Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer.
Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer.
复制标题
DOI：
10.1126/science.aao3130
复制
发表时间：
2017-10-13
期刊：
影响因子：
--
通讯作者：
Clevers H
中科院分区：
文献类型：
--
作者：
Drost J;van Boxtel R;Blokzijl F;Mizutani T;Sasaki N;Sasselli V;de Ligt J;Behjati S;Grolleman JE;van Wezel T;Nik-Zainal S;Kuiper RP;Cuppen E;Clevers H
突变过程是癌症发生和进展的基础。癌症基因组中这些过程的特征可能解释癌症病因，并可能具有诊断和预后价值。我们开发了一种可用于探索癌症相关突变特征起源的策略。我们利用CRISPR - Cas9技术删除人类结肠类器官中的关键DNA修复基因，随后进行延迟亚克隆和全基因组测序。我们发现，错配修复基因MLH1缺陷的类器官中的突变积累是由复制错误驱动的，并且准确地模拟了在错配修复缺陷型结直肠癌中观察到的突变谱。将该策略应用于编码一种碱基切除修复蛋白的癌症易感基因NTHL1，揭示了先前在一个乳腺癌队列中观察到的一种突变足迹（特征30）。我们表明特征30可由种系NTHL1突变产生。
Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair–deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.
登录
查看更多内容
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
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：
64.5
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
通讯作者：
Getz G
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：
64.5
作者：
Huch M;Gehart H;van Boxtel R;Hamer K;Blokzijl F;Verstegen MM;Ellis E;van Wenum M;Fuchs SA;de Ligt J;van de Wetering M;Sasaki N;Boers SJ;Kemperman H;de Jonge J;Ijzermans JN;Nieuwenhuis EE;Hoekstra R;Strom S;Vries RR;van der Laan LJ;Cuppen E;Clevers H
通讯作者：
Clevers H