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Nat Commun. 2016 Aug 31;7:12619. doi: 10.1038/ncomms12619.

Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy.

Zhang W1,2, Mao JH1, Zhu W3, Jain AK4,5, Liu K6,7, Brown JB6,7,8, Karpen GH1,2.

Author information

1
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Mailstop 977, Berkeley, California 94720, USA.
2
Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
3
Department of Translational Bioinformatics, Cellular Biomedicine Group, Inc., Level 5, Building 1, 333 Guiping Road, Shanghai 200233, the People's Republic of China.
4
Department of Therapeutic Radiology, Yale School of Medicine, Yale University, New Haven, Connecticut 06510, USA.
5
Ashland Bellefonte Cancer Center, 122 St Christopher Drive, Ashland, Kentucky 41101, USA.
6
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Mailstop 977, Berkeley, California 94720, USA.
7
Department of Statistics, University of California, Berkeley, California 94720, USA.
8
Department of Environmental Bioinformatics, University of Birmingham, Birmingham, B15 2TT, UK.

Abstract

Chromosomal instability (CIN) is a hallmark of cancer that contributes to tumour heterogeneity and other malignant properties. Aberrant centromere and kinetochore function causes CIN through chromosome missegregation, leading to aneuploidy, rearrangements and micronucleus formation. Here we develop a Centromere and kinetochore gene Expression Score (CES) signature that quantifies the centromere and kinetochore gene misexpression in cancers. High CES values correlate with increased levels of genomic instability and several specific adverse tumour properties, and prognosticate poor patient survival for breast and lung cancers, especially early-stage tumours. They also signify high levels of genomic instability that sensitize cancer cells to additional genotoxicity. Thus, the CES signature forecasts patient response to adjuvant chemotherapy or radiotherapy. Our results demonstrate the prognostic and predictive power of the CES, suggest a role for centromere misregulation in cancer progression, and support the idea that tumours with extremely high CIN are less tolerant to specific genotoxic therapies.

Conflict of interest statement

W.Z., J.-H.M. and G.H.K. are named as inventors for a pending patent application PCT/US15/31413 entitled ‘Centromere/Kinetochore protein genes for cancer diagnosis, prognosis and treatment selection'. The remaining authors declare no competing financial interests.

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