Clonal Signatures of Telomere Biology Disorders

In inherited bone marrow failure syndromes (IBMFS), clonal hematopoiesis (CH) has been increasingly recognized as a molecular fingerprint of the underlying pathophysiology. A specific clonal profile has been reported in telomere biology disorders (TBDs), an IBMFS caused by pathogenic germline variants (PGV) in genes related to telomere maintenance and characterized by short/dysfunctional telomeres and increased risk of cancer. This review summarizes current data on specific somatic mutational profiles seen in TBDs and their associations with clinical features and cancer risk. Recent studies have reported a specific CH landscape in TBDs that is associated with patients’ age, genotype, and phenotype. CH often involves the affected germline gene, with reversion or compensation of the PGV, or mutations in PPM1D, TERT promoter, or POT1—none of which are associated with increased risk of cancer. In contrast, a distinct group of recurrent CH that modulates TP53 pathway has been associated with cancer development in TBDs. These differing patterns of CH in TBDs have important implications for patients’ diagnosis, risk stratification, and surveillance. Characterization of clonal profiles across TBDs cohorts has helped identify potential molecular markers that can aid in diagnosis and guide future adapted surveillance and early intervention strategies. Although opportunities exist to incorporate CH into clinical care of patients with TBDs, multicenter longitudinal studies are still needed for validation and to allow for wide-scale adoption of CH into clinical care protocols.