Format

Send to

Choose Destination
Oncogenesis. 2019 May 15;8(6):35. doi: 10.1038/s41389-019-0141-3.

Transcriptional and functional consequences of TP53 splice mutations in colorectal cancer.

Author information

1
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
2
K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
3
Department of Oncology, Oslo University Hospital, Oslo, Norway.
4
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
5
Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
6
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. ragnhild.a.lothe@rr-research.no.
7
K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway. ragnhild.a.lothe@rr-research.no.
8
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. ragnhild.a.lothe@rr-research.no.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center