Comparative Genomic Analysis of Primary and Synchronous Metastatic Colorectal Cancers

Sun Young Lee,Deokhoon Kim,Sung-Min Ahn,Hui-Jong Jo,Won-Suk Lee,Farhan Haq,Cui Jun,Harriet Wikman

doi:10.1371/journal.pone.0090459

Sun Young Lee, Deokhoon Kim + Show 6 more

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https://doi.org/10.1371/journal.pone.0090459

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Abstract

Approximately 50% of patients with primary colorectal carcinoma develop liver metastases. Understanding the genetic differences between primary colon cancer and their metastases to the liver is essential for devising a better therapeutic approach for this disease. We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss. The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar somatic copy number alteration patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number alterations. Our results suggest that about half of the metastatic colorectal carcinoma had the same clonal origin with their primary colorectal carcinomas, whereas remaining cases were genetically distinct from their primary carcinomas. These findings underscore the need to evaluate metastatic lesions separately for optimized therapy, rather than to extrapolate from primary tumor data.

Highlights

The emerging concept of polyclonality is gaining importance in cancer biology [1]
We found that microsatellite instability (MSI) tumors were associated with a large number of gene deletions/amplifications and increased frequency of loss of heterozygosity (LOH), in other words, chromosomal instability in colorectal liver metastasis (CLM) tumors
By comparing the sequencing and high resolution copy number variation (SCNA) data and mutation profiles of 15 paired CRC and CLM samples, we found that approximately half of them, showed genetic heterogeneity with respect to their corresponding primary CRC

Summary

Introduction

The emerging concept of polyclonality is gaining importance in cancer biology [1]. The monoclonal evolution of a tumor from a single cancer cell has been extensively studied, and is generally considered to involve the selective clonal expansion of dominant tumor clones. The alternative concept of polyclonal evolution has emerged. This model consists of two key concepts: the self-seeding hypothesis and the mutator phenotype model. The former proposes that tumor clones leave the primary site, enter systemic circulation via tumor vasculature, and colonize a distant site, thereby establishing a new subpopulation [2,3]. The mutator phenotype model proposes a small number of highly diverse tumor cell clones (polyclonal) instead of a few competing clonal subpopulations; several solid tumor types, including colon cancers, have been suggested to be highly polyclonal [4]

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