A109-11 Clonal Hematopoiesis Is Associated With Progression of Idiopathic Pulmonary Fibrosis

Abstract Idiopathic Pulmonary Fibrosis (IPF) is an age-associated, chronic and fatal disease, with a variable progression course. Clonal hematopoiesis (CH) is also an age-related phenomenon, defined by the presence of an expanded somatic blood cell clone in persons without other hematological abnormalities. CH has been strongly associated with increased risk of several chronic diseases, as well as with all-cause mortality. Here, we investigated the incidence and potential prognostic significance of CH in IPF patients with variable disease trajectories. Whole blood DNA from 121 IPF patients from LMU (Munich), and 96 from MHH(Hannover), was analyzed using a targeted gene panel including 13 CH genes (ASXL1,CALR, CBL, DNMT3A, JAK2, MPL, PPM1D, SF3B1, SRSF2, TET2, TP53, U2AF2, andZRSR2). IPF and disease progression were diagnosed according with ATS and ERS criteria. CH mutations were present in 38% and 36% of IPF patients in the LMU andHannover cohort, respectively (Fig. 1A). In the LMU cohort, significantly more IPF patientswith CH mutations were rapid progressors (53% vs. 23%, p 0.008) and showed asignificant decrease in 12-month FVC (-45 vs -290 ml, p 0.0009, Fig 1.C). Regressionanalyses showed CH mutations predicted increased progression (OR = 3.6, 95%CI 1.5-10.3; p 0.007) and FVC loss (-306±94 ml; p 0.002) in IPF patients. In both cohorts,DNMT3A, SF3B1 and TET2 and ASXL1 were the most frequently mutated genes, with DNMT3A being the most significantly mutated gene (p 0.0001, Fig. 1B). TET2 mutations being exclusively detected in patients with progression (p 0.02). A breakdown of the mutation types for each gene showed that missense predominated, yet other key protein-altering mutation types, as frameshift, and stop gain, were also found. Clone size was not associated with progression. An analysis of high-impact mutation occurrence revealed that DNMT3A, TET2 and SF3B1 had more than 50% of mutations in functional domains(Fig. 1D). This is the first report that CH and presence of TET2 mutations, are associatedwith IPF progression in two independent patient cohorts. These findings support apotential association between aberrant immune responses and IPF progression. Future work should characterize pathological consequences of CH mutations in IPF patients andexplore the use of these biomarkers in screening patients at-risk for progressivepulmonary fibrosis and exploring potential therapeutic approaches. This abstract is funded by: ERC, LMU Excellence grant