NOEY2: A Putative Tumor Suppressor Gene in 1p31 is Maternally Imprinting

Peng Hong-Qui
Division of Medicine; MD Anderson

NOEY2 is a novel small GTP-binding protein that belongs to the ras/rap superfamily. It is expressed consistently in normal ovarian and breast epithelial cells but downregulated dramatically in ovarian and breast cancers. Re-expression of NOEY2 results in suppression of clonogenic growth of breast and ovarian cancer. Despite a lack of mutation in the coding sequence, LOH at 1p31involving the gene was detected in 41% of ovarian and breast cancers. Methylation studies both Southern blot and or bisulfite/PCR have shown that the promoter of this gene is partially methylated in a variety of both normal and neoplastic tissues such as breast, ovary, colon, bone marrow and brain. Our data suggest that this gene might be imprinted and monoallelically expressed. Using a modified allele-specific methylation assay combined with TA repeat length polymorphism genotype analysis or -750 A/G polymorphism sequence analysis, we were able to demonstrate that NOEY2 gene is maternally imprinted in 4 informative families identified from a total of 10 families. We further confirmed that NOEY2 is monoallelically expressed in all four informative samples by utilizing the coding +231 G/A polymorphism that changes a HhaI restriction enzyme site. We also showed that NOEY2 is paternally expressed in a coding +231 G/A informative family. Thus, NOEY2 appears to be a tumor suppressor gene, which is maternally imprinted. To our knowledge this is the first imprinted tumor suppressor gene to be detected in adult solid tumors.