Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas

Abstract

The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and progression. Single nucleotide polymorphism array analysis was performed on 216 colorectal tumor/normal matched pairs, comprising 60 adenomas and 156 carcinomas. While many chromosomal aberrations were specific to carcinomas, those with the highest frequency in carcinomas (amplification of chromosome 7, 13q, and 20q; deletion of 17p and chromosome 18; LOH of 1p, chromosome 4, 5q, 8p, 17p, chromosome 18, and 20p) were also identified in adenomas. Hierarchical clustering using chromosomal aberrations revealed three distinct subtypes. Interestingly, these subtypes were only partially dependent on tumor staging. A cluster of colorectal cancer patients with frequent chromosomal deletions had the least favorable prognosis, and a number of adenomas (n = 9) were also present in the cluster suggesting that, at least in some tumors, the chromosomal aberration pattern is determined at a very early stage of tumor formation. Finally, analysis of LOH events revealed that copy-neutral/gain LOH (CN/G-LOH) is frequent (>10%) in carcinomas at 5q, 11q, 15q, 17p, chromosome 18, 20p, and 22q. Deletion of the corresponding region is sometimes present in adenomas, suggesting that LOH at these loci may play an important role in tumor initiation.

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

“…The integrative analysis of regions affected by aUPD and the mutational status of genes within these regions revealed evidence that aUPD acts as a “second hit” to inactivate TSGs. Specifically, our results confirmed that aUPD events represent an important mechanism to functionally inactivate APC in colon and rectum adenocarcinomas . Therefore, these results further strengthen the hypothesis that colorectal tumor cells strive to maintain a disomy for chromosome 5 despite the benefit of inactivating APC .…”

Unexpected frequency of genomic alterations in histologically normal colonic tissue from colon cancer patients

“…LOH of 5q was reported in ovarian cancer, frequently accompanied by TP53 mutation [33]. It was also observed in adenoma samples, suggesting that it may play an important role in tumor initiation [34]. In 5q region maps APC gene.…”

The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

“…In contrast, a gain of chromosomal material suggests the presence of the potential oncogenes or genes that favor cell growth or survival. In CRC, gains at chromosome 7, and chromosomal arms 1q, 8q, 12q, 13q and 20q have been repeatedly reported by different research groups (26)(27)(28)(29)(30)(31). It was reasoned that these chromosomal changes are associated with a gain and loss of function of tumor-associated genes offering mutated cells growth and survival advantages, leading to progressive conversion of normal cells into cancer cells (32,33).…”

“…Although the allelic loss of all chromosomal arms has been detected in certain tumors, its frequency varies considerably, and only a few of them are highly recurrent in CRC, including losses at chromosomal arms 1p, 5q, 8p, 17p, 18p, 18q, 20p and 22q (26)(27)(28)(29)(30)(31). A high-frequency allelic loss at a specific chromosomal region denotes the presence of a candidate tumor-suppressor gene, including APC on chromosome 5q, TP53 on chromosome 17p, DCC netrin 1 receptor (DCC), SMAD family member (SMAD2 and SMAD4) on chromosome 18q (31).…”