TY - JOUR
T1 - Elevated mutational age in blood of children treated for cancer contributes to therapy-related myeloid neoplasms
AU - Bertrums, Eline J M
AU - Rosendahl Huber, Axel K M
AU - de Kanter, Jurrian K
AU - Brandsma, Arianne M
AU - van Leeuwen, Anais J C N
AU - Verheul, Mark
AU - van den Heuvel-Eibrink, Marry M
AU - Oka, Rurika
AU - van Roosmalen, Markus J
AU - de Groot-Kruseman, Hester A
AU - Zwaan, C Michel
AU - Goemans, Bianca F
AU - van Boxtel, Ruben
PY - 2022/6/9
Y1 - 2022/6/9
N2 - Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) before and after cancer treatment of 24 children. Of these, 19 developed therapy-related myeloid neoplasms (t-MNs). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naive cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.
AB - Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) before and after cancer treatment of 24 children. Of these, 19 developed therapy-related myeloid neoplasms (t-MNs). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naive cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.
U2 - 10.1158/2159-8290.CD-22-0120
DO - 10.1158/2159-8290.CD-22-0120
M3 - Article
C2 - 35678530
JO - Cancer discovery
JF - Cancer discovery
SN - 2159-8274
ER -