Cell-free DNA 5-hydroxymethylcytosine for immunotherapy response prediction in lung cancer

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurate prediction of individual patient responses to ICIs remains a challenge. We performed a genome-wide analysis of 5-hydroxymethylcytosine (5hmC) in plasma cell-free DNA (cfDNA) samples from 83 lung cancer patients. Using machine learning approaches, we developed a 5hmC signature to predict ICI treatment response and calculated a weighted-predictive score (wp-score) based on the 5hmC levels of signature genes in each sample. A low wp-score was significantly correlated with longer progression-free survival across three independent patient sample sets, and demonstrated superior predictive capability to tumor programmed death-ligand 1. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. Our study suggests that cfDNA 5hmC analysis is a minimally invasive, innovative strategy for guiding treatment selection in lung cancer patients. Analyze 5-hydroxymethyl cytosine (5hmC) genome-wide distribution in plasma cell-free DNA from lung cancer patients treated with immune checkpoint inhibitors. Please note that 17 samples from GSE202988 were re-used in the current study, resulting in total 85 data columns in the processed '5hmC_ReadCount_Genebody_LungCancer.txt' data file. Re-analysed Samples in GSE202988/PRJNA837976: GSM6146017 Z117 SRX15269868 SAMN28239535 GSM6146018 Z36 SRX15269869 SAMN28239534 GSM6146019 Z41 SRX15269870 SAMN28239533 GSM6146020 Z22 SRX15269871 SAMN28239532 GSM6146021 Z29 SRX15269872 SAMN28239531 GSM6146024 Z30 SRX15269875 SAMN28239528 GSM6146025 Z32 SRX15269876 SAMN28239527 GSM6146027 Z12 SRX15269880 SAMN28239525 GSM6146030 Z42 SRX15269726 SAMN28239522 GSM6146031 Z5 SRX15269727 SAMN28239521 GSM6146032 Z25 SRX15269728 SAMN28239520 GSM6146033 Z54 SRX15269729 SAMN28239519 GSM6146034 Z26 SRX15269730 SAMN28239518 GSM6146035 Z17 SRX15269731 SAMN28239517 GSM6146036 Z46 SRX15269732 SAMN28239516 GSM6146037 Z38 SRX15269733 SAMN28239515 GSM6146068 Z106 SRX15269456 SAMN28239484