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

Anita Sveen,Per Eystein Lønning,Halfdan Sorbye,Gro Nilsen,Jon-Helge Angelsen,Ole Christian Lingjærde,Kaja Christine Graue Berg,Inger Marie Løes,Arild Horn,Maren Høland,Ragnhild A Lothe,Stian Knappskog,Sharmini Alagaratnam,Carlo C Maley

doi:10.1371/journal.pgen.1006225

Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most common type of cancer world-wide, responsible for almost 700,000 deaths each year[1]
We describe for the first time a large variation among patients in the level of inter-metastatic heterogeneity at the DNA copy number level in liver metastases from colorectal cancer
We found this heterogeneity to be a biological feature independent both of the number of metastases per patient and of the extent of copy number aberrationsof the metastases

Summary

Introduction

Colorectal cancer (CRC) is the third most common type of cancer world-wide, responsible for almost 700,000 deaths each year[1]. Chromosomal instability is associated both with a poor patient prognosis[8]and multidrug resistance [9], and has recently been implicated as a requirement for metastatic progression in models of CRC [10]. Specific DNA copy number aberrations in primary tumors from patients with metastatic disease have been associated both with metastatic progression[11,12,13] and patient prognosis after chemotherapy[14]. A few aberrations specific to metastatic deposits have been described, the DNA copy number profiles of liver metastases are generally similar to those of primary CRCs [13,16,17,18,19,20]. Our understanding of genetic factors regulating the metastatic process remains poor[20,21]

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Results

Discussion

Conclusion