Mutational Profiling of Phyllodes Tumors
VB Korcheva, J Levine, C Beadling, A Warrick, N Olson, M Heinrich, CL Corless, ML Troxell. Oregon Health and Science University, Portland, OR; Kaiser Permanente, Portland, OR
Background: Phyllodes tumors (PTs) represent 0.3-1% of all breast tumors and have a spectrum of histologic appearances and clinical outcome. PTs are morphologically divided into three categories-benign, borderline, and malignant. Investigators have studied biologic markers as adjuncts to morphology in predicting the behavior of these tumors. For instance, KIT (CD117) overexpression has been noted in malignant PTs in few small studies; however, no KIT activating mutations have been identified to date. The aim of this study was to screen for activating mutations in tyrosine kinases and signalling pathway intermediates in PTs. Characterization of specific genetic alterations could help understand the pathogenic mechanisms involved in the initiation and progression of PTs, and ultimately help guide rational therapeutic strategy.
Design: Genomic DNA was extracted from formalin-fixed, paraffin embedded tissue of 26 PTs (10 benign, 9 borderline, and 7 malignant) and screened for a panel of known hotspot mutations using PCR and mass-spectroscopy analysis (Sequenom MassARRAY). The mutation panel covers 321 mutations in 30 genes, including ABL, AKT1/2/3, BRAF, CDK4, CTNNB1, EGFR1, ERBB2, FBX4, FBXW7, FGFR1/2/3, FLT3, GNAQ, HRAS, JAK2, KIT, KRAS, MAPK2K1/2, MET, NRAS, PDGFRA, PIK3CA, PTPN11, RET, SOS1, and TP53.
Results: Mutation profiling identified the substitution FBX4 S8R in 3 of the 26 PTs (one benign and two borderline cases). One of the seven malignant PTs was found to have MET T992I substitution. No KIT mutations were identified.
Conclusions: Our study identified FBX4 S8R and MET T992I substitutions that likely represent single nucleotide polymorphisms in a limited number of PTs. Nevertheless, a recent study has shown that the S8R alteration in the E3 ubiquitin ligase FBX4 results in diminished cyclin D1 degradation, and hence increased cyclin D1 protein expression. The T992I substitution in the hepatocyte growth receptor (MET) is of unknown functional importance. In conclusion, PTs lack oncogenic mutations that are commonly observed in other types of sarcoma, carcinoma, melanoma, and hematopoietic malignancies.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 1, Wednesday Afternoon