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A functional genomic approach to actionable gene fusions for precision oncology.


ABSTRACT: Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.

SUBMITTER: Li J 

PROVIDER: S-EPMC8827659 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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A functional genomic approach to actionable gene fusions for precision oncology.

Li Jun J   Lu Hengyu H   Ng Patrick Kwok-Shing PK   Pantazi Angeliki A   Ip Carman Ka Man CKM   Jeong Kang Jin KJ   Amador Bianca B   Tran Richard R   Tsang Yiu Huen YH   Yang Lixing L   Song Xingzhi X   Dogruluk Turgut T   Ren Xiaojia X   Hadjipanayis Angela A   Bristow Christopher A CA   Lee Semin S   Kucherlapati Melanie M   Parfenov Michael M   Tang Jiabin J   Seth Sahil S   Mahadeshwar Harshad S HS   Mojumdar Kamalika K   Zeng Dong D   Zhang Jianhua J   Protopopov Alexei A   Seidman Jonathan G JG   Creighton Chad J CJ   Lu Yiling Y   Sahni Nidhi N   Shaw Kenna R KR   Meric-Bernstam Funda F   Futreal Andrew A   Chin Lynda L   Scott Kenneth L KL   Kucherlapati Raju R   Mills Gordon B GB   Liang Han H  

Science advances 20220209 6


Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome At  ...[more]

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