• Annals of surgery · Nov 2012

    Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.

    • Ulrich Nitsche, Robert Rosenberg, Alexander Balmert, Tibor Schuster, Julia Slotta-Huspenina, Pia Herrmann, Franz G Bader, Helmut Friess, Peter M Schlag, Ulrike Stein, and Klaus-Peter Janssen.
    • Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany.
    • Ann. Surg. 2012 Nov 1; 256 (5): 763771763-71; discussion 771.

    ObjectivesIndividualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations.BackgroundRisk 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.MethodsFresh 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).ResultsMutations 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).ConclusionsMACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.

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