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SYK allelic loss and the role of Syk-regulated genes in breast cancer survival.

Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, Kallakury B, Makambi KH, Marian C, Mueller SC - PLoS ONE (2014)

Bottom Line: In cases without immune cell infiltration, loss of SYK copy number was associated with a significant reduction of SYK mRNA.We found that overall survival was significantly reduced in IDC and Luminal A+B cases where copy number and mutations of these 55 genes were affected (Kaplan-Meier, Logrank test p-value 0.007141 and Logrank test p-value 0.001198, respectively).We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.

ABSTRACT
Heterozygotic loss of SYK, a non-receptor tyrosine kinase, gives rise to mouse mammary tumor formation where Syk protein levels are reduced by about half; loss of SYK mRNA is correlated with invasive cell behavior in in vitro models; and SYK loss has been correlated with distant metastases in patients. Here, allelic loss of the SYK gene was explored in breast ductal carcinoma in situ (DCIS) using fluorescence in situ hybridization and pyrosequencing, respectively, and in infiltrating ductal carcinoma (IDC) using genomic data from The Cancer Genome Atlas (TCGA). Allelic loss was present in a subset of DCIS cases where adjacent IDC was present. SYK copy number loss was found in about 26% of 1002 total breast cancer cases and 30% of IDC cases. Quantitative immunofluorescence revealed Syk protein to be six-fold higher in infiltrating immune cells compared with epithelial cells. This difference distorted tumor cell mRNA and protein levels in extracts. 20% of 1002 IDC cases contained elevated immune cell infiltration as estimated by elevated immune-specific mRNAs. In cases without immune cell infiltration, loss of SYK copy number was associated with a significant reduction of SYK mRNA. Here we define a 55 Gene Set consisting of Syk interacting, motility- and invasion-related genes. We found that overall survival was significantly reduced in IDC and Luminal A+B cases where copy number and mutations of these 55 genes were affected (Kaplan-Meier, Logrank test p-value 0.007141 and Logrank test p-value 0.001198, respectively). We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival. A closer examination of the role of Syk interacting motility and invasion genes and their prognostic and/or causative association with metastatic disease and patient outcome is warranted.

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Network interactions amongst the members of the 55 Gene Set.Heavy black circles indicate members of the 55 Gene Set; additional nodes were added based on most related with highest copy number alterations (cBioPortal tools).
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pone-0087610-g007: Network interactions amongst the members of the 55 Gene Set.Heavy black circles indicate members of the 55 Gene Set; additional nodes were added based on most related with highest copy number alterations (cBioPortal tools).

Mentions: We next asked whether SYK regulation of gene expression, specifically with regard to its role in suppressing motility, invasion, and metastasis in in vitro and in vivo models [2], [3], [5], [31]–[33], might be related to the formation of metastases and ultimately patient survival. In a previous study, we had analyzed significant expression changes (up or down regulated > = 1.5 fold) following SYK siRNA knockdown in a benign human breast cancer cell line, MCF10A, cultured on a matrix of collagen I [3]. From that set of 708 genes, we next performed a literature search and culled a list of 51 genes involved in key activities required for invasion, including cell motility and activities regulating invasion including membrane trafficking (39 up-regulated and 12 down-regulated genes; Table S1). The addition of SRC (c-Src), CTTN (cortactin), TP53 (p53) and CHD1 (E-cadherin) to the list of 51 genes to form the 55 gene set was based on published data relating these gene products with Syk signaling including direct interactions [4], [31], [34], [35] (Table S1). c-Src tyrosine kinase activity is suppressed by Syk in breast cancer cells [4] and both c-Src and Syk phosphorylate cortactin (CTTN) [31], [36]. Syk and cortactin are involved in the development and maintenance of cell-cell contacts and interact with cadherin 1 (CDH1) [31], [37], [38]. The relationship between SYK and the other 54 genes is shown in an interaction network generated by cBioPortal (Figure 7). 36% of the 55 Gene Set members are linked in a network according to cBioPortal (Figure 7, % altered cases signified by pink intensity, dark-rimmed encircled genes are members of the 55 Gene Set).


