TP53 mutations, expression and interaction networks in human cancers

Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.

[1]  Wen-quan Wang,et al.  Retraction: Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 ≥ 1,000 U/mL , 2016, Scientific Reports.

[2]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[3]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[4]  E. Kawasaki,et al.  Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. , 1992, Journal of the National Cancer Institute.

[5]  Anushya Muruganujan,et al.  Large-scale gene function analysis with the PANTHER classification system , 2013, Nature Protocols.

[6]  S. Chouaib,et al.  Accumulation of the p53 protein allows recognition by human CTL of a wild-type p53 epitope presented by breast carcinomas and melanomas. , 1998, Journal of immunology.

[7]  Karen H. Vousden,et al.  Mutant p53 in Cancer: New Functions and Therapeutic Opportunities , 2014, Cancer cell.

[8]  Yue Zhang,et al.  Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes , 2016, Medicine.

[9]  P. Visca,et al.  Prognostic role of serum p53 antibodies in lung cancer , 2015, BMC Cancer.

[10]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[11]  L. Zender,et al.  A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer , 2016, Nature Medicine.

[12]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[13]  R. Poon,et al.  Stalled replication induces p53 accumulation through distinct mechanisms from DNA damage checkpoint pathways. , 2006, Cancer research.

[14]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Jiandong Chen.  The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. , 2016, Cold Spring Harbor perspectives in medicine.

[16]  D. Louis,et al.  Accumulation of wild type p53 protein in human astrocytomas. , 1993, Cancer research.

[17]  M. You,et al.  p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer , 2006, Molecular Cancer Research.

[18]  J. Dausset,et al.  The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Mufti,et al.  Applying synthetic lethality for the selective targeting of cancer. , 2014, The New England journal of medicine.

[20]  Emanuel J. V. Gonçalves,et al.  A Landscape of Pharmacogenomic Interactions in Cancer , 2016, Cell.

[21]  J. Boyd,et al.  Mutation and expression of the TP53 gene in early stage epithelial ovarian carcinoma. , 2004, Gynecologic oncology.

[22]  Lawrence B. Gardner,et al.  Nonsense-Mediated RNA Decay Regulation by Cellular Stress: Implications for Tumorigenesis , 2010, Molecular Cancer Research.

[23]  Lei Wang,et al.  Mutations of p53 and K-ras correlate TF expression in human colorectal carcinomas: TF downregulation as a marker of poor prognosis , 2011, International Journal of Colorectal Disease.

[24]  T. Yen,et al.  p53-dependent apoptosis in response to spindle damage is linked to loss of Bub1 , 2009, Cancer biology & therapy.

[25]  Mi-Ri Gwon,et al.  Mitotic centromere‐associated kinase (MCAK/Kif2C) regulates cellular senescence in human primary cells through a p53‐dependent pathway , 2012, FEBS letters.

[26]  Richard Simon,et al.  Identification of potential synthetic lethal genes to p53 using a computational biology approach , 2013, BMC Medical Genomics.

[27]  Damian Szklarczyk,et al.  STRING v9.1: protein-protein interaction networks, with increased coverage and integration , 2012, Nucleic Acids Res..

[28]  S. Fu,et al.  A novel Aurora-A-mediated phosphorylation of p53 inhibits its interaction with MDM2. , 2013, Biochimica et biophysica acta.

[29]  R. Poon,et al.  p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases , 2014, Oncogene.

[30]  A. Børresen-Dale,et al.  TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes , 2007, Oncogene.

[31]  Olga Anczuków,et al.  Does the nonsense‐mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins? , 2008, Human mutation.

[32]  F. Fuller-Pace,et al.  p53-dependent repression of polo-like kinase-1 (PLK1) , 2010, Cell cycle.

[33]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[34]  A. Levine,et al.  The first 30 years of p53: growing ever more complex , 2009, Nature Reviews Cancer.

[35]  S. Shieh,et al.  TTK/hMps1 Mediates the p53-Dependent Postmitotic Checkpoint by Phosphorylating p53 at Thr18 , 2009, Molecular and Cellular Biology.

[36]  D. Lane,et al.  Drugging the p53 pathway: understanding the route to clinical efficacy , 2014, Nature Reviews Drug Discovery.

[37]  K. Coombes,et al.  Identification of Cell Cycle Regulatory Genes as Principal Targets of p53-mediated Transcriptional Repression* , 2006, Journal of Biological Chemistry.

[38]  A. Berchuck,et al.  Expression signatures of TP53 mutations in serous ovarian cancers , 2010, BMC Cancer.

[39]  S. Benchimol,et al.  Transcriptional repression mediated by the p53 tumour suppressor , 2003, Cell Death and Differentiation.

[40]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[41]  Joel Greshock,et al.  Sensitivity of Cancer Cells to Plk1 Inhibitor GSK461364A Is Associated with Loss of p53 Function and Chromosome Instability , 2010, Molecular Cancer Therapeutics.

[42]  H. Gharwan,et al.  Kinase inhibitors and monoclonal antibodies in oncology: clinical implications , 2016, Nature Reviews Clinical Oncology.

[43]  Zhiyong Ma,et al.  Transcriptional Control of BubR1 by p53 and Suppression of Centrosome Amplification by BubR1 , 2005, Molecular and Cellular Biology.

[44]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[45]  Yusuke Nakamura,et al.  Involvement of kinesin family member 2C/mitotic centromere‐associated kinesin overexpression in mammary carcinogenesis , 2007, Cancer science.

[46]  I. Nakano,et al.  MELK—a conserved kinase: functions, signaling, cancer, and controversy , 2015, Clinical and Translational Medicine.

[47]  Y. Bae,et al.  Coexistent Loss of the Expressions of BRCA1 and p53 Predicts Poor Prognosis in Triple-Negative Breast Cancer , 2016, Annals of Surgical Oncology.

[48]  C. Prives,et al.  Transcriptional regulation by p53. , 2010, Cold Spring Harbor perspectives in biology.

[49]  W. Kaelin.  The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.