LB48
Identification of molecular pathways regulated by gene copy number aberrations in breast cancer
Rachael Natrajan1, Britta Weigelt2, Alan Mackay1, Felipe Geyer1, Anita Grigoriadis3, David Tan1, Chris Jones4, Christopher Lord1, Radost Vatcheva1, Socorro Maria Rodriguez-Pinilla5, Jose Palacios6, Alan Ashworth1, Jorge Reis-Filho1
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; 2Cancer Research UK, London Research Institute, UK; 3Breakthrough Breast Research Unit, Guy's Hospital, London, UK; 4The Institute of Cancer Research, Sutton, UK; 5Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; 6Servicio de Anatomia Patologica, Hospital Virgen del Rocıo, Seville, Spain
Background
Breast cancer is a heterogeneous disease caused by the accumulation of
genetic hits in neoplastic cells. We hypothesised that breast cancer phenotypic
characteristics are determined by specific constellations of genes whose
expression is regulated by gene copy number aberrations.
Method
We analysed a series of 48 microdissected grade III invasive ductal
carcinomas using high-resolution microarray comparative genomic hybridisation
and mRNA expression arrays. By integrating genomic and transcriptomic data, we
identified genes whose expression significantly correlated with gene copy
number, and those genes that were significantly overexpressed when amplified
(potential amplicon drivers). Ingenuity Pathway Analysis (IPA) was employed to
identify pathways and networks significantly enriched for genes whose
expression correlated with copy number or were overexpressed when amplified.
Results
5931 genes whose expression significantly correlated with copy number were
identified; out of these, 1897 genes were significantly differentially expressed
between basal-like, HER2 and luminal tumours. IPA revealed that 'G1/S cell
cycle regulation' and 'BRCA1 in DNA damage control' pathways were significantly
enriched for genes whose expression correlated with copy number and were
differentially expressed between the molecular subtypes of breast cancer. IPA
of genes whose expression significantly correlated with copy number in each
molecular subtype individually revealed that ooestrogen receptor (ER)
signalling and DNA repair canonical pathways were significantly enriched for
these genes. We also identified 32, 157 and 265 genes significantly
overexpressed when amplified in basal-like, HER2 and luminal cancers,
respectively. These gene lists included known and novel potential therapeutic
targets (e.g. HER2 and PPM1D in HER2 cancers).
Conclusion
Our results provide strong circumstantial evidence that different patterns
of genetic aberrations in distinct molecular subtypes of breast cancer
contribute to their specific transcriptomic profiles and that biological
phenomena characteristic of each subtype (e.g. proliferation, HER2 and ER
signalling) may be driven by specific patterns of copy number aberrations.
