Structure and methylation-associated silencing of a gene within a homozygously deleted region of human chromosome band 8p22

Abstract

The structure and expression pattern of a human gene located within a homozygously deleted region of a metastatic prostate cancer have been characterized. Multiple cDNA fragments of this gene were isolated by hybrid capture with yeast artificial chromosome clones covering the deletion region. Eleven coding exons spanned 205-220 kb of the 730- to 970-kb deletion. The predicted amino acid sequence was 43% identical to that of an anonymous Caenorhabditis elegans gene and 20% identical to an accessory or regulatory subunit of the oligosaccharyltransferase enzyme complex in Saccharomyces cerevisiae. Hydrophobicity profiles of all three gene products were similar and showed four putative membrane-spanning domains in the molecules' C-terminal halves, suggesting a general conservation of function. The gene was expressed as an approximately 1.5-kb mRNA in most nonlymphoid human cells/tissues including prostate, lung, liver, and colon. Expression was detected in many epithelial tumor cell lines, but was undetectable by Northern blot or RT-PCR in 14 of 15 colorectal, 1 of 8 lung, and 1 of 4 liver cancer cell lines. Lack of expression in tumor cell lines was highly correlated with hypermethylation of a CpG island located at the gene's 5' end. These findings form a basis for further work on this candidate tumor suppressor gene.