Medical genetics

Genome-wide association studies (GWASs) have identified hundreds of genetic “risk” variants for human cancers. But The vast majority likely contribute to cancer development by regulating the expression of other genes, but these target genes remain largely unexplored. Xingyi Guo, PhD, Zhishan Chen, PhD, and colleagues have now systematically evaluated 294 GWAS-associated variants for six types of cancer colorectal, lung, ovary, prostate, pancreas and melanoma using gene expression data from multiple public resources.

The expression of other genes

They identified 270 candidate target genes; including 99 genes with previously unreported associations. Therefore Combined with the group’s previous data from breast cancer; 24 genes are share by at least two cancer types. Therefore The researchers found that 33 target genes were associated with specific mutational signatures and 66 were ;associated with tumor mutational burden in cancer tissues. But The findings; reported in the American Journal of Human Genetics; sharpen understanding of how; GWAS-identified risk variants might contribute to carcinogenesis: by regulating target susceptibility genes that in turn promote the generation of somatic gene mutations.

Pathway controls biological processes via the regulation of target gene expression. Because The expression of direct Wnt target, e.g. cyclin D1 and MYC, is activated by the transcription factor TCF, which binds to specific sequence motifs in the promoter. Indirect target genes are regulated via transcription regulators, which are targets of the Wnt pathway. As an example, MYC regulates the MYC interacting zinc finger protein-1 (MIZ-1), which is able to inhibit the expression of the indirect target p21WAF1. We intended to identify new Wnt target  and to get a deeper insight into the regulatory mechanisms of Wnt target gene expression.

The transcription factor

For this we analyzed the differential expression pattern of Wnt-1 activated cells by microarray analysis. We identified 43 sequences including eight expresse sequence tags (ESTs); which showed increased transcript levels; and 104 sequences including 19 ESTs with decreased RNA levels. Northern blot and real-time quantitative PCR analysis; of the differential expression levels of 15 genes confirmed the differential expression trends of eight candidate genes. But When the Wnt pathway is regulate at the lower level of glycogen synthase kinase-3 beta (GSK-3 beta); or adenomatous polyposis coli (APC); we detected discrepant expression trends.

We compared the number of binding sites of transcription factors in the genomic regions of all candidate target  with the number of sites in control. They found that the genomic regions of the down-regulated  include an increase number of putative MIZ-1 binding sites. Therefore Our study introduces several;But new Wnt target genes and provides indications that the specific  expression pattern depends on the type of the activation trigger or the level of interference with the Wnt pathway. Furthermore; our data indicate that a high proportion of Wnt target genes are regulate by indirect mechanisms.