Histone-related genes are hypermethylated in lung cancer and hypermethylated HIST1H4F could serve as a pan-cancer biomarker

Lung cancer is the leading cause of cancer-related deaths worldwide. Cytological 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 a TCGA lung cancer cohort (n=907) and was further confirmed in 265 bronchoalveolar lavage fluid (BALF) samples with specificity and sensitivity of 96.7% and 87.0%, respectively. More importantly, HIST1H4F was universally hypermethylated in all seventeen tumor types from TCGA datasets (n=7344), which was further validated in nine different types of cancer (n=243). These results demonstrate that HIST1H4F can function as a Universal-Cancer-Only Methylation (UCOM) marker, which may aid in understanding general tumorigenesis and improve screening for early cancer diagnosis.