Association between genomic alterations and metastatic behavior of colorectal cancer identified by array‐based comparative genomic hybridization

Abstract

Colorectal cancers (CRCs) exhibit multiple genetic alterations, including allelic imbalances (copy number alterations, CNAs) at various chromosomal loci. In addition to genetic aberrations, DNA methylation also plays important roles in the development of CRC. To better understand the clinical relevance of these genetic and epigenetic abnormalities in CRC, we performed an integrative analysis of copy number changes on a genome-wide scale and assessed mutations of TP53, KRAS, BRAF, and PIK3CA and DNA methylation of six marker genes in single glands isolated from 39 primary tumors. Array-based comparative genomic hybridization (array-CGH) analysis revealed that genomic losses commonly occurred at 3q26.1, 4q13.2, 6q21.32, 7q34, 8p12-23.3, 15qcen and 18, while gains were commonly found at 1q21.3-23.1, 7p22.3-q34, 13q12.11-14.11, and 20. The total numbers and lengths of the CNAs were significantly associated with the aberrant DNA methylation and Dukes' stages. Moreover, hierarchical clustering analysis of the array-CGH data suggested that tumors could be categorized into four subgroups. Tumors with frequent DNA methylation were most strongly enriched in subgroups with infrequent CNAs. Importantly, Dukes' D tumors were enriched in the subgroup showing the greatest genomic losses, whereas Dukes' C tumors were enriched in the subgroup with the greatest genomic gains. Our data suggest an inverse relationship between chromosomal instability and aberrant methylation and a positive association between genomic losses and distant metastasis and between genomic gains and lymph node metastasis in CRC. Therefore, DNA copy number profiles may be predictive of the metastatic behavior of CRCs.

Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

“…Fifty percent of the models (24/48 models) were KRAS mutant (75% of metastatic origin, 25% from primary tumors), 77% were TP53 mutant (37/48 models: 86% of metastatic origin, 14% from primary tumors), 17% were PIK3CA mutant (7/48 models: 87.5% of metastatic origin, 12.5% from primary tumors), and 8% were BRAF mutant (4/48 models: 50% of metastatic origin, 50% from primary tumors). These results are consistent with published reports comparing the genomic profiles of primary and mCRC tumors (40)(41)(42)(43). Previous and independent studies have demonstrated through use of a panel of tumor models established from cell lines that the status of KRAS, BRAF, PIK3CA, and PTEN did not significantly influence the response to aflibercept (44, data not shown).…”

Next-generation sequencing reveals lymph node metastasis associated genetic markers in colorectal cancer

“…Another study demonstrated that CNVs were able to determine the lymph node metastasis in colorectal cancer (14). Evidence now indicates that the occurrence of CNVs in chromosome 4 may seriously induce lymph node metastasis in colorectal cancer (14)(15)(16).…”

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

“…However, several studies using cytogenetic analysis have found MSI cell lines and cancers to have a considerable presence of chromosomal aberrations, predominantly cnLOH events [27], [28], [29], [30]. Similarly, studies have reported the presence of CIN and CIMP to be inversely correlated [31], [32], and the incidence of frequent methylation to be associated with reduced rates and lengths of CNAs [33], [34], [35]. However, the majority of these studies did not stratify for presence of a BRAF mutation [31], [33], [35].…”

“…Similarly, studies have reported the presence of CIN and CIMP to be inversely correlated [31], [32], and the incidence of frequent methylation to be associated with reduced rates and lengths of CNAs [33], [34], [35]. However, the majority of these studies did not stratify for presence of a BRAF mutation [31], [33], [35].…”