TY - JOUR AU - Maryoung, Lindley AU - Yue, Yangbo AU - Young, Ashley AU - Newton, Chad A. AU - Barba, Cindy AU - van Oers, Nicolai S.C. AU - Wang, Richard C. AU - Garcia, Christine Kim T1 - Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations PY - 2017/03/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI91161 VL - 127 IS - 3 UR - https://doi.org/10.1172/JCI91161 SP - 982 EP - 986 PB - The American Society for Clinical Investigation ER -