Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications

The association between heart failure and incident cancer in women: an analysis of the Women's Health Initiative

AIMS: There is conflicting evidence whether heart failure (HF) is a risk factor for incident cancer. Despite population-based cohorts demonstrating this association, an analysis of the Physician’s Health Study found no association in a cohort of mostly healthy males. We investigated the association of HF with incident cancer among a large cohort of post-menopausal women. METHODS AND RESULTS: A prospective cohort study of 146 817 post-menopausal women age 50 to 79 years enrolled in the Women’s Health Initiative from 1993–1998, and followed through 2015. The primary exposure was adjudicated incident HF diagnosis, including preserved and reduced ejection fraction in a sub-cohort. The primary outcome was adjudicated incident total and site-specific cancers. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazard regression models. Over a median follow-up of 8.4 years, 3272 and 17 474 women developed HF and cancer, respectively. HF developed in 235 women prior to cancer. HF was associated with subsequent incident cancer [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.11–1.48]. Associations were observed for obesity-related cancers (HR 1.24, 95% CI 1.02–1.51), as well as lung and colorectal cancers (HR 1.58, 95% CI 1.09–2.30 and HR 1.52, 95% CI 1.02–2.27, respectively). HF with preserved ejection fraction (HR 1.34, 95% CI 1.06–1.67), but not HF reduced ejection fraction (HR 0.99, 95% CI 0.74–1.34), was associated with total cancer. CONCLUSION: Heart failure was associated with an increase in cancer diagnoses in post-menopausal women. This association was strongest for lung cancer. Further research is needed to appreciate the underlying mechanisms responsible for this association