Histone-Related Genes Are Hypermethylated in Lung Cancer and Hypermethylated <i>HIST1H4F</i> Could Serve as a Pan-Cancer Biomarker

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Cytologic examination is the current "gold standard" for lung cancer diagnosis, however, this has low sensitivity. Here, we identified a typical methylation signature of histone genes in lung cancer by whole-genome DNA methylation analysis, which was validated by The Cancer Genome Atlas (TCGA) lung cancer cohort (<i>n</i> = 907) and was further confirmed in 265 bronchoalveolar lavage fluid samples with specificity and sensitivity of 96.7% and 87.0%, respectively. More importantly, <i>HIST1H4F</i> was universally hypermethylated in all 17 tumor types from TCGA datasets (<i>n</i> = 7,344), which was further validated in nine different types of cancer (<i>n</i> = 243). These results demonstrate that <i>HIST1H4F</i> can function as a universal-cancer-only methylation (UCOM) marker, which may aid in understanding general tumorigenesis and improve screening for early cancer diagnosis. SIGNIFICANCE: These findings identify a new biomarker for cancer detection and show that hypermethylation of histone-related genes seems to persist across cancers.