Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers

Abstract

It is unclear whether somatic copy number alterations (SCNAs) contribute to the development of colorectal cancer (CRC). Here, we aimed to identify the molecular profiles of early colorectal carcinogenesis based on SCNAs and determine the associations of other molecular abnormalities for the detection of neoplasia in both intramucosal neoplasia (IMN) and invasive CRC with invasion into the muscular layer without metastasis (early invasive CRC). A single nucleotide polymorphism array was used to examine 100 colorectal IMNs (low-grade adenoma [LGA], 40; high-grade adenoma [HGA], 25; intramucosal adenocarcinoma [IMA], 35) and early invasive CRC (20 tumors). In addition, genetic mutations (KRAS, BRAF), TP53 overexpression, microsatellite instability (MSI), and DNA methylation (low, intermediate, high) were examined. Hierarchical clustering analysis based on the SCNA pattern was carried out to identify molecular profiles in IMNs and early invasive CRC. Colorectal tumors were classified into three subgroups based on SCNA patterns. Subgroup 1 was characterized by multiple SCNAs, subgroup 3 was closely associated with infrequent SCNAs, and subgroup 2 was an intermediate subgroup in SCNA pattern between subgroups 1 and 3. Although mutations in KRAS were commonly found in all three subgroups, overexpression of TP53 was observed primarily in subgroup 1 and 2. DNA methylation showed a low/intermediate type. Finally, no MSI was detected. Each subgroup was correlated with histology (subgroup 1, early invasive CRC; subgroup 2, LGA; subgroups 2 and 3, HGA and IMA). Considerable SCNAs may be required for acquisition of invasive ability in CRC. Our results provide novel insights into early CRC.

A genome‐wide study of the relationship between chromosomal abnormalities and gene expression in colorectal tumors

“…With regard to the IMCs that we examined here (interpreted as high‐grade colorectal adenomas in the West), it would be beneficial to identify them early in progression 11,12 because they are intermediates between adenomas and invasive CRCs. In the present study, the number of mRNAs that showed altered (upregulated/downregulated) expression of mRNA compared with those in normal crypts was lower in IMC than in adenoma.…”

“…Our crypt isolation method enabled us to obtain pure tumor tissues and normal glands 22,26 . We used an array‐based method that is necessary to evaluate comprehensive genome‐wide alterations of a given tumor 11,12 . Therefore, crypt isolation could certify the origin of DNA or RNA extracted from epithelial tumor cells.…”

“…Comprehensive CINs in CRC have been investigated by many researchers using either comparative genomic hybridization (CGH) or array‐based SNP arrays (SNP array) 8‐10 . These approaches have contributed to the detection of many chromosomal aberrations, including gains and losses, helping to evaluate complex disease progression 11 . SNP arrays may be suitable for gathering more detailed information regarding the possible underlying mechanism of chromosomal abnormalities and to evaluate genetic characteristics.…”

“…SNP arrays may be suitable for gathering more detailed information regarding the possible underlying mechanism of chromosomal abnormalities and to evaluate genetic characteristics. In recent studies, it has been used in place of CGH arrays 11,12 . Accumulated chromosomal alterations involving key regulatory genes are essential genetic events in the initiation and progression of colorectal tumorigenesis 11‐13 .…”

“…In recent studies, it has been used in place of CGH arrays 11,12 . Accumulated chromosomal alterations involving key regulatory genes are essential genetic events in the initiation and progression of colorectal tumorigenesis 11‐13 . Many alterations, such as SCNA can disrupt or change proper gene function 14 .…”