title: Metastasis-associated in colon cancer 1 is an independent prognostic biomarker for survival in Klatskin tumor patients.
abstract: Curative treatment of intrahepatic cholangiocarcinoma (ICC) and hilar cholangiocarcinoma (Klatskin tumors) is limited to surgical resection or orthotopic liver transplantation. However, not all patients benefit from a surgical approach and suffer from early tumor recurrence. Response to chemotherapy is generally poor and, until today, no targeted therapy could be established. Metastasis-associated in colon cancer 1 (MACC1) is a recently discovered regulator of the hepatocyte growth factor (HGF)/Met/mitogen-activated protein kinase pathway, which induces proliferation, migration, and invasion in cell culture, as well as metastasis in mice. MACC1 expression shows a significant correlation with Met expression in colon cancer tissue and is highly prognostic for occurrence of distant metastasis and survival in colon cancer patients. Thus, we aimed to measure the expression of MACC1, Met, and HGF messenger RNA in microdissected tumor tissue and corresponding normal liver tissue of 156 patients with Klatskin tumors (n = 76) and ICC (n = 80) using real-time quantitative reverse-transcriptase polymerase chain reaction. We used immunohistochemical staining to validate the results. MACC1 expression in tumor tissue of both tumor entities was significantly higher than in corresponding normal liver tissue (P < 0.001). Klatskin tumor patients with a history of tumor recurrence had significantly higher MACC1 expression than those without tumor recurrence (P = 0.005). Uni- und multivariate survival analysis showed that Klatskin tumor patients with high MACC1 had a significantly shorter overall (OS) and disease-free survival (DFS; P = 0.001 and P < 0.001, respectively). The multivariate analysis confirmed MACC1 to be an independent factor for overall survival in Klatskin tumor patients (hazard ratio: 2.777; 95% confidence interval: 1.389-5.555; P = 0.004).
  
  
  CONCLUSIONS
  Our study identified MACC1 as a highly prognostic biomarker for OS and DFS in Klatskin tumor patients. MACC1 expression could become an important diagnostic tool and might be a candidate for targeted therapy.
authors.affiliation: Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Department of General-, Visceral- and Transplant Surgery, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Andri
authors.initials: A
authors.lastname: Lederer
authors.affiliation: Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Herrmann
authors.affiliation: Department of General-, Visceral- and Transplant Surgery, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.affiliation: Department of Pathology, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Department of General-, Visceral- and Transplant Surgery, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.affiliation: Charité Comprehensive Cancer Center, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schlag
authors.affiliation: Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D018285:Klatskin Tumor / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D015415:Biomarkers; C544162:MACC1 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors