Intra-individual genetic heterogeneity among liver metastases in metastatic colorectal cancer

555 Background: Almost 50% of patients with colorectal cancer (CRC) develop liver metastases, often as multiple simultaneous metastatic deposits. Up to 25% of the patients are eligible for partial liver resection, but 70% will relapse after surgery and there are currently no good criteria to select patients who will benefit from the treatment. Genetic heterogeneity among metastatic deposits has great potential impact on disease progression, but has not been well described. Methods: Totally 134 liver metastatic deposits were collected from 45 patients undergoing partial liver resection for metastatic CRC according to a prospective study protocol. All deposits were analyzed for high-resolution DNA copy number variation using the Affymetrix SNP Array 6.0. A novel bioinformatic approach was used to measure intra-individual genetic heterogeneity among the metastatic deposits. Results: The patients showed a large variation in the level of intra-individual metastatic heterogeneity, and heterogeneity was independent of the number of liver metastases analyzed per patient. Heterogeneity was a strong and independent prognostic factor in multivariate analysis with known clinicopathological prognostic factors. Patients with a high level of heterogeneity (above the median) had a three-year overall survival rate of 18%, compared with 66% for patients with a low level (hazard ratio, HR = 3.7, P = 0.007). The corresponding survival rates for progression-free survival were 6% and 24% (HR = 2.6, P = 0.01). Conclusions: A high level of intra-individual genetic heterogeneity among liver metastatic deposits is associated with poor survival after partial liver resection in patients with metastatic CRC.