Higher Rate of Clonal Hematopoiesis in Pediatric Cancer Survivors May Be Linked With Treatment-Induced STAT3 Gene Mutations and Risk of Adverse Long-Term Outcomes
Studies show that although clonal hematopoiesis is an age-related phenomenon in the general population, it can also be induced by exposure to chemotherapy, which can affect both the emergence and evolution of clonal hematopoiesis clones, accelerating aging at both the physiologic and molecular levels. To investigate whether pediatric cancer survivors exhibit a higher rate of clonal hematopoiesis that may predispose them to adverse long-term outcomes, researchers at St. Jude Children’s Research Hospital analyzed clonal hematopoiesis in pediatric cancer survivors enrolled in the St. Jude Lifetime Cohort Study (SJLIFE).
Their results—published by Hagiwara et al in Cancer Discovery—show a higher rate of clonal hematopoiesis and significant enrichment in treatment-related STAT3 gene mutations in pediatric cancer survivors who were exposed to alkylating agents, radiation, and bleomycin. The data support the need for longitudinal surveillance of clonal hematopoiesis in pediatric cancer survivors to evaluate its chronicity and associations with clone size, a key feature used for risk stratification in other populations, according to the study authors.
The researchers performed deep sequencing on a panel of 39 clonal hematopoiesis–associated genes in peripheral blood samples from 2,860 survivors of pediatric cancers enrolled in SJLIFE and 324 controls with no history of cancer. The survivors were followed over 5.1 to 51.1 years (median follow-up = 23.5 years) from cancer diagnosis and were aged 6.0 to 66.4 years (median age = 31.6 years) at the time of the sample collection, which was slightly younger than the community controls (18.3 to 70.2 years, median age = 34.6 years).
The childhood cancer diagnoses of the survivors included leukemias (35%), lymphomas (19%), central nervous system (CNS) malignancies (11%), and non-CNS solid tumors (35%). The deep sequencing allowed for the identification of clones with a variant allele frequency as low as 0.1%.
- Pediatric cancer survivors have a higher rate of clonal hematopoiesis and prevalence of treatment-related STAT3 gene mutations compared to age-matched healthy cohorts. Treatment with alkylating agents, radiotherapy, and bleomycin were significantly associated with an increased risk of clonal hematopoiesis.
- Hodgkin lymphoma, soft-tissue sarcoma, germ cell tumors, rhabdomyosarcoma, neuroblastoma, non-Hodgkin lymphoma, and acute lymphoblastic leukemia were also associated with a higher risk of clonal hematopoiesis.
- Reducing use of procarbazine in pediatric patients may help decrease the risk of adverse long-term outcomes.
The researchers assessed whether clonal hematopoiesis driven by normal aging differed from that driven by cancer therapy in terms of mutated genes, types of mutations, and clonal expansion dynamics. To differentiate age-related clonal hematopoiesis clones from therapy-related clones, the research team used data from the control cohort to estimate the probability of a clonal hematopoiesis event occurring naturally at each patient’s age. The researchers then used data from the survivor cohort to estimate the age-adjusted likelihood of developing clonal hematopoiesis following a specific cancer treatment. Each clonal hematopoiesis event was inferred to be age-related (iAR) or treatment-related (iTR) based on which scenario was more likely.
The researchers found higher rates of clonal hematopoiesis in the survivors compared to the controls in each age category, with a statistically significant increase in the overall prevalence: 15.0% of survivors (95% confidence interval [CI] = 13.7%–16.3%) vs 8.6% of controls (95% CI = 5.6%–11.7%). Among the survivors, treatment with alkylating agents, radiotherapy, and bleomycin were significantly associated with an increased risk of clonal hematopoiesis. Certain cancer types—including Hodgkin lymphoma, soft-tissue sarcoma, germ cell tumors, rhabdomyosarcoma, neuroblastoma, non-Hodgkin lymphoma, and acute lymphoblastic leukemia—were also associated with an increased risk of clonal hematopoiesis.
The researchers also identified several genes that were differentially mutated between the iTR and iAR cases, including STAT3, which had not been previously characterized as a clonal hematopoiesis–associated gene among cancer survivors. The prevalence of STAT3 gene mutations was 17.9% among iTR patients and 6.25% among iAR patients, and the mutations were significantly enriched in survivors of Hodgkin lymphoma.
The study authors then performed single-cell, whole-genome sequencing on a handful of samples harboring a common STAT3 mutation and found that the mutation was highly enriched in T cells isolated from the peripheral blood samples. Their analysis further revealed a pattern of mutations that matched closely with COSMIC [Catalogue of Somatic Mutations in Cancer] SBS25, a mutation known to be associated with exposure to procarbazine in Hodgkin lymphoma cells.
“These data support the need for longitudinal surveillance of clonal hematopoiesis in pediatric cancer survivors to evaluate its chronicity and association with clone size, a key feature used for risk stratification in other populations,” concluded the study authors.
The researchers stressed the importance of continuing to follow these patients to better understand how cells with clonal hematopoiesis mutations behave as patients age.
“We need to follow these patients longitudinally to understand the clinical implications of having a clone and how the clones evolve and expand over time,” said co–senior study author Leslie L. Robison, PhD, Emeritus, St. Jude Faculty in the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital, in a public statement.
The study authors suggest that their results may help persuade physicians to reduce their usage of procarbazine in pediatric patients with cancer, a practice that is already implemented in some cancer centers, including at St. Jude Children’s Research Hospital.
“The data are telling us that clonal hematopoiesis mutations are important biomarkers that have potential clinical implications for risk of adverse long-term outcomes among the growing population of survivors of childhood cancer. The research methods applied provide new insights and a new level of research on clonal hematopoiesis that will inform future studies,” said Dr. Robison.
Disclosure: Funding for this study was provided by St. Jude Children’s Research Hospital and the American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit aacrjournals.org/cancerdiscovery.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.