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.
Highlights
Syk, a 72 kD tyrosine kinase, plays diverse and complicated roles in immunity as well as in epithelial cell biology and is required for activation of immune, integrin, and a growing number of other cell surface receptors [1]
The cases contained ductal carcinoma in situ (DCIS) either with or without accompanying evidence of intraductal carcinoma (IDC) and had the same overall characteristics as the entire set with respect to mRNA Syk expression (Figure 2 in ref. [4]; Figure S1, and Table S2 in this study)
De-identified pathology reports and re-examination of sections by an independent pathologist confirmed that 8 cases were DCIS only and 11 cases contained invasive ductal carcinoma (IDC) adjacent to the DCIS (Table S1)
Summary
Syk (spleen tyrosine kinase), a 72 kD tyrosine kinase, plays diverse and complicated roles in immunity as well as in epithelial cell biology and is required for activation of immune, integrin, and a growing number of other cell surface receptors [1]. SYK loss has been attributed to hypermethylation of the promoter in breast cancer tissues and its loss is associated with increased cellular invasiveness [6,7]. Hypermethylation of the SYK promoter is associated with lower SYK mRNA and poor prognosis and metastasis in various cancers including breast, lung, pancreatic, urinary bladder cancers, mesothelioma, and melanoma; in vitro experiments confirm that re-expression of SYK by transfection or inhibitors of hypermethylation reverses the invasive and metastatic phenotype ([7,8,9,10,11,12,13,14,15] and for review [5]). SYK hypermethylation was noted in 45% of DCIS but only 5% of hyperplasia, hypermethylation in DCIS tissues occurs prior to the development of invasive disease [7]. Several studies have identified SNPs and somatic mutations of SYK associated with breast cancer [17,18]
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