[Chromosomal instability, microsatellite instability and CpG island methylator phenotype: roles in small intestinal...

Intestinal carcinogenesis is associated with genetic instability affecting either the chromosomal level (CIN) or microsatellite DNA sequences (MIN). In addition, epigenetic alterations, such as aberrant CpG island methylation (CIMP) may contribute to tumor development. While these single genetic alterations have frequently been addressed in intestinal carcinogenesis little is known about the interaction of the epigenetics and genetics in tumorigenesis. This investigation therefore aimed to define the synergistic effects of CIN, MSI and CIMP in small bowel adenocarcinomas.

A total of 37 primary small bowel adenocarcinomas were investigated for CIN, MSI, CIMP, KRAS and BRAF mutations. The results showed that CIN was found in 22 out of 37 (57%) tumors (3 out of 9 microsatellite instable and 19 out of 28 microsatellite stable carcinomas) and 9 carcinomas (24%) were microsatellite and chromosomally stable. Aberrant CIMP was detected in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas, KRAS was mutated in 55%, 0% and 10% of chromosomal instable, microsatellite instable and microsatellite and chromosomal stable tumors, respectively, while BRAF mutations occurred in 6% of chromosomal instable and 22% of both microsatellite instable and microsatellite and chromosomal stable carcinomas.

Chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomal stable tumors by a high frequency of KRAS mutations and low frequencies of CIMP and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CIMP and BRAF/KRAS mutations are similarly distributed indicating common mechanisms of tumor initiation or progression in the molecular pathogenesis.