Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

Abstract

Key Points Whole-genome sequencing of 11 262 Icelanders reveals that clonal hematopoiesis is very common in the elderly. Somatic mutation of some genes is strongly associated with clonal hematopoiesis, but in most cases, no driver mutations were evident.

Clonal Hematopoiesis in Aging

“…The clones were very small with a median VAF of 0.0024 and many remained stable over a 10-year period. As described earlier, Zink et al employed a whole genome approach to discover that more macroscopic clonal hematopoiesis is very common in the elderly [35]. These findings challenge previous studies in which clonal hematopoiesis was identified in only 5% of middle-aged individuals [46–48] and suggests that clonal hematopoiesis is a near universal feature of aging and not necessarily a pathogenic state.…”

“…Stochastic loss of HSCs via telomere attrition would allow for the expansion of clones with growth advantages. Recent evidence that telomerase activity may play a role in the development of clonal hematopoiesis comes from two studies reporting germline variants in the TERT gene locus [34, 35]. …”

“…Clonality identified by detecting a large number of passenger variants appears to be at least as common as CHIP defined by driver gene mutations. In one WGS study of more than 11,000 Icelanders, individuals with more subclonal somatic mutations, particularly over 250, were increasingly more prevalent with age, approaching 55% for those in their 80s [35]. This majority may be an inevitable consequence of normal aging whereby functional HSC depletion fosters clonal expansion as a result of neutral drift [51].…”

“…Neutral drift argues that even when polyclonal HSCs have equal regenerative potential, stochastic turnover eventually leads to the persistence and expansion of only a few clones. Individuals with this type of clonal hematopoiesis lacking myeloid-malignancy associated mutations were still at comparably increased risk of developing a hematologic malignancy and had higher rates of overall mortality [35]. However, no significant associations were seen with cardiovascular disease, implying that specific mutations might be necessary for inflammatory plaque development as illustrated in recent studies.…”

Prevalent premalignancy

“…Zink et al analyze whole genome sequencing data from the blood of .11 000 healthy Icelandic individuals, and Buscarlet et al perform targeted sequencing on the blood of 2530 healthy older women. 2,3 T he presence of clonal hematopoiesis was first inferred from the finding that X-chromosome inactivation, predicted to be a purely stochastic event, is often skewed in the blood of otherwise healthy women, a subset of whom were later shown to harbor mutations in the TET2 gene. 4 In addition, hematopoietic stem cells (HSCs) carrying preleukemic mutations can be detected in both leukemia and remission samples obtained from patients.…”