Amplification of the FGRF1 Gene and Its Relationship with Gene Expression and Clinical Significance in Breast Cancer
A Gru, AL Salavaggione, J Hoog, J Snyder, Y Tao, M Ellis, DC Allred. Washington Univeristy in St. Louis, Saint Louis, MO
Background: Fibroblast receptor growth factor 1 (FGFR1) plays a pivotal role in breast development. The gene for FGFR1, located on chromosome 8p11.2, is amplified in 10-15% of invasive breast cancers (IBCs). The relationship between gene amplification and expression, and its clinical significance, are not well understood. The purpose of this study was to evaluate these relationships.
Design: A FISH assay was developed to measure FGFR1 gene copy number, based on a newly designed probe for chromosomal region 8p11, and a commercially available probe for the corresponding centromere. FISH was used to determine FGFR1 status on a previously constructed tissue microarray (TMA) containing 139 IBCs with available data on gene expression profiles (microarray analysis), standard clinical-pathological features (age, race, tumor type, grade, size, nodal status, ER, PgR, HER2), and patient survival. SPSS V13.0 software was used to evaluate the significance of relationships between gene copy number and other variables (student t-test, Kaplan-Meir curves, and Cox-Wilson regression).
Results: The FGFR1 gene was amplified in 9.4% (13/139) of IBCs. Gene expression was significantly increased (>2-fold) in amplified vs. non-amplified IBCs (84% vs. 2%, p≤0.05). Several other genes near FGFR1 in the region of chromosome 811p.2 (e.g. BAG4, PPAPDC1B, TM2D2) were also over-expressed. Polysomy of chromosome 8 was observed in 15% (21/139) of cases, but only 19% (4/21) showed elevated expression of FGFR1. There were significant (p=.05) correlations between amplification of FGFR1 and patient age (older), tumor histological grade (higher), ER/PgR status (positive), and invasive lobular subtype of IBC. In multivariate analyses patients with FGFR1 amplified IBCs showed significantly longer average survival than patients with non-amplified tumors (60 vs. 53 months, p=.029).
Conclusions: FGFR1 was amplified in 9.3% of IBCs (n=139). Gene amplification was strongly associated with elevated expression, and significantly longer patient survival.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 16, Monday Morning