title: 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.
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Young Kwang
authors.initials: YK
authors.lastname: Chae
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Anker
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Benedito A
authors.initials: BA
authors.lastname: Carneiro
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Sunandana
authors.initials: S
authors.lastname: Chandra
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Kalyan
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Santa-Maria
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D056915:DNA Copy Number Variations; D045647:DNA Glycosylases / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D042822:Genomic Instability; D023281:Genomics / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012264:Ribonucleotide Reductases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C473642:NEIL2 protein, human
keywords: DNA repair; cancer; copy number variations; gene expression; mutations