Results: 4

1.
Fig. 3.

Fig. 3. From: Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Deletion of the PTPRS phosphatase activates EGFR. (A) Deletion of PTPRS results in loss of expression. Representative tumors with normal PTPRS copy number and eight tumors with PTPRS deletion (red) were examined for PTPRS mRNA levels using quantitative PCR. Error bars depict 1 SD. Normal (blue) denotes data from normal oral mucosa epithelial cells. Experiments were performed in triplicate. (B) Tumors with PTPRS deletion, but no EGFR alterations, had substantial amounts of phospho-EFGR, phospho-AKT, phospho-PRAS40, and phospho-S6, consistent with pathway activation. Pathway activation was not seen in matched normal tissue. (Scale bars, 500 μm.) (C) Knockdown of PTPRS increases levels of phospho-EGFR (pEGFR) in HNSCC cells. Knockdown was performed using two different siRNAs. Western blot was performed as described in SI Materials and Methods. NT, scrambled, nontargeting siRNA. (D) Tumors with PTPRS deletion demonstrate increased levels of phospho-EGFR and phospho-AKT, compared with tumors lacking PTPRS deletion or EGFR amplification. (Scale bars, 100 μm.)

Luc G. T. Morris, et al. Proc Natl Acad Sci U S A. 2011 November 22;108(47):19024-19029.
2.
Fig. 1.

Fig. 1. From: Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Genomic dissection of the EGFR/PI3K-signaling pathway identifies alterations in the pathway, including frequent PTPRS deletion, in HNSCC. (A) Genome-wide copy number aberrations in oral cancers. Amplifications (red) and deletions (blue) are indicated across the 22 autosomes by genomic coordinates. Regions with a false discovery rate (FDR) ≤10% are plotted, with chromosomes indicated at the center and centromeres in red. Analysis and scores were calculated as described (29). Genes of interest within targeted CNAs are shown above the peaks. Genes encoding proteins that are implicated in the EGFR/PI3K pathway are labeled in red. (B) Focal deletions of PTPRS in an aCGH segmentation map showing the region around the PTPRS gene. The genomic location along chromosome 19 is noted along the top. The color legend depicts the extent of copy number loss. PTPRS direction (arrows) and individual exons (thick blue bars) are labeled. (C) Validation of copy number alterations in HNSCC. Quantitative PCR was used to assess all copy number alterations detected by aCGH. Results for representative genes and tumors are shown. Each measurement was performed in triplicate. Error bars denote 1 SD.

Luc G. T. Morris, et al. Proc Natl Acad Sci U S A. 2011 November 22;108(47):19024-19029.
3.
Fig. 4.

Fig. 4. From: Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Loss of PTPRS promotes resistance to pharmacologic inhibition of EGFR. (A) Knockdown of PTPRS increases resistance to erlotinib in EGFR-mutant lung cancer cells (HCC827, H3255) and in (B) HNSCC cells (MDA-584, SCC-1, Tu-167), as demonstrated by a shift in half-maximal inhibitory concentrations. Cell viability experiments were performed six times. Error bars depict 1 SD. NT, scrambled, nontargeting siRNA. (C) PTPRS expression is significantly lower in HNSCC cell lines resistant to cetuximab (as defined in SI Materials and Methods). Each data point represents normalized expression data from three replicate microarrays of HNSCC cell lines (48). Boxplots represent medians and upper/lower quartiles. Groups were compared using a two-tailed t test. (D) Clinical outcome by PTPRS expression in lung adenocarcinomas with TKI-sensitive EGFR mutations. Cases treated at Memorial Sloan-Kettering Cancer Center were categorized as low (below median) or normal PTPRS expressors, and recurrence and survival were calculated using the Kaplan–Meier method and a log-rank test (31).

Luc G. T. Morris, et al. Proc Natl Acad Sci U S A. 2011 November 22;108(47):19024-19029.
4.
Fig. 2.

Fig. 2. From: Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Copy number alterations in HNSCC promote EGFR/PI3K pathway activation and are associated with poorer prognosis. (A) Activating alterations of the EGFR/PI3K-signaling components were observed in 74% of cases. Alterations were defined as either mutations or significant CNAs and then classified as pathway activating (red) or inactivating (blue). Frequencies are indicated as a percentage of total cases (color bar). (B) Unsupervised hierarchical clustering of copy number alterations. (Upper) Copy number or mutation status of the listed genes is indicated as per the color legend. (Lower) Heat map in which red represents amplification, white represents copy neutral, and blue represents deletion. Dendrogram indicates that three groups of HNSCC exist as defined by copy number alteration patterns. (C) Functional activation of the PI3K pathway observed in tumors harboring pathway mutations or amplification. Tumors with the genotypes indicated are stained with the phospho-antibodies indicated at the left. Normal oral mucosa is used a control. (Scale bars, 500 μm.) (D) Disease-specific survival and (E) overall survival by phospho-Akt status. Immunohistochemistry was performed as described in SI Materials and Methods. (F) Disease-free survival by EGFR/PI3K genetic alteration status. Groups were compared using the log-rank test.

Luc G. T. Morris, et al. Proc Natl Acad Sci U S A. 2011 November 22;108(47):19024-19029.

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