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Methylome from liquid biopsy cell-free DNA using enzymatic conversion of unmethylated cysteines

ABSTRACT: Methylome of tumor cell-free DNA (cfDNA) has emerged as a powerful non-invasive technique for cancer subtyping and prognosis. However, its application is frequently hampered by the quality and total cfDNA yield. Here we demonstrate the feasibility of very low-input cfDNA for whole-methylome and copy-number profiling studies using enzymatic conversion of unmethylated cysteines (EMSEQ) to better preserve DNA integrity. We demonstrate that cfDNA methylation of our cohort was comparable with in situ cohorts and built a model that accurately predict MYCN amplification or 11q deletion in validation cohorts. RASSF1A methylation precedes this divergent methylome signature, supporting common and different epigenetic origins. After stratification by 11q, eight CpG methylations show additional prognostic value and two reveal known preclinical targets (CSF1R, CCR7). Methylation in CSF1R and CCR7 associated with differential expression levels and poorer prognosis. Noteworthy, haploinsufficiency of genes located on 11q that repair DNA double-strand breaks display reduced expression by a mechanism independent of promoter methylation. Conclusions: RASSF1A is an early hypermethylation defect that may predispose to later genetic and epigenetic alterations specific to MYCN-amplified or 11q-deleted high-risk neuroblastomas. CSF1R and CCR7 hypermethylation are a hallmark of high-risk 11q-deleted neuroblastomas that could be exploited therapeutically with immunomodulators to override immunosupression and relapse. Our novel findings provide support for use of liquid biopsy as an optimal strategy to assess methylomes of neuroblastoma patients for a precision medicine approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221317 | GEO | 2023/01/25

REPOSITORIES: GEO

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Genome-wide plasma cell-free DNA methylation profiling in lung cancer patients using MeDIP-seq

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