Knijnenburg, Theo ATheo AKnijnenburgWang, LinghuaLinghuaWangZimmermann, Michael TMichael TZimmermannChambwe, NyashaNyashaChambweGao, Galen FGalen FGaoCherniack, Andrew DAndrew DCherniackFan, HuihuiHuihuiFanShen, HuiHuiShenWay, Gregory PGregory PWayGreene, Casey SCasey SGreeneLiu, YuexinYuexinLiuAkbani, RehanRehanAkbaniFeng, BinBinFengDonehower, Lawrence ALawrence ADonehowerMiller, ChaseChaseMillerShen, YangYangShenKarimi, MostafaMostafaKarimiChen, HaoranHaoranChenKim, PoraPoraKimJia, PeilinPeilinJiaShinbrot, EveEveShinbrotZhang, ShaojunShaojunZhangLiu, JianfangJianfangLiuHu, HaiHaiHuBailey, Matthew HMatthew HBaileyYau, ChristinaChristinaYauWolf, DeniseDeniseWolfZhao, ZhongmingZhongmingZhaoWeinstein, John NJohn NWeinsteinLi, LeiLeiLiDing, LiLiDingMills, Gordon BGordon BMillsLaird, Peter WPeter WLairdWheeler, David ADavid AWheelerShmulevich, IlyaIlyaShmulevichMonnat, Raymond JRaymond JMonnatXiao, YonghongYonghongXiaoWang, ChenChenWang2024-10-082024-10-082018-04-03https://boris-portal.unibe.ch/handle/20.500.12422/64168DNA 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.enDNA damage footprints DNA damage repair The Cancer Genome Atlas PanCanAtlas project epigenetic silencing integrative statistical analysis mutational signatures protein structure analysis somatic copy-number alterations somatic mutations600 - Technology::610 - Medicine & healtharticle10.7892/boris.1263842961766410.1016/j.celrep.2018.03.076