The aim of this thesis of Priscilla Kamphuis was to better understand the occurrence and consequences of clonal hematopoiesis in combination with blood count abnormalities or chromosomal alterations in the general population, making use of the prospective Lifelines cohort.
We show that older men more frequently carry high-risk gene mutations and this enrichment may contribute to the male predominance in hematological malignancies. In addition, we show that individuals with thrombocytosis and myeloproliferative neoplasm (MPN)-related mutations have an increased risk of MPN diagnosis.
Aging is often accompanied by myeloid skewing (relative increase in production of myeloid cells). In this thesis, it is shown that clonal hematopoiesis does not explain this aging phenomenon. We further studied the overlap in genetic abnormalities. Although there was no co-occurrence between loss of the Y-chromosome and somatic gene mutations in older men, a synergistic effect of these two alterations may be present in larger clones.
Finally, we applied a machine learning model to predict whether a combination of mutations could lead to inferior survival. Here, we observe that individuals with mutations in both TP53 and DNMT3A show a higher risk of all-cause mortality.
Our findings contribute to a better understanding of clonal hematopoiesis in combination with blood count abnormalities or chromosomal alterations in the general aging population.