SYK allelic loss and the role of Syk-regulated genes in breast cancer survival.

Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, Kallakury B, Makambi KH, Marian C, Mueller SC - PLoS ONE (2014)

Network interactions amongst the members of the 55 Gene Set.Heavy black circles indicate members of the 55 Gene Set; additional nodes were added based on most related with highest copy number alterations (cBioPortal tools).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921124&req=5

pone-0087610-g007: Network interactions amongst the members of the 55 Gene Set.Heavy black circles indicate members of the 55 Gene Set; additional nodes were added based on most related with highest copy number alterations (cBioPortal tools).
Mentions: We next asked whether SYK regulation of gene expression, specifically with regard to its role in suppressing motility, invasion, and metastasis in in vitro and in vivo models [2], [3], [5], [31]–[33], might be related to the formation of metastases and ultimately patient survival. In a previous study, we had analyzed significant expression changes (up or down regulated > = 1.5 fold) following SYK siRNA knockdown in a benign human breast cancer cell line, MCF10A, cultured on a matrix of collagen I [3]. From that set of 708 genes, we next performed a literature search and culled a list of 51 genes involved in key activities required for invasion, including cell motility and activities regulating invasion including membrane trafficking (39 up-regulated and 12 down-regulated genes; Table S1). The addition of SRC (c-Src), CTTN (cortactin), TP53 (p53) and CHD1 (E-cadherin) to the list of 51 genes to form the 55 gene set was based on published data relating these gene products with Syk signaling including direct interactions [4], [31], [34], [35] (Table S1). c-Src tyrosine kinase activity is suppressed by Syk in breast cancer cells [4] and both c-Src and Syk phosphorylate cortactin (CTTN) [31], [36]. Syk and cortactin are involved in the development and maintenance of cell-cell contacts and interact with cadherin 1 (CDH1) [31], [37], [38]. The relationship between SYK and the other 54 genes is shown in an interaction network generated by cBioPortal (Figure 7). 36% of the 55 Gene Set members are linked in a network according to cBioPortal (Figure 7, % altered cases signified by pink intensity, dark-rimmed encircled genes are members of the 55 Gene Set).

Bottom Line: In cases without immune cell infiltration, loss of SYK copy number was associated with a significant reduction of SYK mRNA.We found that overall survival was significantly reduced in IDC and Luminal A+B cases where copy number and mutations of these 55 genes were affected (Kaplan-Meier, Logrank test p-value 0.007141 and Logrank test p-value 0.001198, respectively).We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.

ABSTRACT
Heterozygotic loss of SYK, a non-receptor tyrosine kinase, gives rise to mouse mammary tumor formation where Syk protein levels are reduced by about half; loss of SYK mRNA is correlated with invasive cell behavior in in vitro models; and SYK loss has been correlated with distant metastases in patients. Here, allelic loss of the SYK gene was explored in breast ductal carcinoma in situ (DCIS) using fluorescence in situ hybridization and pyrosequencing, respectively, and in infiltrating ductal carcinoma (IDC) using genomic data from The Cancer Genome Atlas (TCGA). Allelic loss was present in a subset of DCIS cases where adjacent IDC was present. SYK copy number loss was found in about 26% of 1002 total breast cancer cases and 30% of IDC cases. Quantitative immunofluorescence revealed Syk protein to be six-fold higher in infiltrating immune cells compared with epithelial cells. This difference distorted tumor cell mRNA and protein levels in extracts. 20% of 1002 IDC cases contained elevated immune cell infiltration as estimated by elevated immune-specific mRNAs. In cases without immune cell infiltration, loss of SYK copy number was associated with a significant reduction of SYK mRNA. Here we define a 55 Gene Set consisting of Syk interacting, motility- and invasion-related genes. We found that overall survival was significantly reduced in IDC and Luminal A+B cases where copy number and mutations of these 55 genes were affected (Kaplan-Meier, Logrank test p-value 0.007141 and Logrank test p-value 0.001198, respectively). We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival. A closer examination of the role of Syk interacting motility and invasion genes and their prognostic and/or causative association with metastatic disease and patient outcome is warranted.

Show MeSH
Related in: MedlinePlus