Pan-cancer landscape of homologous recombination deficiency.
Pan-cancer landscape of homologous recombination deficiency.
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泛癌景观同源重组缺失。
DOI：
10.1038/s41467-020-19406-4
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发表时间：
2020-11-04
影响因子：
16.6
通讯作者：
Cuppen E
中科院分区：
文献类型：
--
作者：
Nguyen L;W M Martens J;Van Hoeck A;Cuppen E
同源重组缺陷（HRD）导致受损的双链断裂修复，并且是肿瘤发生的常见驱动因素。在这里，我们开发了一个全基因组突变疤痕为基础的泛癌症分类的同源性缺乏症（CHORD），可以区分BRCA 1和BRCA 2亚型。对转移性（n = 3，504）和原发性（n = 1，854）泛癌症队列的分析显示，HRD在卵巢癌和乳腺癌中最常见，其次是胰腺癌和前列腺癌。我们确定BRCA 1、BRCA 2、RAD 51 C或PALB 2的双等位基因失活是HRD最常见的遗传原因，RAD 51 C和PALB 2失活导致BRCA 2型HRD。我们发现，虽然HRD的特定遗传原因是癌症类型特异性的，但双等位基因失活主要与杂合性缺失（洛）相关，在前列腺癌中深度缺失的贡献增加。我们的研究结果证明了基于泛癌症基因组学的HRD测试的价值及其对患者分层的潜在诊断价值，例如聚ADP-核糖聚合酶抑制剂（PARPi）治疗。同源重组缺陷的癌症可以受益于用聚ADP-核糖聚合酶（PARP）抑制剂治疗。在这里，作者生成了一个分类器，可以从基因组数据预测同源重组缺陷，并提出了几种可能受益于PARP抑制剂治疗的癌症类型。
Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n = 3,504) and primary (n = 1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi). Cancers deficient in homologous recombination can benefit from treatment with poly ADP-ribose polymerase (PARP) inhibitors. Here, the authors generated a classifier that can predict homologous recombination deficiency from genomic data and suggest several cancer types that may benefit from PARP inhibitor treatment.
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影响因子：
64.8
作者：
Nik-Zainal S;Davies H;Staaf J;Ramakrishna M;Glodzik D;Zou X;Martincorena I;Alexandrov LB;Martin S;Wedge DC;Van Loo P;Ju YS;Smid M;Brinkman AB;Morganella S;Aure MR;Lingjærde OC;Langerød A;Ringnér M;Ahn SM;Boyault S;Brock JE;Broeks A;Butler A;Desmedt C;Dirix L;Dronov S;Fatima A;Foekens JA;Gerstung M;Hooijer GK;Jang SJ;Jones DR;Kim HY;King TA;Krishnamurthy S;Lee HJ;Lee JY;Li Y;McLaren S;Menzies A;Mustonen V;O'Meara S;Pauporté I;Pivot X;Purdie CA;Raine K;Ramakrishnan K;Rodríguez-González FG;Romieu G;Sieuwerts AM;Simpson PT;Shepherd R;Stebbings L;Stefansson OA;Teague J;Tommasi S;Treilleux I;Van den Eynden GG;Vermeulen P;Vincent-Salomon A;Yates L;Caldas C;van't Veer L;Tutt A;Knappskog S;Tan BK;Jonkers J;Borg Å;Ueno NT;Sotiriou C;Viari A;Futreal PA;Campbell PJ;Span PN;Van Laere S;Lakhani SR;Eyfjord JE;Thompson AM;Birney E;Stunnenberg HG;van de Vijver MJ;Martens JW;Børresen-Dale AL;Richardson AL;Kong G;Thomas G;Stratton MR
通讯作者：
Stratton MR
影响因子：
12.3
作者：
Poti, Adam;Gyergyak, Hella;Szuets, David
通讯作者：
Szuets, David
影响因子：
64.8
作者：
Jonsson, Philip;Bandlamudi, Chaitanya;Taylor, Barry S.
通讯作者：
Taylor, Barry S.
影响因子：
16.6
作者：
Behjati, Sam;Gundem, Gunes;Wedge, David C.;Roberts, Nicola D.;Tarpey, Patrick S.;Cooke, Susanna L.;Van Loo, Peter;Alexandrov, Ludmil B.;Ramakrishna, Manasa;Davies, Helen;Nik-Zainal, Serena;Hardy, Claire;Latimer, Calli;Raine, Keiran M.;Stebbings, Lucy;Menzies, Andy;Jones, David;Shepherd, Rebecca;Butler, Adam P.;Teague, Jon W.;Jorgensen, Mette;Khatri, Bhavisha;Pillay, Nischalan;Shlien, Adam;Futreal, P. Andrew;Badie, Christophe;McDermott, Ultan;Bova, G. Steven;Richardson, Andrea L.;Flanagan, Adrienne M.;Stratton, Michael R.;Campbell, Peter J.
通讯作者：
Campbell, Peter J.
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S