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TP53 mutations among molecular subtypes of HER2-positive tumors
Breast Cancer Research volume 7, Article number: P4.45 (2005)
The HER2/ERBB2 receptor tyrosine kinase plays a critical role in the pathogenesis of breast cancer. Amplification and/or overexpression of HER2 occurs in 20–30% of Caucasian breast cancers and correlates with poor prognosis. However, within the group of patients overexpressing HER2, there are obvious differences regarding the course of the disease. This study identifies different molecular subtypes among 47 HER2-positive tumors based on genome-wide expression profiling. A subset of these tumors was analyzed for TP53 mutations, a gene commonly mutated among breast carcinomas.
Materials and methods
RNA isolated from 35 infiltrating ductal breast carcinomas (IDC) with associated HER2 immunohistochemistry (IHC) data were analyzed using 42,000 clone cDNA microarrays. Seventeen of these samples that showed 2+ or 3+ protein expression were evaluated by fluorescence in situ hybridization (FISH). Using microarray data from this cohort, we determined an RNA expression threshold associated with IHC/FISH positivity. Twenty-nine IDCs from Norway with TP53 mutation data and whose RNA expression of HER2 exceeded this threshold were added to the subsequent analysis, giving a total of 47 samples defined as HER2-positive. ANOVA correction was used to address differences in methodology and the data were analyzed with hierarchical clustering and disease-specific genomic analysis.
At least three molecular subtypes of HER2-positive breast carcinomas were identified by hierarchical clustering of the 18 HER2-positive samples based on the 42K array data. One subgroup contained tumors that overexpressed estrogen receptor (ER)-associated genes, another subgroup expressed cell-to-cell and cell-to-stroma signaling genes as well as varying amounts of the ER-associated genes, whereas a third subgroup showed no expression of the ER-associated gene cluster. These subgroups were confirmed when analyzing the 47 samples. TP53 mutation data were available for 32 of the 47 samples and 21 of these had a somatic TP53 mutation. We found less mutations in the ER group, with five mutations and seven wild type, than in the other two groups (four wild type and 16 mutated). This difference was significant (P = 0.034).
The TP53 mutations seem to be differentially distributed among the molecular subtypes of HER2-positive tumors. Further studies are required to shed light on the implications of this finding.
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Helland, Å., Nicolau, M., Ji, Y. et al. TP53 mutations among molecular subtypes of HER2-positive tumors. Breast Cancer Res 7, P4.45 (2005) doi:10.1186/bcr1175
- Breast Carcinoma
- Molecular Subtype
- TP53 Mutation
- Ductal Breast Carcinoma
- Expression Threshold