Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function: a prospective study

Abstract

Background: Little 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. Results: Approximately 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. Postchemotherapy, 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. Conclusions: Chemotherapy 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.

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer

“…While chemotherapy profoundly impacts DNA methylation landscape in cancer patients [20,21], resistance to treatment continues to be a major obstacle for the success of cancer therapy. In our study, increased in the CpG site methylation levels among responders were all mapped to CpG islands including CDC25B, WBSCR27, ADNP, NEK9, COQ2, SOX5, ACPL2, RBM15, TLE2, RB1CC1 (Table 2).…”

Identification of RASSF1A Promoter Hypermethylation as a Biomarker for Hepatocellular Carcinoma

“…With regards to clinical heterogeneity, only 20.5% (9/44) of our enrolled articles mentioned the presence or absence of preoperative treatment [38,40,41,45,47,50,53,55]. Some studies suggested that both radiotherapy and chemotherapy can alter a patient's DNA methylation status; therefore, the type of preoperative treatment performed should be clari ed [87,88]. Moreover, four studies investigated the relationship between RASSF1A hypermethylation in peripheral blood and the risk of HCC, and the diagnosis of HCC was con rmed by imaging techniques and serum AFP levels, rather than through pathological examination [56][57][58][59].…”

Identification of RASSF1A Promoter Hypermethylation as a Biomarker for Hepatocellular Carcinoma

“…With regards to clinical heterogeneity, only 20.5% (9/44) of our enrolled articles mentioned the presence or absence of preoperative treatment [38,40,41,45,47,50,53,55]. Some studies suggested that both radiotherapy and chemotherapy can alter a patient's DNA methylation status; therefore, the type of preoperative treatment performed should be clari ed [83,84]. Moreover, four studies investigated the relationship between RASSF1A hypermethylation in peripheral blood and the risk of HCC, and the diagnosis of HCC was con rmed by imaging techniques and serum AFP levels, rather than through pathological examination [56][57][58][59].…”