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Integrative Marker Analysis Allows Risk Assessment for Metastasis in Stage II Colon Cancer

Nitsche, Ulrich MD*; Rosenberg, Robert MD*,†; Balmert, Alexander*; Schuster, Tibor PhD; Slotta-Huspenina, Julia MD§; Herrmann, Pia; Bader, Franz G. MD*; Friess, Helmut MD*; Schlag, Peter M. MD‖,¶; Stein, Ulrike PhD; Janssen, Klaus-Peter PhD*

doi: 10.1097/SLA.0b013e318272de87
Original Articles From the ESA Proceedings

Objectives: 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.

Supplemental Digital Content is Available in the Text.Assessing the risk of tumor recurrence is essential for patients with UICC stage II colon cancer but still not feasible in clinical practice. We identified patient subgroups using integrative analysis of 6 molecular genetic markers, allowing stratification for distant metastasis risk well beyond currently used histopathological parameters.

*Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Department of Surgery, Kantonsspital Baden, Baden, Switzerland

Institute of Statistics and Epidemiology, Technische Universität München, Munich, Germany

§Institute of Pathology, Technische Universität München, Munich, Germany

Experimental and Clinical Research Center, a Joint Cooperation of the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Charité Comprehensive Cancer Center, Berlin, Germany.

Reprints: Klaus-Peter Janssen, PhD, Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675, Munich, Germany. E-mail:

K.-P.J. and U.S. contributed equally to this work.

This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, SFB456, to K.-P.J.), from the KKF (Kommission für klinische Forschung, Fakultät für Medizin, Technische Universität München, to U.N. and K.-P.J.), and from the Monika-Kutzner foundation (to U.S. and P.M.S.).

Disclosure: The authors declare no conflicts of interest.

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© 2012 Lippincott Williams & Wilkins, Inc.