title: Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4067, Australia.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4067, Australia.
authors.forename: Sriganesh
authors.initials: S
authors.lastname: Srihari
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, QLD 4029, Australia.
authors.forename: Samir
authors.initials: S
authors.lastname: Lal
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
authors.forename: Benoît
authors.initials: B
authors.lastname: Gautier
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, QLD 4029, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: QIMR-Berghofer Medical Research Institute, Herston, Brisbane, QLD 4029, Australia.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4067, Australia. Electronic address: m.ragan@uq.edu.au.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ragan
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia. Electronic address: k.lecao@uq.edu.au.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Lê Cao
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D043171:Chromosomal Instability; D004260:DNA Repair; D005260:Female; D006801:Humans; D057285:Precision Medicine
keywords: Breast cancer; Chromosomal instability; DNA repair; Homologous recombination; Pathway analysis