title: Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.
abstract: OBJECTIVE
  Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations.
  
  
  BACKGROUND
  Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics.
  
  
  METHODS
  Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients).
  
  
  RESULTS
  Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26).
  
  
  CONCLUSIONS
  MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Balmert
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Julia
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.forename: Pia
authors.initials: P
authors.lastname: Herrmann
authors.forename: Franz G
authors.initials: FG
authors.lastname: Bader
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D003062:Codon; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D003627:Data Interpretation, Statistical; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009367:Neoplasm Staging; D053495:Osteopontin / Q000235:genetics; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment; D015996:Survival Rate; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D003062:Codon; C117307:KRAS protein, human; C544162:MACC1 protein, human; D011518:Proto-Oncogene Proteins; C474743:SASH1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D053495:Osteopontin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins