Highlights in Cancer Research: May 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.

9. Dynamics of age- versus therapy-related clonal hematopoiesis in long-term survivors of pediatric cancer

Hagiwara, K., Natarajan, S., Wang, Z., Zubair, H. et al. Cancer Discov. 13 (4): 844–857. (2023).
doi: 10.1158/2159-8290.CD-22-0956.

Summary of the findings

Somatic mutations in hematopoietic stem cells (HSCs) that confer growth advantage, known as clonal hematopoiesis (CH), are associated with the normal aging process. To investigate how cancer therapy may impact CH in pediatric cancer survivors who are at risk of accelerated physiological aging, the authors performed deep sequencing on 2,860 childhood cancer survivors (median follow-up time is 23.5 years) along with 324 age- and ethnicity-matched community controls. CH was detected in 15% of the survivors, a prevalence significantly higher than the 8.5% in community controls, and was associated with exposures to alkylating agents, radiation, and bleomycin. To differentiate age-related CH clones from therapy-related CH clones, the authors calculated the probability of a CH event occurring naturally at a specific age from the control cohort, which was then used to estimate the age-adjusted likelihood of developing CH for each survivor following a given cancer treatment. Therapy-related CH shows significant enrichment in TP53 as well as STAT3, a CH gene specific to Hodgkin lymphoma survivors. Single-cell profiling of peripheral blood samples from Hodgkin lymphoma survivors revealed STAT3 mutations to be predominantly present in T-cells and contributed by SBS25, a mutational signature known to be associated with procarbazine exposure. Serial-sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, while therapy-related CH remains stable decades post-treatment.

Future impact

Clonal hematopoiesis (CH) in childhood cancer survivors with long-term follow-up is attributable to both ageing and prior therapy exposure. CH mutations in STAT3 matched COSMIC signature 25 known to be associated with exposure to procarbazine, were detected in 10% of the Hodgkin lymphoma survivors and confer a growth advantage in T cells.

Despite the dramatic improvement in the 5-year survival rate in pediatric cancer over the last 50 years, survivors are still at risk of late effects associated with treatment. This first comprehensive CH analysis in long-term survivors of pediatric cancer identifies accelerated clonal hematopoiesis in pediatric cancer survivors, which is linked to both chemo- and radiotherapy. The contrasting dynamics of clonal expansion for age-related versus therapy-related CH suggest the need for longitudinal monitoring, which may involve genomic profiling at single cell level, to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors.