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

• Published in: Nature communications 2016-08, Vol.7 (1), p.12619-12619, Article 12619
• Main Authors: Zhang, Weiguo, Mao, Jian-Hua, Zhu, Wei, Jain, Anshu K., Liu, Ke, Brown, James B., Karpen, Gary H.
• Format: Article
• Language: English
• Subjects: 38/61; Bioinformatics; Breast - pathology; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer; Cell cycle; Centromere - genetics; Centromere - metabolism; Chemotherapy; Chemotherapy, Adjuvant - methods; Chromosomal Instability - genetics; Chromosomes; Datasets as Topic; Epidermal growth factor; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genomes; Genomics; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Lung - pathology; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Medical prognosis; multidisciplinary; Neoplasm Staging; Prognosis; Proteins; Radiation therapy; Radiotherapy, Adjuvant - methods; Science; Science & Technology - Other Topics; Science (multidisciplinary); Tissue Array Analysis - methods; Treatment Outcome; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12619

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. Centromeres and kinetochores are important in maintaining chromosomal stability. Here, the authors show that overexpression of a subset of centromere and kinetochore genes is associated with chromosomal instability and mutation burden in cancer, and predict patient survival and response to genotoxic therapies.