Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer

Liu, Chao, Srihari, Sriganesh, Lal, Samir, Gautier, Benoit, Simpson, Peter T., Khanna, Kum Kum, Ragan, Mark A. and LeCao, Kim-Anh (2015) Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer. Molecular Oncology, 10 1: 179-193. doi:10.1016/j.molonc.2015.09.007

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Author Liu, Chao
Srihari, Sriganesh
Lal, Samir
Gautier, Benoit
Simpson, Peter T.
Khanna, Kum Kum
Ragan, Mark A.
LeCao, Kim-Anh
Title Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer
Journal name Molecular Oncology   Check publisher's open access policy
ISSN 1878-0261
1574-7891
Publication date 2015-06-17
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.molonc.2015.09.007
Open Access Status File (Author Post-print)
Volume 10
Issue 1
Start page 179
End page 193
Total pages 15
Place of publication Amsterdam, The Netherlands
Publisher Elsevier
Collection year 2016
Language eng
Formatted abstract
The Homologous Recombination (HR) pathway is crucial for the repair of DNA double-strand breaks (DSBs) generated during DNA replication. Defects in HR repair have been linked to the initiation and development of a wide variety of human malignancies, and exploited in chemical, radiological and targeted therapies. In this study, we performed a personalised pathway analysis independently for four large sporadic breast cancer cohorts to investigate the status of HR pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics. Specifically, we first manually curated a list of HR genes according to our recent review on this pathway (Liu et al., 2014), and then applied a personalised pathway analysis method named Pathifier (Drier et al., 2013) on the expression levels of the curated genes to obtain an HR score quantifying HR pathway dysregulation in individual tumours. Based on the score, we observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes, and by using two published HR-defect signatures, we found HR pathway dysregulation reflects HR repair deficiency. Furthermore, we identified a novel association between HR pathway dysregulation and chromosomal instability (CIN) in sporadic breast cancer. Although CIN has long been considered as a hallmark of most solid tumours, with recent extensive studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in sporadic cancers remains poorly understood. Our results imply that HR pathway dysregulation might contribute to CIN in sporadic breast cancer.
Keyword Breast cancer
Chromosomal instability
DNA repair
Homologous recombination
Pathway analysis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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