Testicular germ cell tumor: a comprehensive review

Abstract

Testicular tumors are the most common tumors in adolescent and young men and germ cell tumors (TGCTs) account for most of all testicular cancers. Increasing incidence of TGCTs among males provides strong motivation to understand its biological and genetic basis. Gains of chromosome arm 12p and aneuploidy are nearly universal in TGCTs, but TGCTs have low point mutation rate. It is thought that TGCTs develop from premalignant intratubular germ cell neoplasia that is believed to arise from the failure of normal maturation of gonocytes during fetal or postnatal development. Progression toward invasive TGCTs (seminoma and nonseminoma) then occurs after puberty. Both inherited genetic factors and environmental risk factors emerge as important contributors to TGCT susceptibility. Genome-wide association studies have so far identified more than 30 risk loci for TGCTs, suggesting that a polygenic model fits better with the genetic landscape of the disease. Despite high cure rates because of its particular sensitivity to platinum-based chemotherapy, exploration of mechanisms underlying the occurrence, progression, metastasis, recurrence, chemotherapeutic resistance, early diagnosis and optional clinical therapeutics without long-term side effects are urgently needed to reduce the cancer burden in this underserved age group. Herein, we present an up-to-date review on clinical challenges, origin and progression, risk factors, TGCT mouse models, serum diagnostic markers, resistance mechanisms, miRNA regulation, and database resources of TGCTs. We appeal that more attention should be paid to the basic research and clinical diagnosis and treatment of TGCTs.

Keywords: Database; MiRNA; Mouse models; Platinum resistance; Risk factors; Serum makers; Spermatogenesis; Teratoma.

Fig. 1

Model of normal spermatogenesis and occurrence of TGCTs. Spermatogenesis is a tightly regulated process of the continuous supply of spermatozoa. Differentiation of primordial germ cells (PGCs) into gonocytes, self-renewal and differentiation of spermatogonial stem cells, and subsequent commitment to meiotic spermatocytes and haploid round/elongating spermatids are the key events of spermatogenesis. Under pathological conditions, gonocytes that fail to undergo correct spermatogenic differentiation, but develop into intratubular germ cell neoplasia (IGCN) or carcinoma in situ (CIS) represent the precursor cells for TGCTs during early stage of germline development. CIS can further progress into invasive seminoma (S) and (or then) nonseminoma, including undifferentiated EC, as well as differentiated teratoma (TE), choriocarcinoma (CH) and yolk sac tumor (YST)

Fig. 2

The current known TGCT susceptibility loci that have been identified through GWAS. Single nucleotide polymorphisms, locus on chromosome (Chr) and candidate gene or genes are listed

Fig. 3

GEO datasets representing a community resource to study TGCTs. a The dataset GSE1818 is particularly useful for comparisons between various histological subtypes of TGCTs versus each other or versus normal testis. b DEGs between relapsed and non-relapsed TGCTs are obtained by analyzing GSE99420. c Noel et al. provided an expression profiling of parental and cisplatin-resistant TGCT cell lines under accession no. GSE14231

Fig. 4

An example of data analysis using TCGA and cBioPortal. MiRNA profiling data of 31 patients with EC and 69 patients with seminoma was extracted from the TCGA database and DEGs were analyzed. Notably, miR-515 family that lists between DPRX and NLRP12 gene in Chr 19 accounts for approximately 55% of predominantly expressed genes in ECs