TERT gene fusions characterize a subset of metastatic Leydig cell tumors

Abstract

Objective: Metastatic Leydig cell tumors (LCT) are rare, difficult to treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. Patients and Methods: Twenty-nine LCT (27 male and 2 female patients) were profiled using NGS and immunohistochemistry. Results: TERT gene fusions were detected only in testicular metastatic Leydig cell tumors, in three of seven successfully analyzed cases (RMST:TERT, LDLR:TERT and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in one metastatic tumor without a TERT fusion. Five primary (four testicular and one ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1 and SS18 genes. At the protein level, 4/7 metastatic and 6/10 primary testicular LCTs over-expressed TOP1. Androgen receptor (AR) was overexpressed in 10/13 primary testicular tumors and 2/5 metastatic testicular LCT (without detectable ARv7 mRNA or ARv7 protein). Only one metastatic testicular LCT exhibited high TMB while all tested cases were MSI stable and did not express PD-L1. Conclusions: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic Leydig cell tumors. TOP1 and AR may guide decisions on chemo- and/or hormone therapy for selected individual patients.