Genomic landscape of DNA repair genes in cancer

Abstract

DNA repair genes are frequently mutated in cancer, yet limited data exist regarding the overall genomic landscape and functional implications of these alterations in their entirety. We created comprehensive lists of DNA repair genes and indirect caretakers. Mutation, copy number variation (CNV), and expression frequencies of these genes were analyzed in COSMIC. Mutation co-occurrence, clinical outcomes, and mutation burden were analyzed in TCGA. We report the 20 genes most frequently with mutations (n > 19,689 tumor samples for each gene), CNVs (n > 1,556), or up- or down-regulated (n = 7,998). Mutual exclusivity was observed as no genes displayed both high CNV gain and loss or high up- and down-regulation, and CNV gain and loss positively correlated with up- and down-regulation, respectively. Co-occurrence of mutations differed between cancers, and mutations in many DNA repair genes were associated with higher total mutation burden. Mutation and CNV frequencies offer insights into which genes may play tumor suppressive or oncogenic roles, such as NEIL2 and RRM2B, respectively. Mutual exclusivities within CNV and expression frequencies, and correlations between CNV and expression, support the functionality of these genomic alterations. This study provides comprehensive lists of candidate genes as potential biomarkers for genomic instability, novel therapeutic targets, or predictors of immunotherapy efficacy.

Keywords: DNA repair; cancer; copy number variations; gene expression; mutations.

Figure 1. Analysis of DNA repair mutations by repair pathway, direct or indirect classification, and co-occurrence or mutual exclusivity between tumors

A. Breakdown by pathway for direct DNA repair genes mutated in > 1% of each cancer type (number of included genes in parentheses). B. Average gene mutation frequency for all COSMIC analyzed genes, direct DNA repair genes, and indirect genomic stability maintenance genes by cancer type. C.-H. Tendency toward co-occurrence or mutual exclusivity for all possible 190 pairs of the top 20 most frequently mutated DNA repair genes from Table 1 for each cancer types, analyzed in TCGA. † All analyzed genes in All cancer excludes cancer types with < 200 sequenced tumors or < 1000 analyzed genes. Ψ Values for Caretaker genes involved in genomic stability excludes TP53.

Figure 2. DNA repair gene CNV frequencies

A. Top 20 DNA repair genes most frequently with CNV gain or loss, analyzed in COSMIC. Bold = direct DNA repair genes, non-bold = caretaker genes indirectly involved in genomic stability. B. Mutual exclusivity of CNV gain and loss within each DNA repair gene (r = −0.285). C. Mutual exclusivity of CNV gain and loss within common breast cancer oncogenes and tumor suppressors (r = −0.335), analyzed in COSMIC. D. Overall survival and disease free survival curves for cases with and without CNV or mutations in NEIL2, from TCGA. E. Overall survival curves for cases with and without RRM2B CNV, from TCGA. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3. DNA repair gene up- and down-regulation frequencies

A. Top 20 DNA repair genes most frequently overexpressed or underexpressed, analyzed in COSMIC. Bold = direct DNA repair genes, non-bold = caretaker genes indirectly involved in genomic stability. B. Mutual exclusivity of overexpression and underexpression within each gene (r = −0.249). ***p < 0.001.

Figure 4. Association between DNA repair CNV and gene expression

A. Positive correlation between CNV gain and gene overexpression (r = 0.632). B. Positive correlation between CNV loss and gene underexpression (r = 0.178). *p < 0.05, ***p < 0.001.

Figure 5. Somatic mutational burden in tumors with DNA repair gene mutations

Average A. colorectal and B. melanoma tumor mutation burden in samples containing a mutation within specific control genes or the most frequently mutated direct DNA repair genes from Table 1, analyzed in TCGA. Number of samples containing mutations in each gene and the percentage of samples containing a mutation (out of 220 for CRC, 278 for melanoma) included in parentheses. Red line represents the value for the average mutation count overall in CRC or melanoma. *p < 0.05, **p < 0.01, as determined by one-way ANOVA with post-hoc Dunnett analysis.