Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection

PLoS Genet. 2016 Jul 29;12(7):e1006225. doi: 10.1371/journal.pgen.1006225. eCollection 2016 Jul.


Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients' clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2-0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1-0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged, 80 and over
  • Chemotherapy, Adjuvant
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / surgery
  • DNA Copy Number Variations / genetics*
  • Disease-Free Survival
  • Female
  • Genetic Heterogeneity*
  • Genome, Human
  • Hepatectomy
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Liver Neoplasms / surgery
  • Male
  • Middle Aged
  • Prognosis
  • Treatment Outcome

Grant support

This study was supported by the Southern and Eastern Norway Regional Health Authority (; Research Grant “Genome Medicine of Colorectal Cancer”, project number 2011024 to RAL, supporting AS as a postdoc), the Norwegian Cancer Society (; project numbers 72190-PR-2006-0442 to RAL, 561569-2015 to PEL), the University of Bergen (; project number 720006 supporting IML as a PhD student), Health Region West Funding (; project numbers 911872 and 380065 to PEL), and the Research Council of Norway through its Centres of Excellence funding scheme (; project number 179571 to RAL, funding SA as staff scientist). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.