Figure 2. Epigenetic Silencing of DDR Genes and Pathways in Cancer.
(A) Gene/probe pairs showing evidence of silencing. Gene expression for gene/probe pairs (x axis) was Z score-transformed based on probe methylation level then plotted as a mean Z score among samples within a methylated group. Negative false discovery rate (FDR)-corrected log10-transformed p values are plotted on the y axis. Green dashed lines indicate the cutoffs for mean Z scores and FDRs. Genes meeting cutoffs for evidence of silencing have red labels, with specific probes listed in parentheses (see STAR Methods for additional details).
(B) Gene expression and methylation are inversely correlated for silenced genes. Scatterplots show silenced gene/probe pairs for MGMT (two probes), EXO5, RAD51C, MLH1, and FANCF. Gene expression level is plotted on the y axis and methylation on the x axis with red dots representing silenced samples.
(C) Silenced genes are variably distributed across cancer types. Left: oncoprint plot displays the overall frequency of deleterious mutations, deletions, and epigenetic silencing events for each significantly silenced DDR gene (rows, with gene names listed to the right) across 8,739 PanCanAtlas samples. Cancer type is shown in the color key to the right. Frequencies were calculated over the entire cohort, with only altered samples plotted. Right top scale indicates the number of events by molecular type, with the distribution of alterations across cancer types.
(D) Heatmap depicting variable frequency of epigenetic silencing events across 33 cancer types and DDR pathways. Cancer types (rows, shown using the same color code as in C) and 12 significantly silenced DDR genes (columns). Bar plots (right) summarize the frequency of silencing events by pathway: DR (ALKBH3 and MGMT), HR(BRCA1, RAD51C, and NSMCE3), and MMR (MLH1, MLH3, and PMS2). Numbers (x axis) below each bar graph indicate the proportion of samples by cancer type with at least one epigenetically silenced gene annotated to that pathway.
(E) EXO5 silencing shows cancer subtype variation. Scatterplots as in (B) display the same silenced samples, now color-coded according to cancer subtypes as indicated by the dot color code bottom left. Grey dots represent samples that were expressed/not silenced. See also Figure S2 and S3.