Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

• Published in: Cell reports (Cambridge) Vol. 23; no. 1; pp. 239 - 254.e6
• Main Authors: Knijnenburg, Theo A., Liu, Yuexin, Kim, Pora, Zhang, Shaojun, Zhao, Zhongming, Laird, Peter W., Ferguson, Martin L., Liu, Jia, Lawrence, Michael S., Saksena, Gordon, Voet, Doug, Dhankani, Varsha, Hegde, Apurva M., Ladanyi, Marc, Sander, Chris, Anur, Pavana, Wong, Christopher K., Yau, Christina, Ally, Adrian, Kasaian, Katayoon, Ma, Yussanne, Shih, Juliann, Maglinte, Dennis T., Drummond, Jennifer, Hale, Walker, Korchina, Viktoriya, Morgan, Margaret, Morton, Donna, Sheth, Margi, Wang, Linghua, Wheeler, David A., Kandoth, Cyriac, Lau, Kevin, Thompson, Eric, Leraas, Kristen M., Huntsman, David, Horowitz, Neil, Fulop, Jordonna, Sloan, Andrew E., Tucker, Kelinda, Zelinka, Tomas, Iacocca, Mary, Sepulveda, Antonia, Roman-Roman, Sergio, Stern, Marc-Henri, Lipp, Eric, Delman, Keith, Gillis, Ad, Korpershoek, Esther, Looijenga, Leendert, Perin, Alessandro, Stoehr, Christine, Stoehr, Robert, Wach, Sven, Kycler, Witold, Chung, Ki, Martin, Julie, Bubley, Glenn, De Rienzo, Assunta, Richards, William G., Campo, Elias, Evason, Kimberley, Borad, Mitesh, Kocher, Jean-Pierre, Petersen, Gloria, Que, Florencia, Ajani, Jaffer A., Esmaeli, Bita, Logothetis, Christopher, Sood, Anil, Mann, Graham, Gopalan, Anuradha, Zaren, Howard, Yang, Hannah, Caraman, Irina, Mura, Sergiu, Stancul, Irina, Albert, Monique, Arnaout, Angel, Rassl, Doris M., Barnett, Gene, Farver, Carol, Raymond, Daniel, Dinkin, Mikhail, Kumar, Bahavna, Waldmann, Jens, Fassnacht, Martin, Tennstedt, Pierre, Glenn, Pat, Kendler, Ady, Steele, Ruth, Campos, Benito, Adebamowo, Sally N., Giordano, Thomas, Mes-Masson, Anne-Marie, Moxley, Katherine, Pinero, Edna M. Mora, Carey, Thomas, Wolf, Gregory, Ley, Timothy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.04.2018; Elsevier
• Subjects: Cell Line, Tumor; DNA Damage; DNA damage footprints; DNA damage repair; epigenetic silencing; Gene Silencing; Genome, Human; Humans; integrative statistical analysis; Loss of Heterozygosity; Machine Learning; Mutation; mutational signatures; Neoplasms - classification; Neoplasms - genetics; protein structure analysis; Recombinational DNA Repair; somatic copy-number alterations; somatic mutations; The Cancer Genome Atlas PanCanAtlas project; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; somatic mutations; DNA damage repair; protein structure analysis; mutational signatures; somatic copy-number alterations; DNA damage footprints; The Cancer Genome Atlas PanCanAtlas project; epigenetic silencing; integrative statistical analysis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.076

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. [Display omitted] •DNA damage repair (DDR) gene alterations are prevalent in many human cancer types•Homology-dependent recombination (HR) and direct repair were most frequently altered•Loss of DDR function is linked to frequency and types of cancer genomic aberrations•Altered HR function can be associated with better or worse outcomes by cancer type Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.