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TP53  mutations are common in colorectal cancer (CRC). Most  TP53  sequencing studies have been restricted to coding regions, but recent studies have revealed that splice mutations can generate transcript variants with distinct tumorigenic and prognostic properties. Here, we performed unrestricted sequencing of all coding sequences and splice regions of  TP53  in a single-hospital series of 401 primary CRCs.  TP53  splice mutations were detected in 4% of the cases ( N  = 16), considerably more frequent than reported in major databases, and they were mutually exclusive to exon mutations. RNA sequencing revealed high-level expression of aberrant transcript variants in the majority of splice mutated tumors (75%). Most variants were predicted to produce truncated TP53 proteins, including one sample expressing the potentially oncogenic and druggable p53ψ isoform. Despite heterogeneous transcript structures, downstream transcriptional profiling revealed that  TP53  splice mutations had similar effects on TP53 target gene expression and pathway activity as exonic mutations. Intriguingly,  TP53  splice mutations were associated with worse 5-year relapse-free survival in stage II disease, compared to both  TP53  wild-type and exon mutations ( P  = 0.007). These data highlight the importance of including splice regions when examining the biological and clinical consequences of  TP53  mutations in CRC.

Transcriptional and functional consequences of TP53 splice mutations in colorectal cancer