ cell cancer before and after orchiectomy assessed by digital-droplet PCR in a prospective study. Sci Rep 202 Aug 2; 11: 15582.
21. Dieckmann KP, Dumlupinar C, et al. Serum microRNA-371a-3p and classical tumor markers in testicular neoplasms: a statistical analysis. J Cancer Res Clin Oncol. 2023; 149:7079-7090.
22. Laffin JT, Kenigsberg AP, Meng X, et al. Serum small RNA sequencing and miR-375 assay do not identify the presence of pure teratoma at post chemotherapy retroperitoneal lymph node dissection. Eur Urol. Open Sci. 2021; 26:83-87.
23. Belge G, Grobelny F, Matthies C, et al. Serum level of microRNA-375-3p is not a reliable biomarker of teratoma. In Vivo. 2020;34(1):163-168.
24. Nappi L, Thi M, Adra N, et al. Integrated expression of circulating miR-375 and miR-371 to identify teratoma and active germ cell malignancy components. Eur Urol. 2021;79(1):16-19.
25. Lobo J, Leo R, Gillis AJM, et al. Utility of serum miR-371a-3p in predicting relapses on surveillance in patients with clinical stage I testicular germ cell cancer. Eur Urol. Oncol. 2021;4(3):483-491.
26. Fankhauser CD, Christiansen AJ, Rothermundt C, et al. Detection of recurrences using serum miR-371a-3p during active surveillance in men with stage I testicular germ cell tumors. Br J Cancer. 2022;126(8):1140-1144.
27. Nappi L, Saxena N, Pautasso S, et al. Long-term follow-up analysis of plasma miR-371 expression to detect early relapses in patients with clinical stage I testicular germ cell tumors on surveillance. J Clin Oncol. 2023;41(16_suppl):5006.
28. Parizi M, Singla M, Daneshmand S, et al. Diagnostic efficacy of serum microRNAs in predicting pathology of retroperitoneal lymph node dissection in patients with testicular germ cell tumors: A systematic review and meta-analysis. World J Urol. 2025; 43:192.
29. Morup N, Rajpert-De Meyts E, Juul A, et al. Evaluation of circulating miRNA biomarkers of testicular tumors during therapy and follow-up: A Copenhagen experience. Cancers (Basel). 2020;12 (3):759.
30. Weiten R, Engler T, Schorle H, et al. The tumor biomarker miRNA-371a-3p influences cisplatin sensitivity of testicular germ cell tumor cell lines. J Mol Cell Med. 2024;28(24).
31. Ozgun G, Abdalvand N, Ozcan G, et al. Predicting teratoma histology in post chemotherapy residual lesions of non-seminoma testicular cancer (NSTC) patients using integrated CT radiomics and circulating MicroRNAs modelling. J Clin Oncol. 2025;43(16_suppl):5035. ASCO Annual Meeting Poster Session.