Genomic landscape of DNA repair genes in cancer

// Young Kwang Chae 1,2,3,* , Jonathan F. Anker 3,* , Benedito A. Carneiro 1,2,3 , Sunandana Chandra 1,2,3 , Jason Kaplan 1,2,3 , Aparna Kalyan 1,2,3 , Cesar A. Santa-Maria 1,2,3 , Leonidas C. Platanias 1,2,3,4 and Francis J. Giles 1,2,3 1 Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA * These authors have contributed equally to this work Correspondence to: Young Kwang Chae, email: // Keywords : DNA repair, cancer, mutations, copy number variations, gene expression Received : October 12, 2015 Accepted : March 02, 2016 Published : March 19, 2016 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.