Abstract 45: MACC1 expression and KRas13 mutation for improved survival prognosis of colorectal cancer patients

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide. The metastatic dissemination of the primary tumor is directly linked to patient survival. We previously discovered the gene metastasis-associated in colon cancer 1 (MACC1). MACC1 has been identified as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and for a variety of solid cancers. MACC1 expression in tumor tissues and patient blood correlates with tumor formation and progression, development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis. Here we aim at the refinement of risk assessment in a retrospective study of 100 CRC patients with tumors staged I, II and III by combinatorial analyses of MACC1 with the KRas and BRaf mutation status. First, we correlated the single parameters, KRas12, KRas13, BRaf600 mutation and MACC1 expression with clinical outcome data, such as metastasis-free survival (MFS). We found correlations of high MACC1 expression with shorter MFS (P<0.001). Likewise, patients with a somatic KRas13 mutation showed decreased MFS (P=0.003). Interestingly, KRas12 or BRaf600 mutations as well as their wild type counterparts had no impact on survival prognosis. Multivariate analyses combining MACC1 expression level with the single parameters KRas12, KRas13 and BRaf600 mutation revealed an improved prognosis exclusively for KRas13 mutated tumors vs. MACC1 expression alone. High MACC1 expressers with KRas13 mutation had the poorest median MFS (17.2 months) compared to MACC1 high/KRas wild type patients (37.2 months; P=0.039). Further, we addressed the impact of KRas13 on regulation of MACC1 expression in vitro. We used RNAi to analyze the impact of KRas signaling on MACC1 in several CRC cell lines with different KRas mutation status. In addition, we employed HCT116 cells harboring the activating G13D KRAS mutation together with the HCT116-derived sublines Hkh-2 and Hke-3 lacking the mutated KRas13 allele by homologous recombination. Disrupting the constitutive active KRas signaling led to increased MACC1 mRNA and protein expression levels in HCT116 cells, either by knock-down of the endogenous G13D mutated KRas expression by RNAi or through gene targeting. In summary, MACC1 expression levels together with KRas13 mutation status was the only combination that improved the identification of CRC patients at high risk for metastasis formation and the prediction of MFS when compared to MACC1 alone Citation Format: Katharina Ilm, Wolfgang Kemmner, Gudrun Koch, Pia Herrmann, Marc Osterland, Senji Shirasawa, Takehiko Sasazuki, Ulrike S. Stein. MACC1 expression and KRas13 mutation for improved survival prognosis of colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 45. doi:10.1158/1538-7445.AM2014-45