Genomic Evaluation of Testicular Germ Cell Tumors and its Role in Treatment Planning

Testicular germ cell tumors (TGCTs) have an incidence of up to 10.5 in 100,000 men and are the most common solid tumors affecting the young male population (1). In fact, although testicular cancers are a rare cancer type, it is worrying that the incidence of testicular cancer has doubled in the past 30 years according to statistical analyses in countries such as the USA and UK (1,2). Almost all primary testicular tumors (95%) are TGCT, while the remaining minority includes nongerminal neoplasms such as Leydig cell tumors, Sertoli cell tumors, or lymphomas. These tumors are comprised of seminomas, which account for approximately 50% of cases and are derived from undifferentiated primordial germ cells, and nonseminomas, which constitute approximately 40% of cases and exhibit different stages of differentiation. The other 10% of cases show mixed histology (3). Seminomas and nonseminomas are derived from both gonadal and extragonadal anatomic sites and have distinct biological and metastatic properties. Nonseminoma germ cell tumors include embryonic and extraembryonic components and are classified as embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma (3,4). Mortality due to testicular cancer is very low. The main reason for this is the high success rates in the treatment of lowand moderate-risk testicular cancer. Treatment success depends on careful grading during diagnosis, initiation of chemotherapy, as well as effective early treatment with radiotherapy and surgery if necessary, followed by fairly good follow-up. TGCT patients are treated with radiotherapy or chemotherapy depending on histological type and tumor stage after surgery. Nonseminoma germ cell tumors are more aggressive in terms of early spread, have poorer prognosis in advanced stage disease, and are sensitive to platinum-based combination chemotherapy but less responsive to radiation, except for teratomas. In contrast, seminomas have a good prognosis and are highly sensitivity to both chemotherapy and radiation (5). Despite their differences in morphology and time of appearance, recent genome-wide association studies (GWAS) have shown that seminomas and nonseminomas share a common molecular pathogenetic process. Both seminoma and nonseminoma tumors are believed to be derived from carcinoma in situ (CIS), also known as intratubular germ cell neoplasia (ITGCN), where the generation and expansion of tumor cells is restricted in the seminiferous tubules. ITGCN is a precursor lesion often visualized close to invasive TGCT (6,7). The incidence of testicular germ cell tumors (TGCT) has significantly increased over the last 40 years and continues to increase among the young male population. The geographical differences show that a combination of genetic and environmental factors play a role in the pathogenesis of TGCT. However, since the actual mechanisms involved in the development of this disease have still not been fully explained, studies at the genomic level have gained importance. Although TGCTs respond well to chemotherapy, 20-30% of patients display classical chemotherapy resistance. There exists a need for detailed investigation of the molecular mechanisms responsible for such resistance. In this review, we briefly discussed the current information on some risk factors and genomic factors involved in the development of TGCTs.