Integrative identification of non-coding regulatory regions driving metastatic prostate cancer

被引：0

作者：

Woo, Brian J. ^{[1
,2
,3
,6
]}

Moussavi-Baygi, Ruhollah ^{[1
,2
,3
]}

Karner, Heather ^{[1
,2
,3
,6
]}

Karimzadeh, Mehran ^{[1
,2
,3
,6
]}

Yousefi, Hassan ^{[1
,2
,3
,6
]}

Lee, Sean ^{[1
,2
,3
,6
]}

Garcia, Kristle ^{[1
,2
,3
]}

Joshi, Tanvi ^{[1
,2
,3
]}

Yin, Keyi ^{[1
,2
,3
]}

Navickas, Albertas ^{[1
,2
,3
]}

Gilbert, Luke A. ^{[1
,2
,3
,6
]}

Wang, Bo ^{[4
,5
]}

Asgharian, Hosseinali ^{[1
,2
,3
,7
]}

Feng, Felix Y. ^{[2
,3
,8
]}

Goodarzi, Hani ^{[1
,2
,3
,6
,7
]}

机构：

[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[4] Vector Inst, Toronto, ON, Canada

[5] Univ Hlth Network, Peter Munk Cardiac Ctr, Toronto, ON, Canada

[6] Arc Inst, Palo Alto, CA 94305 USA

[7] Univ Calif San Francisco, Bakar Computat Hlth Sci Inst, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA

来源：

CELL REPORTS | 2024年 / 43卷 / 09期

关键词：

TERT PROMOTER MUTATIONS; VARIANTS; GENOME; DISCOVERY; DATABASE; CELLS;

D O I：

10.1016/j.celrep.2024.114764

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Large-scale sequencing efforts have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of variants occur within non-coding genomic regions. We designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Applying this framework to sequencing data from a large prostate cancer patient cohort revealed a large set of candidate drivers. We used (1) in silico analyses, (2) massively parallel reporter assays, and (3) in vivo CRISPR interference screens to systematically validate metastatic castration-resistant prostate cancer (mCRPC) drivers. One identified enhancer region, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of the U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. SF3A1 and CCDC157 promote tumor growth in vivo. . We nominated a number of transcription factors, notably SOX6, to regulate expression of SF3A1 and CCDC157. Our integrative approach enables the systematic detection of non-coding regulatory regions that drive human cancers.

引用

页数：26

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