Integration of Microarray CGH and Expression Analysis Reveals Potential Breast Cancer Therapeutic Targets
A Muggerud, H Horlings, MB Lambros, R Natrajan, A Mackay, A Ashworth, MJ van de Vijver, JS Reis-Filho. ICR, London, United Kingdom; Academic Medical Center, Amsterdam, Netherlands
Background: Breast cancer is a heterogeneous disease at the molecular, histopathological and clinical levels. Our aims were to define regions of amplification recurrently amplified in the distinct molecular subtypes of breast cancer (i.e. basal-like, luminal, HER2 and normal breast-like) and to identify genes that are consistently overexpressed when amplified in each molecular subtype.
Design: Two independent cohorts of breast cancer were analysed: i) 69 consecutive frozen invasive breast carcinomas, where samples contained a tumour cell content >70% and ii) 53 frozen, microdissected, grade III invasive ductal carcinomas of no special type (IDCs-NST). Samples from both cohorts were subjected to aCGH using a tiling path 32K BAC array platform and gene expression profiling using the Agilent 25K gene expression arrays (n=69) or the Illumina WG6 v2 platform (n=53). These tumours were classified into luminal, HER2, basal-like and normal-like subgroups based on gene expression profiles. Genes overexpressed when amplified were identified by overlaying aCGH and expression data and performing a multi-Mann-Whitney U test with p values adjusted for multiple comparisons.
Results: In the series of 69 invasive breast cancers, 22% were classified as basal-like, 9% HER2, 68% luminal and 1% normal-like, whereas in the series of 53 IDCs-NST, 26% were classified as basal-like, 26 % HER2, 45% luminal and none as normal breast-like. By overlaying aCGH and gene expression data sets, we identified 4435 genes whose expression was significantly associated with copy number, of which 257 genes were significantly overexpressed when amplified. 116 genes consistently overexpressed when amplified in both datasets include CCND1, ORAOV1, CTTN on 11q13.2-q13.4 and PPM1D and APPBP2 in 17q23.2. Genes recurrently amplified and significantly overexpressed when amplified in specific subtypes of breast cancer included ERLIN2, PROSC and BRF2 on 8p11.2 in 12% of luminal cancers, GDI2, FBXO18, and ATP5C1 on 10p14-10p15 in 18% of basal-like tumours and WDR68, CCDC44, CCDC47, DDX42, FTSJ3, PSMC5 and SMARCD2 on 17q23.3 in 26% of HER2 tumours.
Conclusions: Different breast cancer molecular subtypes harbour distinct recurrent amplifications, which encompass genes that may be exploited as therapeutic targets.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 61, Tuesday Morning