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The Identification and Characterization of Endogenous EGFR Regulatory Locus in Xiphophorus Genome

 

Research Story

 


Melanoma incidence continues to grow 3-7% per year despite the incidence of most cancer is decreasing. Thus, melanoma etiology research remains a priority for disease control and treatment. Similarity of gene expression and pathological features between the Xiphophorus melanoma and human melanoma allowed researchers to adapt discoveries from Xiphophorus model system to the human condition. Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma.

EGFR is found frequently mutant in many different types of cancers (e.g., 10-47% in non-small cell lung cancer; 50% in malignant glioma (e.g., EGFRvIII); 8%-13% in prostate cancer; 11.4% in triple-negative breast cancer), including the mutations enhancing ligand-independent receptor dimerization. EGFR is also highly expressed in the majority of human carcinomas. For example, on average, 50-70% of lung, colon, and breast cancers express EGFR. The driver oncogene in the Xiphophorus melanoma model, xmrk, is a mutant fish egfr gene. The xmrk auto-dimerizes and activates in a ligand-independent manner, similar to certain carcinogenesis mechanism of human EGFR mutant. Considering the mutant egfr nature of the xmrk, R(Diff) represent an endogenous egfr regulator of unknown mechanism. Therefore, identifying the molecular genetic features whereby R(Diff) suppresses the deleterious activity of a mutant egfr is of significant value, not only to disease etiology research, but also development of new treatment strategies for EGFR related cancers.

Our recent study has defined the R(Diff) tumor regulatory locus to a 5.8 Mbp locus on chromosome 5. Considering the large size and number of gene models (164 genes) encoded in this region, functional and mechanistic studies are impractical. Our research work aims to improve our understanding of this locus by first localizing the R(Diff) candidate gene(s) using Genome-wide Association Study (GWAS); and evaluating the effectiveness of R(Diff) candidate gene(s) in the ability to regulate the xmrk oncogene in transgenic animal models.

By Dr. Yuan Lu