ARG72PRO modulates DNA methylation in WNA HCC. (A) Hierarchical clustering and corresponding heatmap of the methylation status at 10 loci in 45 WNA HCCs. Clustering was obtained using a 1-rank correlation distance calculation and an average linkage on DChip software. Squares indicate the presence of a somatic change or a pathogenic variant in the corresponding samples. TP53 somatic mutation (p = 0.017), LOH at chromosome 17p (p = 0.0094) and chromosome instability (p = 0.067) are associated with the high methylation index cluster whereas Pro/Pro at codon 72 of TP53 is significantly associated (p = 0.048) with a medium or low methylation index. (B) In WNA HCC, methylation of LINE elements correlates significantly with the presence of other somatic changes as point mutations (in TP53, CTNNB1 and AXIN1) or allelic loss at chromosome 17p where is mapping TP53. (C) Distribution of the Fractional Allelic Loss (FAL) according to the methylation status of RASSF1. mRASSF1, methylated or hemimethylated locus; uRASSF1, unmethylated locus. FAL was assessed on 6 chromosomes (1p, 4q, 6q, 8p, 9p, and 17p). LOH, loss of heterozygosity. (D) Distribution of the methylation index according to the genotype at codon 72 of p53. Methylation index is calculated as the methylated fraction at 9 loci (SOCS1, RASSF1, RIZ1, GSTP1, TNFRSF10C, miR203, NRG1, CLU and TERT).