Recent evidence indicates that
RNA-dependent RNA polymerase (RdRP) activity of human
telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in
tumor formation in a telomere-independent manner. Non-canonical function of hTERT has been considered as a therapeutic target for
cancer therapy. We have previously shown that hTERT phosphorylation at
threonine 249 (p-hTERT), which promotes RdRP activity, is an
indicator of an aggressive phenotype and poor prognosis in liver and
pancreatic cancers, using two cohorts with small sample sizes with polyclonal p-hTERT antibody. To clarify the clinical relevance of p-hTERT, we developed a specific
monoclonal antibody and determined the diagnostic and prognostic value of p-hTERT in
cancer specimens using a large cohort. A
monoclonal antibody for phosphorylated hTERT (p-hTERT) at
threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of
formalin-fixed,
paraffin-embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and
kidney cancers. We detected elevated p-hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p-hTERT expression was an independent prognostic factor for lung, pancreatic, and
liver cancers. Furthermore, p-hTERT expression was associated with immature and aggressive features, such as
adenosquamous carcinoma (lung and pancreas), invasive type of
cancer (lung), high serum
alpha-fetoprotein level (liver), and triple-negative status (breast). In conclusion, RdRP activity indicated by p-hTERT expression predicts aggressive
cancer phenotypes in various types of
cancer. Thus, p-hTERT is a novel
biomarker for the diagnosis of aggressive
cancers with a poor prognosis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.