Abstract 4856: High mRNA expression of splice variant SYK short correlates with poor hepatic metastasis free survival in untreated lymph node negative colon cancer patients
Authors: Robert R. Coebergh van den Braak, Anieta M. Sieuwerts, Zarina S. Lalmahomed, Sandra Bril, Annemieke M. Timmermans, Vanja de Weerd, Michelle van der Vlugt - Daane, Anne van Galen, Shanshan Xiang, Katharina Biermann, John A. Foekens, John W. Martens, Jan N. IJzermans
Journal: Cancer Research (2017)

Abstract Introduction: In lymph node negative (LNN) colon cancer 20% of the patients will develop recurrence of disease. Identification of these patients is an unmet need. SYK, a protein kinase, has been ascribed both a tumor promoter and suppressor role in epithelial cancers. The prognostic value of SYK and its splice variants, largely uknown in colorectal cancer however, was explored in a clinically well-defined cohort of colon cancer patients. Methods: Total mRNA expression of SYK [SYK(T)] and of its two splice variants SYK short(S) and SYK long(L) were measured using RT-qPCR in a clinically well-defined prospectively collected cohort of 240 colon cancer patients (n=160 untreated lymph node negative [LNN] and n=80 adjuvant treated lymph node positive [LNP] patients) selected from the MATCH-cohort. mRNA expression levels were related to microsatellite instability (MSI), mRNA expression of epithelial (EPCAM), stromal (BGN, FAP, INHBA) and infiltrate markers (VEGFA, CD45), known CRC mutations (n=238), and disease free (DFS), hepatic metastasis free (HFS) and overall survival (OS). Results: Overall increased SYK levels were associated with stage I/II, a left-sided located primary tumor and MicroSatellite Stability (MSS). However, these associations and their interrelation differed significantly between SYK(T), SYK(S) and SYK(L) expression implicating an added value for measuring mRNA expression of the splice variants next to SYK(T). SYK(T), SYK(S) and SYK(L) levels all showed a significant positive correlation with the expression of EPCAM, FAP was weakly negatively associated with SYK(S) and VEGFA was weakly positively correlated with SYK(T) and SYK(S). This suggests a higher expression of SYK in epithelial-rich, stromal-poor tumors. SYK(T) and SYK(S) expression was significantly lower in tumors with a BRAF or PTEN mutation (mt) compared to wild type (wt) tumors. Although others reported differential expression of SYK between KRAS-dependent and KRAS-independent cell lines and KRAS mt versus wt tumors in 221 TCGA-samples (p=0.008), we observed no significant differences for expression of SYK(T), SYK(S) and SYK(L) between KRAS-mutant (mt) and KRAS-wild type (wt) tumors. In the LNN group, using univariate Cox regression analysis increasing mRNA expression of SYK(T) (HR=2.05 95%CI=1.01-4.17 p=0.047) and SYK(S) (HR=1.83 95%CI=1.09-3.05 p=0.021) was associated with worse HFS, which remained significant for SYK(S) when correcting for the number of assessed lymph nodes (HR=1.83; 95% CI=1.08-3.12; p=0.026 and HR=1.27; 95%CI=1.009-1.60; p=0.042). No other significant associations between SYK(T), SYK(S) and SYK(L), and DFS, HFS and OS were observed. Conclusion: In our untreated LNN colon cancer cohort SYK(S) is a pure prognostic marker for HFS. These results may help to identify LNN patients at overall low risk to develop liver metastases. Note: This abstract was not presented at the meeting. Citation Format: Robert R. Coebergh van den Braak, Anieta M. Sieuwerts, Zarina S. Lalmahomed, Sandra Bril, Annemieke M. Timmermans, Vanja de Weerd, Michelle van der Vlugt - Daane, Anne van Galen, Shanshan Xiang, Katharina Biermann, John A. Foekens, John W. Martens, Jan N. IJzermans. High mRNA expression of splice variant SYK short correlates with poor hepatic metastasis free survival in untreated lymph node negative colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4856. doi:10.1158/1538-7445.AM2017-4856