title: Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.
abstract: BACKGROUND
  Metastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Here, we investigate the geographic expression pattern of MACC1 in colorectal adenocarcinoma and tumor buds in correlation with clinicopathological and molecular features for improvement of survival prognosis.
  
  
  METHODS
  We performed geographic MACC1 expression analysis in tumor center, invasive front and tumor buds on whole tissue sections of 187 well-characterized CRCs by immunohistochemistry. MACC1 expression in each geographic zone was analyzed with Mismatch repair (MMR)-status, BRAF/KRAS-mutations and CpG-island methylation.
  
  
  RESULTS
  MACC1 was significantly overexpressed in tumor tissue as compared to normal mucosa (p < 0.001). Within colorectal adenocarcinomas, a significant increase of MACC1 from tumor center to front (p = 0.0012) was detected. MACC1 was highly overexpressed in 55% tumor budding cells. Independent of geographic location, MACC1 predicted advanced pT and pN-stages, high grade tumor budding, venous and lymphatic invasion (p < 0.05). High MACC1 expression at the invasive front was decisive for prediction of metastasis (p = 0.0223) and poor survival (p = 0.0217). The geographic pattern of MACC1 did not correlate with MMR-status, BRAF/KRAS-mutations or CpG-island methylation.
  
  
  CONCLUSIONS
  MACC1 is differentially expressed in CRC. At the invasive front, MACC1 expression predicts best aggressive clinicopathological features, tumor budding, metastasis formation and poor survival outcome.
authors.affiliation: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. viktor.koelzer@pathology.unibe.ch.|Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. viktor.koelzer@pathology.unibe.ch.
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Department of Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125, Berlin, Germany. pia.herrmann@charite.de.
authors.forename: Pia
authors.initials: P
authors.lastname: Herrmann
authors.affiliation: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. inti.zlobec@pathology.unibe.ch.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. eva.diamantis@pathology.unibe.ch.|Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. eva.diamantis@pathology.unibe.ch.
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.affiliation: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. alessandro.lugli@pathology.unibe.ch.|Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland. alessandro.lugli@pathology.unibe.ch.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Department of Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125, Berlin, Germany. ustein@mdc-berlin.de.|German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany. ustein@mdc-berlin.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C544162:MACC1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors