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Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer

¹ Comprehensive Cancer Center and Departments of ² Surgery and ³ Epidemiology and Biostatistics, University of California, San Francisco, California and ⁴ Second Department of Surgery, Showa University School of Medicine, Tokyo, Japan

Requests for reprints: Frederic M. Waldman, University of California, San Francisco, Comprehensive Cancer Center, 2340 Sutter Street, Room S436, San Francisco, CA 94143-0808. Phone: 415-476-3821; Fax: 415-476-8218; E-mail: waldman{at}cc.ucsf.edu.

Purpose: Although liver resection is the primary curative therapy for patients with colorectal hepatic metastases, most patients have a recurrence. Identification of molecular markers that predict patients at highest risk for recurrence may help to target further therapy.

Experimental Design: Array-based comparative genomic hybridization was used to investigate the association of DNA copy number alterations with outcome in patients with colorectal liver metastasis resected with curative intent. DNA from 50 liver metastases was labeled and hybridized onto an array consisting of 2,463 bacterial artificial chromosome clones covering the entire genome. The total fraction of genome altered (FGA) in the metastases and the patient's clinical risk score (CRS) were calculated to identify independent prognostic factors for survival.

Results: An average of 30 ± 14% of the genome was altered in the liver metastases (14% gained and 16% lost). As expected, a lower CRS was an independent predictor of overall survival (P = 0.03). In addition, a high FGA also was an independent predictor of survival (P = 0.01). The median survival time in patients with a low CRS (score 0-2) and a high (20%) FGA was 38 months compared with 18 months in patients with a low CRS and a low FGA. Supervised analyses, using Prediction Analysis of Microarrays and Significance Analysis of Microarrays, identified a set of clones, predominantly located on chromosomes 7 and 20, which best predicted survival.

Conclusions: Both FGA and CRS are independent predictors of survival in patients with resected hepatic colorectal cancer metastases. The greater the FGA, the more likely the patient is to survive.

Key Words: colorectal neoplasm • metastasis • clinical risk score • CGH

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