Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

Recent evidence has revealed the occurrence of an apoptotic phenotype in Saccharomyces cerevisiae that is inducible with oxidative stress. Here, exposure of S. cerevisiae to 20–200 mM acetic acid for 200 min at pH 3·0 resulted in cell death. Yeast mortality induced by 120–200 mM acid was not inhibited by cycloheximide and was accompanied by ultrastructural alterations typical of necrosis. In contrast, alterations associated with cell death induced by 20–80 mM acetic acid included: (i) cycloheximide-inhibitable chromatin condensation along the nuclear envelope; (ii) exposure of phosphatidylserine on the surface of the cytoplasmic membrane, revealed by the FITC–annexin V reaction; and (iii) the occurrence of DNA strand breaks, demonstrated by the TUNEL assay. These results show that a programmed cell death process sharing common features with an apoptotic phenotype can be induced by acetic acid in S. cerevisiae. This observation raises the possibility of this mode of cell death being more generalized in yeasts than previously considered and extended to cell death induced by other stress agents.

Oxyphil or Hürthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-β and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hürthle cell carcinomas. A germline mutation was detected in a Hürthle cell papillary carcinoma arising in a thyroid with multiple Hürthle cell nodules. No mutations were detected in any of the 20 non-Hürthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hürthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hürthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hürthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hürthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.