PI: Prof.dr. Leendert Looijenga
Germ Cell Tumors (GCT) are considered to be highly heterogeneous and complex, both regarding origin, histological constitution as well as clinical behavior. Investigations on normal developmental processes related to germ cell and gonadal formation and maturation combined with integrated and omics-based studies on germ cell tumors, stimulated novel and clinically relevant insights. This resulted in a modified classification system, currently recommended by the WHO (World Health Organization, 2016), including application of diagnostic tools. Current studies will further elucidate the mechanism(s) responsible for their origin and clinical behavior, including their overall sensitivity to systematic treatment and the exceptional resistance. This will allow optimal treatment of the individual patient with minimal (long term) side effects.
Informative liquid biopsy biomarkers are highly instructive for the diagnosis and follow-up of patients with a germ cell tumor. Currently the proteins AFP and hCG and to a lesser extend LDH are applied and found to be relevant in a clinical setting. However, they have significant limitations due to false negative and positive findings. We demonstrated that a defined (embryonic) set of small noncoding RNA (i.e., microRNAs) are highly informative as serum/plasma and cerebrospinal fluid molecular biomarker for malignant germ cell tumors. In addition, these miRNAs are informative to detect undifferentiated (and potentially malignant) elements in Induced Pluripotent Stem Cell (IPSC) and Embryonic Stem Cell (ESC) derivatives, potentially used for regenerative medicine. Current studies are performed to clinically implement the embryonic miRNA as molecular biomarkers for the optimal diagnosis and treatment of patients with germ cell tumors. In addition, it is investigated whether a similar approach will also be applicable for other cancer types as well.
Dorssers LCJ, Gillis AJM, Stoop H, van Marion R, Nieboer MM, van Riet J, van de Werken HJG, Oosterhuis JW, de Ridder J, Looijenga LHJ. Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development, Br J Cancer. 2019 Feb 11. doi: 10.1038/s41416-019-0381-1 PubMed PMID: 30739914
Lobo J, Gillis AJM, Jerónimo C, Henrique R, Looijenga LHJ. Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic, Int J Mol Sci. 2019 Jan 10;20(2). pii: E258. doi: 10.3390/ijms20020258. Review. PubMed PMID: 30634670
Salvatori DCF, Dorssers LCJ, Gillis AJM, Perretta G, van Agthoven T, Gomes Fernandes M, Stoop H, Prins JB, Oosterhuis JW, Mummery C, Looijenga LHJ. The MicroRNA-371 Family as Plasma Biomarkers for Monitoring Undifferentiated and Potentially Malignant Human Pluripotent Stem Cells in Teratoma Assays, Stem Cell Reports. 2018 Dec 11;11(6):1493-1505. doi: 10.1016/j.stemcr.2018.11.002. Epub 2018 Nov 29. PubMed PMID: 30503260
Nieboer MM, Dorssers LCJ, Straver R, Looijenga LHJ, de Ridder J. TargetClone: A multi-sample approach for reconstructing subclonal evolution of tumors, PLoS One. 2018 Nov 29;13(11):e0208002. doi: 10.1371/journal.pone.0208002. eCollection 2018. PubMed PMID: 30496231
Cheng L, Albers P, Berney DM, Feldman DR, Daugaard G, Gilligan T, Looijenga LHJ. Testicular cancer. (2018) Nat Rev Dis Primers. Oct 5; 4(1): 29-53. doi: 10.1038/s41572-018-0029-0. PubMed PMID: 30291251
Leão R, van Agthoven T, Figueiredo A, Jewett MAS, Fadaak K, Sweet J, Ahmad AE, Anson-Cartwright L, Chung P, Hansen A, Warde P, Castelo-Branco P, O'Malley M, Bedard PL, Looijenga LHJ, Hamilton RJ. Serum miRNA Predicts Viable Disease after Chemotherapy in Patients with Testicular Nonseminoma Germ Cell Tumor. (2018) J Urol. 200(1):126-135. doi: 10.1016/j.juro.2018.02.068. Epub 2018 Feb 21. PubMed PMID: 29474847
Spoor JA, Oosterhuis JW, Hersmus R, Biermann K, Wolffenbuttel KP, Cools M, Kazmi Z, Ahmed SF, Looijenga LHJ. Histological Assessment of Gonads in DSD: Relevance for Clinical Management. (2018) Sex Dev. 12(1-3):106-122. doi: 10.1159/000481757. Epub 2017 Nov 3. PubMed PMID: 29131109
Cools M, Wolffenbuttel KP, Hersmus R, Mendonca BB, Kaprová J, Drop SLS, Stoop H, Gillis AJM, Oosterhuis JW, Costa EMF, Domenice S, Nishi MY, Wunsch L, Quigley CA, T'Sjoen G, Looijenga LHJ. Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling. (2017) Hum Reprod. 32(12):2561-2573. doi: 10.1093/humrep/dex300. PubMed PMID: 29121256
Killian JK, Dorssers LC, Trabert B, Gillis AJ, Cook MB, Wang Y, Waterfall JJ, Stevenson H, Smith WI Jr, Noyes N, Retnakumar P, Stoop JH, Oosterhuis JW, Meltzer PS, McGlynn KA, Looijenga LHJ. Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors. (2016) Genome Res. 26(11):1490-1504. Epub 2016 Oct 20. PubMed PMID: 27803193