Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

Abstract

The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at −245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

“…In our cohort of TGCT patients, we recently reported that well‐known hallmarks of cancer, as microsatellite instability (MSI), V600E BRAF , and TERT promoter mutations, are not present (Carcano et al ., ,b). Recently, Bagrodia et al .…”

Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis

“…Recurrent mutations in the death-associated protein (DAXX) and the alphathalassemia X-linked protein (ATRX) have been correlated with ALT occurrence and potentially contribute to ALT maintenance 33,34 . Of note, there is evidence that telomerase activity supresses ALT, although the suppressive mechanism is yet to be identified [34][35][36][37][38][39][40][41][42][43][44][45][46][47] . In a comprehensive analysis of 6,110 human tumour specimens from various cancer types, ALT was observed in only ~4% of samples 48 .…”

“…Please provide further evidence to back up your statement. ] By contrast, the absence of TERT promoter mutations in cancers arising from highly proliferative tissues with a stem cell compartment 38,132 . [Au:Please add examples and reference.]…”

Telomerase: The Devil Inside

“…The most noticeable conclusion from these findings is that, irrespective of the reactivation mechanism, the data support the idea that at least a subset of tumors originate from an initially telomerase negative cell. Remarkably, hTERT promoter mutations are frequently detected in cancers with low self-renewal rates [55,56,57,58,59,60,61,62] whereas they are extremely rare in tumors originating from highly proliferating tissues [63,64,65]. We suggest that hTERT promoter mutations may account for both reactivation concepts 1 and 2.…”

“…On the other hand, other tumor entities have a low frequency or no hTERT promoter mutations which are described up to the recent date, including testicular germ cell tumors, colorectal adenocarcinoma, pancreatic cancer, papillary thyroid cancers, and most types of leukemia [63,64,65] despite high telomerase activity in these tumors [66,67,68]. These observations indicate that other mechanisms, e.g., loss of negative regulatory factors or chromatin remodeling may be responsible for telomerase reactivation in the tumor types (e.g., loss of suppression: see above).…”