Evolution of clonal hematopoiesis during cancer treatment and its impact on outcomes
Mona Arabzadeh, Yi-Han Tang, Christelle Colin-Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K. Kresovich, Iman Washington, Heather A. Parsons, Judy E. Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis
Mona Arabzadeh, Yi-Han Tang, Christelle Colin-Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K. Kresovich, Iman Washington, Heather A. Parsons, Judy E. Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis
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Research Article Clinical Research Genetics Oncology

Evolution of clonal hematopoiesis during cancer treatment and its impact on outcomes

Abstract

Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of patients with breast cancer and show that cytotoxic treatments led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. Positively selected CH that expanded through dose-dependent therapeutic bottlenecks harbored mutations in TP53, PPM1D, SRCAP, DNMT3A, and YLPM1. Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared with patients with unchanging or negatively selected CH across all therapies. These findings, validated in independent breast cancer and pan-cancer cohorts, provide strong evidence for the clinical relevance of monitoring CH during cancer treatment.

Authors

Mona Arabzadeh, Yi-Han Tang, Christelle Colin-Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K. Kresovich, Iman Washington, Heather A. Parsons, Judy E. Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis

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Figure 2

Mutational spectrum and diversity of CH prior to treatment for breast cancer.

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Mutational spectrum and diversity of CH prior to treatment for breast ca...
(A) Oncoplot of CH mutations detected across a panel of 81 genes in patients with breast cancer. Columns represent individual patients, and colors correspond to the mutation type, including frameshift insertion and deletions, in-frame deletions, and missense and nonsense single nucleotide variants. (B) Fold excess of nonsense mutations in each gene relative to the expected distribution from the genes’ nucleotide content; χ2 statistics are shown with 95% CIs for genes with 3 or more protein-changing substitutions and 1 or more nonsense mutations. (C) CH mutation co-occurrence illustrated by a Circos plot. Colored lines highlight the most frequently mutated genes and co-mutations. (D) Number of patients with CHIP mutations (VAF ≥2%) across genes. (E) Divergence in CH allelic frequency, defined by the mean CH VAF per patient, compared between patients with CHIP mutations (VAF ≥2%) versus patients with CH mutations (VAF <2%).