Abstract 4822: Nonsense mediated decay defines deleterious TP53 mutations and tumor aggressiveness in ovarian cancer

Abstract Genetic mutations leading to premature termination of protein translation, nonsense mutations, result in aberrant precursor mRNA processing and subsequent UPF1-dependent exosomal degradation of mRNA. The significance of this surveillance mechanism in controlling the expression of key mutated tumor suppressor genes in cancer in vivo has remained unclear. We have recently shown that TP53 mutations are almost invariably present in high-grade serous ovarian cancers (Ahmed at al., Journal of Pathology, 2010;221:49) and that about one third of such mutations are nonsense. We have now tested the hypothesis that nonsense mutations induce nonsense mediated decay resulting in TP53 mRNA depletion. We analyzed microarray expression profiling data from 136 epithelial ovarian cancers with known TP53 mutation status and found a strikingly statistically significant underexpression of TP53 mRNA transcript in cancers with truncating mutations (p<0.0001) compared to other types of mutations. This effect allowed the identification of a class of TP53-non-expressing serous epithelial cancers that comprised all TP53 truncating mutations. We next conducted a systematic analysis of 18 publically available expression profiling ovarian cancer studies published at the Gene Expression Omnibus database. We validated the results by showing that cancers that had nonsense mutations had a significantly lower TP53 expression irrespective of stage. Importantly, this systematic analysis of multiple independent data set established that lack of TP53 expression was, almost exclusively, a feature of high grade serous cancers and invasion as opposed to low grade disease or tumors of low malignant potential (p<0.0001 and p=0.002, respectively). Expression profiling analysis revealed that cancers with truncating mutations had a distinct gene expression signature compared to those with missense mutations. This signature was enriched for genes that regulated angiogenesis such as CSPG4 and metabolism. Surprisingly, however, the magnitude of expression differences was not high. Based on these results, we propose a model for the biogenesis of a subset of high-grade serous ovarian cancers that is defined by nonsense mediated decay of nonsense TP53 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4822. doi:10.1158/1538-7445.AM2011-4822