Identification of novel cancer-related genes through genomic and epigenomic analyses of gastrointestinal cancer

Abstract

Although many genomic/epigenomic alterations involved in pathogenesis of gastrointestinal tumors have been reported, their precise molecular mechanisms remain unclear. Using those alterations as landmarks, genes, which are involved in the cancer development/progression and useful for diagnostic markers as well as therapeutic targets in personalized medicine, can be identified.

We have focused on genomic copy-number aberrations, especially the remarkanle aberrations, i.e., local high-level amplifications and homozygous deletions, and tried to identify novel tumor-related genes as targets for those alterations in various types of neoplasms including gastrointestinal cancers. We applied conventional and in-house bacterial artificial chromosome (BAC)-array-based comparative genomic hybridization (CGH). As amplification targets, many genes were identified, and some of them, such as cIAP1 and ZASC1 identified from esophageal cancer and CCND3 from colon cancer, seem to be important as prognosticators as well as therapeutic targets. From homozygously deleted regions detected in esophageal and gastric cancer, several genes were also identified as tumor suppressors frequently silenced through homozygous loss (genetic) or promoter hypermethylation (epigenetic). In addition, BAC array-based methylated CpG island amplification (BAMCA), a newly developed method to screen abnormally methylated sequences using BAC-array, accelerated the identification of tumor suppressor genes whose expression was altered by DNA methylation.

Genome-wide surveys of genetic and epigenetic abnormalities interpreting them in the context of broader knowledge of cancers facilitates the identification of crucial genes and pathways involved in the gastrointestinal carcinogenesis, resulting in the development of new diagnostic methods and molecular targeting therapies of gastrointestinal cancers.