Fifty years ago, Armitage and Doll 1 in the United Kingdom and Nordling 2 in the United States used epidemiologic data to show that the age-specific incidence of a variety of cancers followed a remarkably similar pattern, with rates increasing to the sixth power of age. They suggested that this relationship could be explained if a cancer cell was the result of six or seven successive mutations in a specified order. Remarkably, recent studies of cancer genomes have confirmed this observation, and most cancers have between three and seven mutations in genes causally implicated in cancer pathogenesis (so-called driver genes). 3 Early precancerous states can be identified for several tumor types and often contain single cancer-initiating mutations. 4-7 The acquisition of somatic mutations detected in the blood leading to the clonal expansion of mutated hematopoietic cells is referred to as clonal hematopoiesis (CH). CH is commonly detected in healthy individuals, but confers an increased risk of hematologic disease. 4, 7 CH mutations generally occur at low frequencies in genes implicated in myeloid neoplasms such as DNMT3A, TET2, ASXL1, and TP53. 8 Aging is the strongest known risk factor for CH, with the prevalence increasing greatly with each decade of life. 9-11 CH is associated with an increased risk of hematologic malignancies (especially myeloid neoplasms), shorter overall survival, and increased risk of cardiovascular disease (CVD). 9-11

Recent studies suggest CH is more prevalent in patients with solid cancer, with approximately 30% harboring CH mutations in their blood. 12 With the increased use of genetic sequencing to inform clinical decision-making in oncology, the possibility of unintentional discovery of CH in the setting of genomic analysis is increasingly likely. First, CH can be discovered incidentally when sequencing blood for the purpose of germline testing. 13, 14 Second, tumor sequencing is often accompanied by blood sequencing as a matched control, and from analysis of the blood sequencing data, CH can be uncovered as an incidental finding. 12 Third, CH can be discovered in tests of cell-free DNA, much of which comes from WBCs