Synthetic lethality between CCNE1 amplification and loss of BRCA1

D Etemadmoghadam; BA Weir; G Au-Yeung; K Alsop; G Mitchell; J George; S Davis; AD D'Andrea; K Simpson; WC Hahn; DDL Bowtell

Journal article

Synthetic lethality between CCNE1 amplification and loss of BRCA1

D Etemadmoghadam, BA Weir, G Au-Yeung, K Alsop, G Mitchell, J George, S Davis, AD D'Andrea, K Simpson, WC Hahn, DDL Bowtell

Proceedings of the National Academy of Sciences of the United States of America | Published : 2013

DOI: 10.1073/pnas.1314302110

Abstract

High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor..

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University of Melbourne Researchers

Kaylene Simpson Author

David Bowtell Author

Kathryn Alsop Author

George Au-Yeung Author

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Grants

Awarded by National Cancer Institute

Funding Acknowledgements

The authors acknowledge assistance from Daniel Thomas and Yanny Handoko in conducting siRNA experiments in the Victorian Centre for FunctionalGenomics, PeterMacCallumCancer Centre. The Australian Ovarian Cancer Study (AOCS) acknowledges the cooperation of the participating institutions in Australia and the contribution of the study nurses, research assistants, and all clinical and scientific collaborators. We thank all of thewomen who participated in the study. This study was funded by National Health and Medical Research Council (NHMRC) Project Grant APP 1042358, Cancer Australia Grant APP 1004673, and US National Institutes of Health Grant U01 CA176058. The AOCS was supported by US Army Medical Research andMateriel Command Grant DAMD17-01-1-0729, the Cancer Council Tasmania, the Cancer Foundation of Western Australia, and NHMRC Grant ID400413. Genotyping of AOCS patient samples was supported by Ovarian Cancer Research Program of the US Department of Defense Grants W81XWH-08-10684 andW81XWH-08-1-0685; Cancer Australia and National Breast Cancer Foundation Grants ID509303, CG-08-07, and ID509366; the Peter MacCallum Cancer Centre Foundation; and the Cancer Council Victoria. The Victorian Centre for Functional Genomics is funded by the Australian Cancer Research Foundation and the Victorian Department of Industry, Innovation and Regional Development. The Australian Phenomics Network is supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative, the Australasian Genomics Technologies Association, the Brockhoff Foundation, and the Peter MacCallum Cancer Centre Foundation.