2195

FAT1

CDHF7|CDHR8|FAT|ME5|hFat1;FAT tumor suppressor homolog 1 (Drosophila);FAT1;FAT tumor suppressor homolog 1 (Drosophila)

FAT tumor suppressor 1|cadherin ME5|cadherin family member 7|cadherin-related family member 8|cadherin-related tumor suppressor homolog|protein fat homolog|protocadherin Fat 1

4q35

protein-coding

Count: 3; Pubmed_search,TAG,Generif

BACKGROUND: We had earlier used the comparison of RAPD (Random Amplification of Polymorphic DNA) DNA fingerprinting profiles of tumor and corresponding normal DNA to identify genetic alterations in primary human glial tumors. This has the advantage that DNA fingerprinting identifies the genetic alterations in a manner not biased for locus. METHODS: In this study we used RAPD-PCR to identify novel genomic alterations in the astrocytic tumors of WHO grade II (Low Grade Diffuse Astrocytoma) and WHO Grade IV (Glioblastoma Multiforme). Loss of heterozygosity (LOH) of the altered region was studied by microsatellite and Single Nucleotide Polymorphism (SNP) markers. expression study of the gene identified at the altered locus was done by semi-quantitative reverse-transcriptase-PCR (RT-PCR). RESULTS: Bands consistently altered in the RAPD profile of tumor DNA in a significant proportion of tumors were identified. One such 500 bp band, that was absent in the RAPD profile of 33% (4/12) of the grade II astrocytic tumors, was selected for further study. Its sequence corresponded with a region of FAT, a putative tumor suppressor gene initially identified in Drosophila. Fifty percent of a set of 40 tumors, both grade II and IV, were shown to have Loss of Heterozygosity (LOH) at this locus by microsatellite (intragenic) and by SNP markers. Semi-quantitative RT-PCR showed low FAT mRNA levels in a major subset of tumors. CONCLUSION: These results point to a role of the FAT in astrocytic tumorigenesis and demonstrate the use of RAPD analysis in identifying specific alterations in astrocytic tumors.

Homozygous deletions (HD) provide an important resource for identifying the location of candidate tumor suppressor genes. To identify the tumor suppressor gene in oral cancer, we employed high-resolution comparative genomic hybridization (CGH)-array analysis. We identified a homozygous loss of FAT (4q35), a new member of the human cadherin superfamily, from genome-wide screening of copy number alterations in one primary oral cancer. This result was evaluated by genomic polymerase chain reaction in 13 oral cancer cell lines and 20 primary oral cancers and Southern blot in the cell lines. We found frequent exonic HD of FAT in the cell lines (3/13, 23%) and in primary oral cancers (16/20, 80%). FAT expression was absent in these cell lines. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). Moreover, loss of gene expression was identified in other types of squamous cell carcinoma. The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Our results identify mutations in FAT as an important factor in the development of oral cancer and indicate the importance of FATs function in some squamous cell carcinomas.

We have recently cloned a novel growth inhibitor and candidate tumor suppressor called p33ING1 (I. Garkavtsev et al., Nature Genet., 14: 415-420, 1996). Because some tumor suppressors participate in the regulation of apoptosis, we hypothesized that the ING1 gene may also play a role in this process. Our results show that p33ING1 levels increase upon the induction of apoptosis in P19 teratocarcinoma cells by serum deprivation. Elevated expression of ING1 in P19 and rodent fibroblast cells containing a tetracycline-controlled human c-myc gene enhanced the extent of serum starvation-induced apoptosis. This suggests that the pathway by which ING1 modulates cell death is synergistic with Myc-dependent apoptosis. Conversely, constitutive expression of an antisense construct of INGI conferred protection against apoptosis in these cells. These data support the idea that loss of proper ING1 function may facilitate tumorigenesis, in part, by reducing the cell's sensitivity to apoptosis.