1541 - TERT gene fusions characterize a subset of metastatic Leydig cell tumors

Background

Metastatic Leydig cells tumours (LCT) are rare, difficult to treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed 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 LCT.

Methods

20 LCT (7 metastatic and 13 primary tumours) from 3 participating institutions (Caris Life Sciences, Phoenix, USA; Clinical Hospital Center, Zagreb, Croatia and Biopticka Laborator, Plzen, Czech Republic) were analyzed using massively parallel DNA and RNA sequencing (NGS) approach. Immunohistochemistry (IHC) was used for detection of selected protein biomarkers.

Results

TERT gene fusions were detected only in metastatic Leydig cell tumours, in three of 5 successfully analyzed cases (RMST:TERT, LDLR:TERT and B4GALT5:TERT, respectively). The case with B4GALT5:TERT fusion also showed amplifications (>6 copies) of TOP1 and CCND3 genes. TP53 mutation (M246I) was detected in one metastatic tumour without TERT fusion. No gene fusions were found in any primary tumours (0/8 successfully analyzed). 3/6 primary tumours showed multiple gene amplifications, without a consistent pattern. At the protein level (IHC) 5/7 metastatic and 6/7 primary tumours over-expressed TOP1. Full length androgen receptor (AR) was overexpressed in 7/8 primary tumours (without detectable ARv7 mRNA or ARv7 protein), but only in 1 of 5 metastatic LCT. No tumours exhibited high tumour mutational burden, microsatellite instability nor expressed PD-L1 in tumour cells.

Conclusions

Our study for the first time identified TERT gene fusions as a main/sole detected genetic alteration and a potential therapeutic target in malignant, metastatic Leydig cell tumours. Additional biomarkers (TOP1 amplification and over-expression) may help guide decisions on chemotherapy for selected individual patients. Androgen receptor blockade may be considered in AR overexpressing tumours without evidence of ARv7 presence.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Caris Life Sciences.

Funding

Caris Life Sciences.

Disclosure

Z. Gatalica: Leadership role: Caris Life Sciences. J. Xiu: Leadership role, employment: Caris Life Sciences. J. Swensen: Leadership role, employment: Caris Life Sciences. All other authors have declared no conflicts of interest.