An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.
An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.
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DOI：
10.1038/s41467-021-24919-7
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发表时间：
2021-07-29
影响因子：
16.6
通讯作者：
Gilbert LA
中科院分区：
文献类型：
--
作者：
Das R;Sjöström M;Shrestha R;Yogodzinski C;Egusa EA;Chesner LN;Chen WS;Chou J;Dang DK;Swinderman JT;Ge A;Hua JT;Kabir S;Quigley DA;Small EJ;Ashworth A;Feng FY;Gilbert LA
数千种肿瘤的基因组测序揭示了许多与特定类型癌症相关的基因。类似地，大规模的CRISPR功能基因组学工作已经在数百个细胞系中绘制了癌细胞增殖或存活所需的基因。尽管如此，对于特定的疾病亚型，如转移性前列腺癌，可能有许多未发现的肿瘤特异性驱动基因，可能代表潜在的药物靶点。为了确定这种遗传依赖性，我们在转移性前列腺癌模型中进行了基因组规模的CRISPRi筛选。然后，我们创建了一个管道，其中我们将泛癌症功能基因组学数据与我们的转移性前列腺癌功能和临床基因组学数据相结合，以确定可以驱动侵袭性前列腺癌表型的基因。我们对这些数据的综合分析揭示了已知的前列腺癌特异性驱动基因，如AR和HOXB 13，以及一些特征不佳的热门基因。在这项研究中，我们强调了整合的临床和功能基因组学管道的优势，并专注于两个热门基因，KIF4A和WDR 62。我们证明，无论AR状态如何，KIF4A和WDR 62在体外和体内多种模型中均驱动侵袭性前列腺癌表型，并且还与患者预后不良相关。据推测，转移性前列腺癌有许多肿瘤特异性驱动基因。在这里，作者进行了全基因组CRISPRi筛选，并将这些数据与转移性前列腺癌功能和临床基因组学数据整合，以表明KIF4A和WDR 62驱动侵袭性前列腺癌表型。
Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome. It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1056/nejmoa1110000
发表时间：
2012-01-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
通讯作者：
Cooney KA
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P