The importance of p53 pathway genetics in inherited and somatic cancer genomes

Abstract

Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.

Figure 1.. Somatic, causal mutations occur in a high proportion of p53 pathway genes.

(A) A pathway diagram of the p53 pathway as annotated by KEGG. Genes for which mutations have been causally implicated in cancer appear darker and are outlined (Cancer Gene Census, Sanger). A blue outline indicates causally mutated genes in epithelial cancers, red in leukemia/lymphomas, purple in mesenchymal cancers and orange in other types of cancers. (B) A bar graph of the percent of genes in the p53 pathway with known causal mutations compared to all annotated autosomal genes of the genome. 15 out of 67 genes in the p53 pathway (22.38%) are known to be causally mutated, which represents a significant 11.15-fold enrichment over the rest of the genes in the genome (p-value: 3.74e-12 is also depicted). (C) A scatter plot showing the fold enrichment of causally mutated genes on the x-axis (log-scale), and the p-value on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted-p-value: 0.05). The enrichment of causal mutations in p53 pathway genes (in yellow) is the highest and the most significant compared to the other 214 annotated KEGG pathways (in blue). Overall, 30% pathways demonstrated significant enrichment of causally mutated genes.

Figure 2.. One hundred and sixty five GWAS studies of many cancers types have been performed in European populations.

A histo-pathological classification of all the cancers present in the NHGRI GWAS catalog (download date: 09/11/2015) and a bar graph illustrating the number of tag-SNPs which have been found to significantly associate with differential susceptibility to the particular cancer. Cancers are also classified as epithelial (blue), lymphoma/leukemia (red), mesenchymal (purple) and others (orange).

Figure 3.. Cancer-associated SNPs occur in a high proportion of p53 pathway genes.

(A) A karyogram of the 541 genes which harbor at least 1 cancer GWAS SNP within 10Kb from their boundaries (Cancer Susceptibility Genes, CSGs). CSGs are noted in red. (B) A bar graph of the percent of CSGs in the p53 pathway compared to all annotated genes of the genome. 10 CSGs are found among the 67 genes of the p53 pathway (14.93%), which represents a significant 6.77-fold enrichment compared to the rest of autosomal genes in the genome (p-value: 2.00e-06 depicted in the figure, adjusted p-value: 4.39e-04). (C) A scatter plot showing the fold enrichment of CSGs on the x-axis (log-scale), and the adjusted p-value on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted-p-value: 0.05), which is the pre-fixed significance threshold. The enrichment of CSGs in p53 pathway genes (in yellow) is the highest and the most significant compared to the other 220 annotated KEGG pathways (in blue). Overall, 1.36% pathways demonstrated significant enrichments of CSGs.

Figure 4.. Cancer-associated eQTL occur in a high proportion of p53 pathway genes.

(A) A karyogram of the 133 genes which harbor an eSNP within 10Kb from their boundaries, which overlaps at least 1 cancer GWAS SNP (cis-eCSG). Cis-eCSGs are shown in red. (B) A bar graph of the percent of e-CSGs in the p53 pathway compared to all annotated genes of the genome. Six cis-eCSG are found among the 67 genes of the p53 pathway, which represents a significant 10.51-fold enrichment compare to the 11,887 genes with at least 1 eSNP (p= 2.09e-05 denoted in the graph, adjusted p= 4.59e-03). (C) A scatter plot showing the fold enrichment of e-CSGs on the x-axis (log-scale), and the adjusted p-value on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted-p-value: 0.05), which is the prefixed significance threshold. The enrichment of cis-eCSG in the genes of the p53 pathway (in yellow) is the highest and the most significant compared to all the other KEGG pathways (in blue). Overall, 0.45% pathways demonstrated significant enrichment of cis-eCSG.

Figure 5.. CSGs are significantly enriched in the p53 pathway genes, but not susceptibility genes for other major disease groupings.

Scatter plots showing fold enrichment of susceptibility genes (SGs) in KEGG pathways for the 9 ICD10 disease groups that had at least 1 pathway significantly enriched in SGs out of 19 ICD10 groups. The fold enrichment of SGs is on the x-axis (log-scale), and the adjusted p-value is on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted p-value: 0.05), which is the pre-fixed significance threshold. The enrichment of p53 pathway SGs is shown in yellow; a significant enrichment is observed in cancer (Neoplasms), but not in any other disease groups. The y-axis represents the percentage of pathways that demonstrated significant enrichments of SGs for the given disease grouping.

Figure 6.. CSG enrichment in p53 pathway genes is not limited to KEGG Pathway Annotation.

Scatter plots showing the fold enrichment of susceptibility genes in Biocarta (A) and Panther (B) annotated pathways for ICD10 disease groups with at least 1 significant pathway. The fold enrichment of SGs is reported on the x-axis (log-scale), and the adjusted p-value on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted-p-value: 0.05). The enrichment of SGs in the p53 pathway is observed in cancer (Neoplasms) with both pathway annotations, but never for other diseases. The y-axis represents the percentage of pathways that demonstrated significant enrichments of SGs for the given disease grouping.

Figure 7.. p53 pathway mutations and cancer-associated SNPs both occur in a high proportion of pathway genes in multiple cancer types.

(A) Scatter plots show the enrichment of genes with causal, somatic mutations in KEGG pathways grouped by cancer type. Fold enrichment of causally mutated genes is reported on the x-axis (log-scale), and the adjusted p-value on the y-axis (-log10 scale). The horizontal line represents the 5% Family Wise Error Rate threshold (Bonferroni adjusted-p-value: 0.05). The y-axis represents the percentage of pathways that demonstrated significant enrichments of SGs for the given cancer type. (B) A Venn Diagram showing the number of pathways with a significant enrichment of causally mutated genes across the four different types of cancer considered. (C) Analogously, a scatter plot shows the enrichment of CSGs in KEGG pathways grouped by cancer type, and a Venn Diagram (D) showing the number of pathways with a significant enrichment of CSGs grouped by cancer type. For all scatter plots the p53 pathway is in yellow.

Figure 8.. p53 pathway CSGs are frequently causally mutated in cancer.

(A) A Venn diagram depicting the overlap of p53 pathway genes that harbor causal mutations and pathway genes that are CSGs. (B) A pathway diagram of the CSGs annotated to the p53 pathway. (C). A bar graph depicting the percentage of CSGs found among those p53 pathway genes with known causal mutations in cancers and those pathway genes without known mutations. (D) A bar-plot depicting the enrichment of CSGs in genes known harbor causal somatic mutations relative to non-causally mutated genes in non-p53 pathway genes.