Abstract
ObjectiveOverall and splice specific expression of Spleen Tyrosine Kinase (SYK) has been posed as a marker predicting both poor and favorable outcome in various epithelial malignancies. However, its role in colorectal cancer is largely unknown. The aim of this study was to explore the prognostic role of SYK in three cohorts of colon cancer patients.MethodsTotal messenger RNA (mRNA) expression of SYK, SYK(T), and mRNA expression of its two splice variants SYK short (S) and SYK long (L) were measured using quantitative reverse transcriptase (RT-qPCR) in 240 primary colon cancer patients (n = 160 patients with chemonaive lymph node negative [LNN] and n = 80 patients with adjuvant treated lymph node positive [LNP] colon cancer) and related to microsatellite instability (MSI), known colorectal cancer mutations, and disease-free (DFS), hepatic metastasis-free (HFS) and overall survival (OS). Two independent cohorts of patients with respectively 48 and 118 chemonaive LNN colon cancer were used for validation.ResultsExpression of SYK and its splice variants was significantly lower in tumors with MSI, and in KRAS wild type, BRAF mutant and PTEN mutant tumors. In a multivariate Cox regression analysis, as a continuous variable, increasing SYK(S) mRNA expression was associated with worse HFS (Hazard Ratio[HR] = 1.83; 95% Confidence Interval[CI] = 1.08–3.12; p = 0.026) in the LNN group, indicating a prognostic role for SYK(S) mRNA in patients with chemonaive LNN colon cancer. However, only a non-significant trend between SYK(S) and HFS in one of the two validation cohorts was observed (HR = 4.68; 95%CI = 0.75–29.15; p = 0.098).ConclusionIn our cohort, we discovered SYK(S) as a significant prognostic marker for HFS for patients with untreated LNN colon cancer. This association could however not be confirmed in two independent smaller cohorts, suggesting that further extensive validation is needed to confirm the prognostic value of SYK(S) expression in chemonaive LNN colon cancer.
Highlights
Colon cancer is the second most common malignancy in the Western World with close to 450,000 new cases in Europe in 2012 [1]
We discovered Spleen tyrosine kinase (SYK)(S) as a significant prognostic marker for Hepatic metastasis free survival (HFS) for patients with untreated lymph node negative (LNN) colon cancer
This association could not be confirmed in two independent smaller cohorts, suggesting that further extensive validation is needed to confirm the prognostic value of SYK(S) expression in chemonaive LNN colon cancer
Summary
Colon cancer is the second most common malignancy in the Western World with close to 450,000 new cases in Europe in 2012 [1]. Tyrosine-protein kinases are key regulators of cell proliferation associated with poor survival and tumorigenesis, and are extensively studied in the field of oncological biomarker research [6, 7]. Spleen tyrosine kinase (SYK) has been posed as marker predicting both poor and favorable outcome in various epithelial malignancies including colorectal cancer [8,9,10,11]. Most of these studies have focused on functional outcome in cell lines or associated tumor characteristics to the total mRNA or protein expression of SYK instead of linking mRNA and/or protein expression of SYK to long term clinical outcome. In patients with hepatocellular cancer, the expression of SYK(S) has been reported to be a significant indicator of poor prognosis [12]
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