Mapping of Genetic Abnormalities of Primary Tumours from Metastatic CRC by High-Resolution SNP Arrays

Abstract

BackgroundFor years, the genetics of metastatic colorectal cancer (CRC) have been studied using a variety of techniques. However, most of the approaches employed so far have a relatively limited resolution which hampers detailed characterization of the common recurrent chromosomal breakpoints as well as the identification of small regions carrying genetic changes and the genes involved in them.Methodology/Principal FindingsHere we applied 500K SNP arrays to map the most common chromosomal lesions present at diagnosis in a series of 23 primary tumours from sporadic CRC patients who had developed liver metastasis. Overall our results confirm that the genetic profile of metastatic CRC is defined by imbalanced gains of chromosomes 7, 8q, 11q, 13q, 20q and X together with losses of the 1p, 8p, 17p and 18q chromosome regions. In addition, SNP-array studies allowed the identification of small (<1.3 Mb) and extensive/large (>1.5 Mb) altered DNA sequences, many of which contain cancer genes known to be involved in CRC and the metastatic process. Detailed characterization of the breakpoint regions for the altered chromosomes showed four recurrent breakpoints at chromosomes 1p12, 8p12, 17p11.2 and 20p12.1; interestingly, the most frequently observed recurrent chromosomal breakpoint was localized at 17p11.2 and systematically targeted the FAM27L gene, whose role in CRC deserves further investigations.Conclusions/SignificanceIn summary, in the present study we provide a detailed map of the genetic abnormalities of primary tumours from metastatic CRC patients, which confirm and extend on previous observations as regards the identification of genes potentially involved in development of CRC and the metastatic process.

Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

“…Herein, we describe a comprehensive, detailed map of CNAs present in primary tumors from patients with metastatic versus nonmetastatic sCRC who were followed for a relatively long time, as assessed by high‐resolution, 500‐K SNP arrays and confirmed by iFISH studies. A high correlation also was observed between the SNP‐array results and iFISH analyses performed on the same series of primary tumor samples with regard to the most commonly deleted (eg 17p and 18q) and gained (eg 7 and 13q) chromosomal regions, in line with in our previous findings . To our knowledge, this is the most extensive study in which high‐resolution SNP arrays have been used to define and compare the CNA profiles of both groups of sCRC tumors.…”

“…Del(18q) has long been observed in sCRC using a broad panel of techniques that vary from conventional cytogenetics and iFISH to comparative genomic hybridization, comparative genomic hybridization arrays, and SNP arrays . Within the long arm of chromosome 18, the 18q21 cytoband was the most frequently altered (range, 50%‐70% of CRCs) in those studies . This region contains both the DCC and SMAD genes, which are well established genetic biomarkers of sCRC and typically are associated with advanced disease.…”

Predictive Markers of Colorectal Cancer Liver Metastases

“…Other emerging techniques include the detection of exosomes (microvesicles shed by tumor), which are increasingly thought to play a role in angiogenesis and metastasis by facilitating the transfer of proteins, RNA and miRNA [85]. Finally, as next-generation sequencing technologies evolve, innovative methods of identifying altered genes and chromosomal imbalances, such as high-resolution single nucleotide polymorphism arrays, can be used in translational studies to better define the genetic changes that are causally linked to the development of metastases [86,87]. These methods are emerging and their role in the prediction of colorectal liver metastases is, as yet, unproven.…”

Molecular Biomarkers in Colorectal Carcinoma

“…Copy gain number of 20q should result in increased expression of its resident genes and is probably promoted by the contribution of multiple loci, whose identification may be relevant in the screening of adenomas at high risk of progression. Furthermore, TPX2 and AURKA downregulation inhibited invasion [131], supporting their role in 20q gain, which has been associated with metastasis in many studies [132][133][134][135][136]. Furthermore, TPX2 and AURKA downregulation inhibited invasion [131], supporting their role in 20q gain, which has been associated with metastasis in many studies [132][133][134][135][136].…”