Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations
Lindley Maryoung, … , Richard C. Wang, Christine Kim Garcia
Lindley Maryoung, … , Richard C. Wang, Christine Kim Garcia
Published February 13, 2017
Citation Information: J Clin Invest. 2017;127(3):982-986. https://doi.org/10.1172/JCI91161.
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Brief Report Aging Pulmonology

Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations

Abstract

Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function. While these promoter mutations were initially identified as oncogenic drivers of cancer, individuals expressing the mutations have no history of cancer. Neither promoter mutation was found in population-based cohorts of similar or advanced age. The TERT promoter mutations were found more frequently in cis with the WT allele than the TERT coding sequence mutation. EBV-transformed lymphoblastoid B cell lines (LCLs) derived from subjects with TERT promoter mutations showed increased telomerase expression and activity compared with cell lines from family members with identical coding mutations. TERT promoter mutations resulted in an increased proliferation of LCLs and demonstrated positive selection over time. The persistence and recurrence of noncoding gain-of-function mutations in these cases suggests that telomerase activation is not only safely tolerated but also advantageous for clonal expansion.

Authors

Lindley Maryoung, Yangbo Yue, Ashley Young, Chad A. Newton, Cindy Barba, Nicolai S.C. van Oers, Richard C. Wang, Christine Kim Garcia

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Figure 3

TERT promoter mutation is associated with increased telomerase activity and a higher proliferative capacity.

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TERT promoter mutation is associated with increased telomerase activity...
(A) Telomeric repeat amplification protocol (TRAP) activity of equivalent numbers of EBV-transformed lymphoblastoid cells derived from different individuals. Data are expressed relative to the activity of a WT control and represent the mean of 5 experiments. A representative gel is shown in the inset. P values were significant after correcting for multiple comparisons. (B) Expression of human TERT by real-time qPCR. Data are expressed relative to a WT control and represent the mean of triplicate experiments from 1 of 3 representative experiments. Data in A and B were analyzed by a 2-tailed Student’s t test. Rel, relative. (C) Flow sorting of the UT248-EBV cell line to separate cells according to their proliferative capacity, followed by sequencing of the TERT promoter. SSC, side scatter. (D) Sequencing of the TERT promoter from DNA purified from the UT248-EBV cell line at different time points. The position of the –146 variant is marked by arrows in C and D.