Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas - PubMed (original) (raw)

Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas

Tamotsu Sugai et al. J Mol Diagn. 2006 May.

Abstract

To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINT1, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel.

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Figures

Figure 1

Figure 1

a: Relationship of mutations in p53, Ki-ras, and APC in LOH-high status tumors based on tumor location. b: Relationship of mutations in p53, Ki-ras, and APC in LOH-low status tumors based on tumor location. c: Relationship of mutations in p53, Ki-ras, and APC in CIMP-high status tumors based on tumor location.

Figure 2

Figure 2

Frequencies of methylation of MINT1, MINT2, MINT31, MLH-1, MGMT,p14, p16, and RASSF1A promoters for left- and right-sided cancers.

Figure 3

Figure 3

A representative example of molecular alterations in left-sided cancer. b, d, f, h, and i: Multiple LOHs were seen (arrowhead). Although methylation at MINT 1 was found, MINT2, MINT31, p16, p14 (not shown), and RASSF1A promoters were not methylated. Furthermore, mutations of p53, Ki-ras, and APC genes were found (arrowhead). k: A GGC to GAC transition in Ki-ras codon 12 was found, resulting in a Gly to Asp substitution (sequence by reverse primer). l: A CTG to CAG transversion in exon 5 of p53 gene was observed. m: Finally, a CGA to TGA transition in codon 805 of APC gene was found, resulting in a stop codon. The three detectable mutated nucleotides in tumor DNA are indicated by arrows in the photograph (k, l, and m).

Figure 4

Figure 4

A representative example of molecular alterations in right-sided cancer. b, d, and f: Multiple LOHs were seen (arrowhead). Arrowheads indicate LOH. k, l, m, o, p, q, and r: In addition, multiple promoter regions were methylated (arrowhead). However, the p53 gene was not mutated (not shown).

Figure 5

Figure 5

The molecular profile of left- and right-sided colorectal cancers.

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