Abstract
BackgroundLittle is known about the effects of chemotherapeutic drugs on DNA methylation status of leukocytes, which may be predictive of treatment benefits and toxicities. Based on a prospective national study, we characterize the changes in leukocyte DNA methylome from pre- to post-chemotherapy (approximately 4 months apart) in 93 patients treated for early stage breast cancer and 48 matched non-cancer controls. We further examined significant methylation changes with perceived cognitive impairment, a clinically significant problem related to cancer and chemotherapy.ResultsApproximately 4.2% of the CpG sites measured using the Illumina 450K methylation array underwent significant changes after chemotherapy (p < 1e-7), in comparison to a stable DNA methylome in controls. Post-chemotherapy, the estimated relative proportions of B cells and CD4+ T cells were decreased by a median of 100% and 39%, respectively, whereas the proportion of monocytes was increased by a median of 91%. After controlling for leukocyte composition, 568 CpGs from 460 genes were still significantly altered following chemotherapy. With additional adjustment for chemotherapy regimen, cumulative infusions, growth factors, and steroids, changes in four CpGs remained significant, including cg16936953 in VMP1/MIR21, cg01252023 in CORO1B, cg11859398 in SDK1, and cg19956914 in SUMF2. The most significant CpG, cg16936953, was also associated with cognitive decline in breast cancer patients.ConclusionsChemotherapy profoundly alters the composition and DNA methylation landscape of leukocytes in breast cancer patients. Our results shed light on the epigenetic response of circulating immune cell populations to cytotoxic chemotherapeutic drugs and provide possible epigenetic links to the degeneration of cognitive function associated with chemotherapy.
Highlights
Chemotherapy remains an important treatment modality for patients with breast cancer who are at high risk of recurrence [1]
Chemotherapy had a marked impact on leukocyte DNA methylome
Between paired samples collected from breast cancer patients pre- and post-chemotherapy with a median of 128 days apart (IQR 113–157 days), significant changes in methylation value were found at a total of 16,679 CpG sites, or 4.2% of the CpG probes tested, across the methylome (p < 1e-7) (Fig. 1a), whereas no significant change was found between paired samples collected from age-matched non-cancer female controls at two time points separated by a similar median of 130 days (IQR 92–155 days) (Fig. 1b)
Summary
Chemotherapy remains an important treatment modality for patients with breast cancer who are at high risk of recurrence [1]. Mainly DNA methylation, drives hematopoiesis and is highly responsive to internal and external insults, it has been widely speculated that chemotherapy would have a profound impact on DNA methylation of blood leukocytes. This effect could influence treatment efficacy, toxicity outcomes, and symptom trajectories. Based on a prospective national study, we characterize the changes in leukocyte DNA methylome from pre- to post-chemotherapy (approximately 4 months apart) in 93 patients treated for early stage breast cancer and 48 matched non-cancer controls. We further examined significant methylation changes with perceived cognitive impairment, a clinically significant problem related to cancer and chemotherapy
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