Systematic characterization of p53-regulated long non-coding RNAs across human cancers reveals remarkable heterogeneity among different tumor types.

The p53 tumor suppressor protein, a sequence specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. While the protein coding target genes of p53 have been well studied, less is known about its role in regulating long non-coding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1000) of long non-coding RNAs(lncRNAs) that are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, while others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 non-coding response. The newly identified non-coding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis. Implications: Our results not only identify myriad p53-regulated lncRNAs, they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.