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 1

Somatic gain-of-function TERT promoter mutations are found in circulating leukocytes of patients with heterozygous germline TERT coding mutations.

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Somatic gain-of-function TERT promoter mutations are found in circulatin...
(A) Schematic of the TERT gene with the 2 gain-of-function promoter mutations located at –124 and –146 relative to the TERT cDNA start site. TSS, transcription start site. (B) Sanger sequence tracings of the TERT promoter amplified from skin and blood from unrelated subjects. (C) Flow sorting of blood leukocytes from 1 subject (UT248) shows different peak heights of the 2 different promoter mutations in various cell types. The –146C>T promoter mutation is boxed; the –124C>T promoter mutation is marked by an arrow. (D) Sanger sequence tracings of the TERT promoter –146C>T mutation amplified from independent blood samples collected from 1 subject over time.