Accelerating Discovery of Functional Mutant Alleles in Cancer

Cancer Discovery - Tập 8 Số 2 - Trang 174-183 - 2018
Matthew T. Chang1,2,3, Tripti Shrestha Bhattarai1,2, Alison M. Schram4, Craig M. Bielski5, Mark T.A. Donoghue5, Philip Jonsson1,2, Debyani Chakravarty5, Sarah Phillips5, Cyriac Kandoth5, Alexander Penson1,2, Alexander N. Gorelick1,2, Tambudzai Shamu1,2, Swati Patel1, Christopher Harris5, Jianjiong Gao5, S. Onur Sumer5, Ritika Kundra5, Pedram Razavi4, Bob T. Li4, Dalicia N. Reales5, Nicholas D. Socci5,6, Gowtham Jayakumaran7, Ahmet Zehir7, Ryma Benayed7, Maria E. Arcila7, Sarat Chandarlapaty1,4, Marc Ladanyi7, Nikolaus Schultz2,5, José Baselga4, Michael F. Berger5,7, Neal Rosen4,8, David B. Solit1,4,5,9, David M. Hyman4, Barry S. Taylor1,2,5
11Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
22Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
33Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
44Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
55Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
66Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York.
77Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
88Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
99Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York.

Tóm tắt

AbstractMost mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.Significance: Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically significant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identification, thereby expanding the reach of precision oncology in patients with cancer. Cancer Discov; 8(2); 174–83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127

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Cancer Discovery

Tập 8 Số 2

174-183

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