Abstract 3397: Patterns of DNA copy number changes in colorectal cancer metastasis are highly similar to their corresponding primaries with additional focal alterations that differ between individual patients

Abstract

Abstract Objective: Metastasis is a complex process that remains an obstacle in the management of colorectal cancer (CRC). Over the years many models have been developed to explain the metastatic process in detail, however, the molecular basis is still poorly understood. To gain better insight into the biology of metastases we investigated genomic aberrations in matched triplets of normal, CRC primaries and metastases of various distant sites. Methods: In total, 63 primary colorectal tumours, 63 matched normal specimens, and 69 matched metastases (liver, lung, ovarian, omentum and distant lymph nodes) were analysed by high resolution array comparative genomic hybridization (array CGH). Our findings were validated in a publicly available dataset consisting of 21 matched primary tumours and liver metastases.1 Fluorescence in situ hybridization (FISH) was used to confirm our findings and to evaluate intra-tumour heterogeneity of the observed copy number differences. Results: The overall pattern of copy number aberrations was highly similar between primary tumours and their metastases. However, higher deflections were observed in the metastases compared to the primary tumours, which was confirmed in the validation set. Across all patients, 17 regions showed significantly lower DNA copy number ratio and 2 regions showed significantly higher DNA copy number ratio in the metastases compared to the primary tumour. None of these significant DNA copy number changes occurred in a substantial percentage of our patients. In the training set we did not detect a higher frequency of chromosome 11p15.5 gain in liver metastasis compared to the primary tumour, as previously reported in the validation set. In two different patients, two specific regions showed amplifications in the three metastases (one patient with two metastatic sites) which were absent in the primary tumours. One of these regions harboured the MYC oncogene. FISH analysis confirmed the extensive MYC amplification in the three metastases, but also showed tumour cell populations with smaller MYC amplifications within the primary tumour, which were not detected by array CGH. Conclusions: Highly similar patterns of DNA copy number profiles between metastatic and primary CRC were observed using array CGH. Focal differences that were observed in individual patients are probably explained by heterogeneity within the primary tumour in contrast to the metastatic sub clone. True additional copy number aberrations are rare and rather specific for individual patients, which is consistent with the hypothesis that the metastatic potential is already present in the primary tumour. Referentie: 1. Stange DE, Engel F, Longerich T et al. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut 2011;59:1236-44. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3397. doi:1538-7445.AM2012-3397