Investigating the transformative potential of different TP53 mutations in cell line models of early high-grade serous ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSC) is the most common and aggressive form of ovarian cancer, accounting over 60% of cases and up to 90% of ovarian cancer related deaths. Mutant TP53 appears to be a consistent and defining feature, reported to occur in over 96% of HGSC. This suggests mutant TP53 is an important feature in HGSC tumourigenesis. Several years ago, our laboratory identified an immortalised ovarian surface epithelial cell line (IOSE) that had undergone spontaneous transformation, acquiring different, successive TP53 mutations. This suggested different TP53 mutations could have varying transformative potential. To investigate this hypothesis, IOSE cell lines from different patients were transduced with R175H or R273H mutant TP53 and examined for the acquisition of transformed traits. The cell line IOSE21-R175H demonstrated the greatest acquisition of transformed traits; suggesting R175H mutant TP53 may have greater transformative potential than R273H. However, IOSE21-R175H could not form tumours in immunodeficient mice, suggesting mutant TP53 is insufficient to induce malignant transformation. The expression of a number of other transformed traits could also not be directly linked to mutant TP53. This suggests other molecular events may have facilitated the premalignant transformation of IOSE cell lines. In this respect, we conclude that mutant TP53 is permissive of other tumourigenic events necessary for premalignant transformation.