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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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Comparisons of SYK-regulated mRNA changes, average copy numbers, and percent of cases altered.A. The % altered IDC cases were plotted for each member of the 55 Gene Set. B. The average copy number was plotted for each member of the 55 Gene Set . C. Fold changes in mRNAs (log) of genes regulating motility and invasion following SYK siRNA knockdown in ER-negative, MCF10A breast cells [3] were plotted for 51 mRNA species.
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pone-0087610-g008: Comparisons of SYK-regulated mRNA changes, average copy numbers, and percent of cases altered.A. The % altered IDC cases were plotted for each member of the 55 Gene Set. B. The average copy number was plotted for each member of the 55 Gene Set . C. Fold changes in mRNAs (log) of genes regulating motility and invasion following SYK siRNA knockdown in ER-negative, MCF10A breast cells [3] were plotted for 51 mRNA species.

Mentions: To characterize the frequency of the copy number changes in IDC cases and the average copy number of each of the genes from the 55 Gene Set, means were determined and the results were plotted (Figure 8A–B). Of the 9 genes for which the percent of cases altered for the 55 Gene Set was greater than 4.5% (CN, copy number and MUT, mutations) (Figure 8A), all had increased average copy number (Figure 8B); of those, 2 were from genes whose mRNA was down-regulated by SYK siRNA (ADAM15 and ECT2) and 7 were from genes whose mRNA was up-regulated by SYK siRNA (SPRR1A, RAB11FIP1, MUC1, RHOD, and SPTBN2). The 8 genes whose copy number frequency alterations (% altered cases) were the greatest were TP53, RAB11FlP1, CTTN, ADAM15, MUC1, SPRR1A, SPRR1B, and RAB25 (Figure 8A). Of these genes, all but one had greater than normal average copy number, TP53 being the exception (Figure 8B). The SYK mRNA changes in motility and invasion genes resulting from siRNA treatment of MCF10A cells were plotted for comparison (Figure 8C).


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)

Comparisons of SYK-regulated mRNA changes, average copy numbers, and percent of cases altered.A. The % altered IDC cases were plotted for each member of the 55 Gene Set. B. The average copy number was plotted for each member of the 55 Gene Set . C. Fold changes in mRNAs (log) of genes regulating motility and invasion following SYK siRNA knockdown in ER-negative, MCF10A breast cells [3] were plotted for 51 mRNA species.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0087610-g008: Comparisons of SYK-regulated mRNA changes, average copy numbers, and percent of cases altered.A. The % altered IDC cases were plotted for each member of the 55 Gene Set. B. The average copy number was plotted for each member of the 55 Gene Set . C. Fold changes in mRNAs (log) of genes regulating motility and invasion following SYK siRNA knockdown in ER-negative, MCF10A breast cells [3] were plotted for 51 mRNA species.
Mentions: To characterize the frequency of the copy number changes in IDC cases and the average copy number of each of the genes from the 55 Gene Set, means were determined and the results were plotted (Figure 8A–B). Of the 9 genes for which the percent of cases altered for the 55 Gene Set was greater than 4.5% (CN, copy number and MUT, mutations) (Figure 8A), all had increased average copy number (Figure 8B); of those, 2 were from genes whose mRNA was down-regulated by SYK siRNA (ADAM15 and ECT2) and 7 were from genes whose mRNA was up-regulated by SYK siRNA (SPRR1A, RAB11FIP1, MUC1, RHOD, and SPTBN2). The 8 genes whose copy number frequency alterations (% altered cases) were the greatest were TP53, RAB11FlP1, CTTN, ADAM15, MUC1, SPRR1A, SPRR1B, and RAB25 (Figure 8A). Of these genes, all but one had greater than normal average copy number, TP53 being the exception (Figure 8B). The SYK mRNA changes in motility and invasion genes resulting from siRNA treatment of MCF10A cells were plotted for comparison (Figure 8C).

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