Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer

被引：76

作者：

Bielski, Craig M. ^{[1
]}

Donoghue, Mark T. A. ^{[1
]}

Gadiya, Mayur ^{[2
]}

Hanrahan, Aphrothiti J. ^{[2
]}

Won, Helen H. ^{[3
]}

Chang, Matthew T. ^{[2
,4
]}

Jonsson, Philip ^{[2
,4
]}

Penson, Alexander, V ^{[2
,4
]}

Gorelick, Alexander ^{[2
,4
]}

Harris, Christopher ^{[1
]}

Schram, Alison M. ^{[5
]}

Syed, Aijazuddin ^{[3
]}

Zehir, Ahmet ^{[3
]}

Chapman, Paul B. ^{[5
]}

Hyman, David M. ^{[5
,6
]}

Solit, David B. ^{[1
,2
,5
,6
]}

Shannon, Kevin ^{[7
,8
]}

Chandarlapaty, Sarat ^{[2
,5
]}

Berger, Michael F. ^{[1
,3
]}

Taylor, Barry S. ^{[1
,2
,4
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[6] Weill Cornell Med Coll, New York, NY 10065 USA

[7] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

来源：

CANCER CELL | 2018年 / 34卷 / 05期

关键词：

KRAS; MUTATION; DISCOVERY; EXAPTATION; GENETICS;

D O I：

10.1016/j.ccell.2018.10.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy.

引用

页码：852 / +

页数：15

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