title: SYK allelic loss and the role of Syk-regulated genes in breast cancer survival.
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.
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Jan
authors: J
authors: Blancato
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Ashley
authors: A
authors: Graves
authors: Department of Pathology, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Banafsheh
authors: B
authors: Rashidi
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors: Maria
authors: M
authors: Moroni
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America ; University of the District of Columbia/Lombardi Comprehensive Cancer Center Partnership, Washington, D. C., United States of America.
authors: Leopold
authors: L
authors: Tchobe
authors: Department of Pathology, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Metin
authors: M
authors: Ozdemirli
authors: Department of Pathology, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Bhaskar
authors: B
authors: Kallakury
authors: Department of Biostatistics and Bioinformatics, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Kepher H
authors: KH
authors: Makambi
authors: Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America ; Biochemistry Department, University of Medicine and Pharmacy, "Victor Babes", Timisoara, Romania.
authors: Catalin
authors: C
authors: Marian
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C., United States of America.
authors: Susette C
authors: SC
authors: Mueller
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002874:Chromosome Mapping; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000072377:Syk Kinase; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse