The Role of HNF4A in Germ Cell Tumor Development




Pierce, Joshua Logan

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Yolk sac tumor is a histological category of germ cell tumors, which represent the most frequent malignancy in young men. Little is known about the molecular mechanisms responsible for the aberrant differentiation and oncogenic potential of yolk sac tumors. Multiple recurrent chromosomal copy number variations are the primary genetic lesions discovered in yolk sac tumors. Frequent gains of chromosome 20q13 provide clues as to the identity of important YST driver genes. We have determined that the Hepatocyte Nuclear Factor 4 alpha locus, which resides in this region, is frequently amplified in YSTs. Overexpression of HNF4A in an undifferentiated GCT line is sufficient to drive extraembryonic endodermal gene programs. This endodermal program subsequently utilizes endogenous WNT signaling to grow. Additionally, isoform specific manipulation of HNF4A revealed differential oncogenic potential amongst HNF4A isoforms. This isoform specific manipulation was involved in modulation of the WNT pathway which has previously been identified as active in YSTs. These results allowed us to uncover HNF4A isoform specific differences in histological samples from YST patients. Our findings reveal a possible new drug target in YST treatment and reveal an interesting isoform dependent mechanism for understanding tumor development.

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