PD08-09: PTPN12 Gene Expression Signature in Triple Negative Breast Cancer Cohort.
Authors: A Ghazalpour, RP Bender, MJ McGinniss, R Ashfaq
Journal: Cancer Research (2011)

Abstract PTPN12 tyrosine phosphatase may play a role in tumor development/progression in triple negative breast cancer patients (TNP). The effects of PTPN12 appear to be mediated through several tyrosine kinase receptors including EGFR, HER2, and PDGFR-beta. We investigated the variability associated with PTPN12 transcript in the microarray gene expression data obtained from 105 TNP as determined by IHC for ER and PR and IHC and FISH for HER2 during our clinical molecular profiling on solid tumors. The mRNA levels of PTPN12 in our cohort was highly variable suggesting a complex genetic regulation of PTPN12 transcription in TNP patients. The highly variable nature of PTPN12 mRNA levels lead us to perform a correlation-based analysis of the transcriptome in TNP samples to gain insight into pathways and cellular processes associated with PTPN12 variation. Specifically, we quantile-normalized and performed two-dimensional hierarchical clustering of the 1000 top correlated genes with PTPN12 expression across the 105 TNP samples. We identified seven distinct gene clusters and three distinct patient subpopulations. The three distinct subtypes of TNP were comprised of low expressing PTPN12 (median log2 expression of 12.3), medium expressing PTPN12 (median log2 expression of 13.1), and high expressing PTPN12 (median log2 expression of 13.4). From the 7 gene clusters identified, 6 were positively correlated and one cluster (cluster 3) was negatively correlated with PTPN12 expression. Upon examining the genes within each cluster, we found that all contain unique set of genes related to cell proliferation, cell death, cell motility, cell cycle regulation and other cancer related pathways. From the 7 clusters, clusters 1, 6 and 7 had the highest fraction of such genes. The gene expression pattern and the gene content of these three clusters is as follows: Cluster 1 (208 genes) were genes that were highly expressed in all three TNP groups and the expression of the genes was highest in high PTPN12 expressing patients. Functional classification of genes by the DAVID bioinformatics tool at NCBI showed several genes related to cancer, including 19 MAP kinase signaling genes, and 15 genes involved in regulation of apoptosis. Cluster 6 (150 genes) contained genes showing very low expression in low-expressing TNPs, moderately expressed in medium expressing TNPs, and highly expressed in high-expressing TNPs. Cluster 6 had the highest fraction of cancer related genes including 7 mitosis and cell cycle check point genes, 6 cytoskeletal genes, 4 phosphatases and 6 kinases including KRAS, 4 DNA repair genes, 8 signal transduction genes, 3 positive regulator of apoptosis, and 22 genes involved in regulation of gene expression. Cluster 7 (166 genes) contained genes that were expressed at low level throughout the three TNP groups but the severity of under-expression was higher in TNP patients with low PTPN12 expression. In cluster 7 there were 5 genes belonging to the EGFR and FGF signaling pathways, and 6 genes involved in mitosis. It is worth noting that EGFR pathway has been postulated to crosstalk with PTPN12 protein. All together our results provide support for the involvement of PTPN12 in cancer development and highlights a promising therapeutic target for TNP patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-09.