Copy number profiles of paired primary and metastatic colorectal cancers.

Futoshi Kawamata,Toshiya Kamiyama,Catherine Bond,Diane Mckeone,Troy Dumenil,Shigenori Homma,Moto Fukai,Akinobu Taketomi,Cheng Liu,Hideki Yokoo,Nozomi Kobayasi,Vicki Whitehall,Christos S Karapetis,Nicola Waddell,Hiroshi Nishihara,Sally-Ann Pearson,Kátia Nones ,Ann‐Marie Patch ,Matthew Burge ,Günter Härtel ,Barbara A Leggett

doi:10.18632/oncotarget.23277

Abstract

Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide, conferring significant morbidity, mortality and cost to the public health system [1]
KRAS mutational discordance between primary and paired metastatic tumors was identified in 2 patients (2/16, 13%), whilst BRAF mutation was concordant in the single patient with a BRAF mutant allele (Table 2)
We performed single nucleotide polymorphism (SNP) arrays to investigate copy number profiles between paired primary and metastatic colorectal cancer samples to better understand the global differences that may occur between these two disease states

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, conferring significant morbidity, mortality and cost to the public health system [1]. Even among patients with KRAS wild type primary tumors, a recent study showed only 10– 20 % of metastatic CRC patients benefitted from an EGFR inhibitor [7]. One contributory reason for this low rate of response may be discordance in KRAS mutation status between primary tumors and corresponding metastases [8, 9]. It is likely for some cases that effector molecules downstream of the EGFR, including members of the MAPK and AKT signaling pathways [7], may be further altered during the metastatic process or following therapeutic intervention [10, 11]. Clarification of whether it is sufficient to assay the primary tumor or necessary to biopsy metastatic deposits for biomarker assessment is critical for optimizing management of patients with metastatic disease

Methods

Results

Conclusion