Cancer-associated TERT promoter mutations abrogate telomerase silencing

Area of Science:

• Cancer biology
• Genetics
• Stem cell research

Background:

• Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations observed in human cancers.
• The precise molecular mechanisms by which these TERT promoter mutations contribute to tumorigenesis remain largely unelucidated.

Purpose of the Study:

• To elucidate the molecular mechanism by which TERT promoter mutations contribute to human cancer development.
• To investigate the role of TERT promoter mutations in cellular immortalization and tumorigenesis.

Main Methods:

• Utilized genome editing in human pluripotent stem cells with physiological telomerase expression.
• Engineered embryonic stem cells to carry common TERT promoter mutations.
• Analyzed TERT transcription, telomerase activity, and telomere length during stem cell differentiation into somatic cells.

Main Results:

• TERT promoter mutations caused only a modest increase in TERT transcription and no change in telomerase activity in pluripotent stem cells.
• Upon differentiation, cells with TERT promoter mutations failed to silence TERT expression, unlike normal somatic cells.
• This failure to silence led to increased telomerase activity, resulting in aberrantly long telomeres in differentiated cells.

Conclusions:

• TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening, even without additional tumor-specific mutations.
• These mutations promote cellular immortalization and contribute to the tumorigenesis of incipient cancer cells by maintaining telomerase activity.