Loss of 16q in High Grade Breast Cancer Is Associated with ER Status: Evidence for Progression in Luminal Tumours?
R Natrajan, MBK Lambros, C Marchio, DSP Tan, R Vatcheva, F Geyer, KK Shiu, D Hungermann, SM Rodriguez- Pinilla, J Palacios, A Ashworth, H Buerger, JS Reis-Filho. Institute of Cancer Research, London, United Kingdom; University of Muenster, Muenster, Germany; CNIO, Madrid, Spain; Hospital Universitario Virgen del Roco, Seville, Spain; Institute of Pathology, Paderborn, Germany
Background: Loss of the long arm of chromosome 16 (16q) is a common phenomenon in low grade/grade I (GI) invasive ductal carcinomas of no special type (IDC-NSTs) of the breast, whereas this event is uncommonly seen in high grade/grade III (GIII) IDC-NSTs. Together with data on the pathology and genetics of breast cancer recurrences, this has led to the concept that GI and GIII breast cancers evolve through distinct genetic pathways and that progression from GI to GIII is an uncommon biological phenomenon. Our aim was to define the genetic profiles of GIII IDC-NSTs with and without 16q loss.
Design: Frozen sections of 93 GIII IDC-NSTs were microdissected, DNA was extracted and subjected to microarray-based comparative genomic hybridisation analysis using a 32K tiling path bacterial artificial chromosome (BAC) array platform, which has a resolution of 50kb. We compared the genomic profiles of GIII tumours with 16q whole arm loss (16qWL) in the groups of oestrogen receptor (ER) positive (ER+) and negative (ER-) cancers.
Results: We demonstrate that 36.5% of GIII breast cancers display 16qWL. This genetic aberration was associated with ER expression and luminal phenotype. ER positive GIII IDC-NSTs with 16qWL displayed significantly higher genomic instability than ER positive IDC-NSTs without 16qWL. Furthermore, ER positive and ER negative IDC-NSTs stratified according to the presence of 16qWL harboured distinct patterns of genetic aberrations. Interestingly, ER+/ 16qWL tumours displayed genetic features usually found in tumours with homologous DNA repair defects (ie sawtooth genomic profiles) and significantly more frequently displayed loss of BRCA2 than the remaining ER+ cancers.
Conclusions: Our results demonstrate that only a minority of GIII IDC-NSTs harbour 16qWL, confirming that progression from low to high grade breast cancer is an uncommon phenomenon. 16qWL was associated with ER-positivity and luminal phenotype. Given that GI cancer are consistently positive for ER and harbour a luminal phenotype, our results suggest that if progression from GI to GIII breast cancer happens may preferentially occur in breast cancers of luminal phenotype.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 11, Wednesday Morning