Integrated Molecular Analysis Reveals 2 Distinct Subtypes of Pure Seminoma of the Testis

Abstract

Objective: Testicular germ cell tumors (TGCT) are the most common solid malignancy in adolescent and young men, with a rising incidence over the past 20 years. Overall, TGCTs are second in terms of the average life years lost per person dying of cancer, and clinical therapeutics without adverse long-term side effects are lacking. Platinum-based regimens for TGCTs have heterogeneous outcomes even within the same histotype that frequently leads to under- and over-treatment. Understanding of molecular differences that lead to diverse outcomes of TGCT patients may improve current treatment approaches. Seminoma is the most common subtype of TGCTs, which can either be pure or present in combination with other histotypes. Methods: Here we conducted a computational study of 64 pure seminoma samples from The Cancer Genome Atlas, applied consensus clustering approach to their transcriptomic data and revealed 2 clinically relevant seminoma subtypes: seminoma subtype 1 and 2. Results: Our analysis identified significant differences in pluripotency stage, activity of double stranded DNA breaks repair mechanisms, rates of loss of heterozygosity, and expression of lncRNA responsible for cisplatin resistance between the subtypes. Seminoma subtype 1 is characterized by higher pluripotency state, while subtype 2 showed attributes of reprograming into non-seminomatous TGCT. The seminoma subtypes we identified may provide a molecular underpinning for variable responses to chemotherapy and radiation. Conclusion: Translating our findings into clinical care may help improve risk stratification of seminoma, decrease overtreatment rates, and increase long-term quality of life for TGCT survivors.

Updating germ cell tumour pathogenesis – the ability of seminomas for FOXA2‐driven extra‐embryonic differentiation

“…Very recently, Medvedev et al 15 identified from the TCGA GCT cohort two subtypes of seminomas, i. e. subtype 1 with a high level of pluripotency, while subtype 2 showed attributes of reprogramming into a non-seminoma. Correlating the samples grouped into subtype 2 by Medvedev et al 15 to the seminoma samples with detectable FOXA2 expression identified in this study (Supporting information, Figure S1) shows that five of the eight (62.5%) FOXA2 + seminomas were grouped to subtype 2 (2G-AAHA, 2G-AAHN, ZM-AA0F, ZM-AA06, XE-AA0L) by Medvedev (2 to subtype 1 (XE-A9SE, YU-A912); 1 was not grouped (2G-AAG9)). Thus, the FOXA2 + seminoma identified in this study and the seminoma of subtype 2 from the Medvedev study might represent a similar subtype prone to differentiate into YST.…”

“…Very recently, Medvedev et al 15 . identified from the TCGA GCT cohort two subtypes of seminomas, i. e. subtype 1 with a high level of pluripotency, while subtype 2 showed attributes of reprogramming into a non‐seminoma.…”

Immune-related mechanisms and immunotherapy in extragonadal germ cell tumors

“…Clinically, Tregs have been shown to be closely associated with tumor staging and prognosis, and removal of Tregs can evoke effective anti-tumor immunity by eliminating the immune response to syngeneic tumors. In addition, myeloid-derived suppressor cells (MDSCs) are also widely present in peripheral blood and tumor tissues of EGCT patients ( 30 ). These cells include immature macrophages, granulocytes, dendritic cells (DCs), and so on.…”

Deep learning for subtypes identification of pure seminoma of the testis

“…After undergoing chemotherapy, patients with TGCT exhibited a decrease of 3.6 dB in hearing for each additional 100 mg/m2 of cumulative cisplatin dose 8,9 . Relapse occurs in approximately 20% of seminoma cases, and the underlying reasons for this phenomenon remain unclear 10 , however there are several well-known seminoma risk factors such as rete testis, lymphovascular invasion, cryptorchidism, mutations in KRAS and KIT genes 11,12 . Patients experiencing a relapse will receive further treatment involving chemotherapy and radiation therapy, which intensify the side effects considerably.…”

“…Patients experiencing a relapse will receive further treatment involving chemotherapy and radiation therapy, which intensify the side effects considerably. Recently we discovered two distinct subtypes of pure seminoma of the testis based on omics data 13,14 . Two identified seminoma subtypes revealed significant differences in the rates of loss of heterozygosity, the level of expression of lncRNA associated with cisplatin resistance, the activity of double stranded DNA breaks repair mechanisms and the pluripotency stage.…”