Alternative splicing of p53 and p73: the novel p53 splice variant p53|[delta]| is an independent prognostic marker in ovarian cancer

摘要

Similar to p73, the tumor suppressor gene p53 is subject to alternative splicing. Besides p53ΔE6 and p53β, we identified p53ζ, p53δ and p53ε, arising from alternative splicing of exon 6 and intron 9, respectively. p53 splice variants were present in 18 of 34 ovarian cancer cell lines (52.9%) and 134 of 245 primary ovarian cancers (54.7%). p53δ expression was associated with impaired response to primary platinum-based chemotherapy (P=0.032). Also, p53δ expression constituted an independent prognostic marker for recurrence-free and overall survival (hazard ratio 1.854, 95% confidence interval 1.121–3.065, P=0.016; and hazard ratio 1.937, 95% confidence interval 1.177–3.186, P=0.009, respectively). p53β expression was associated with adverse clinicopathologic markers, that is, serous and poorly differentiated cancers (P=0.002 and P=0.008, respectively), and correlated with worse recurrence-free survival in patients exhibiting functionally active p53 (P=0.049). ΔN′p73 constituted the main N-terminally truncated p73 isoform and was preferentially found in ovarian cancer cell lines showing functionally active p53, supporting our hypothesis that N-terminally truncated p73 isoforms can alleviate the selection pressure for p53 mutations by the inhibition of p53 protein function.