title: Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer.
abstract: TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations.
authors: Department of Otolaryngology Head and Neck Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors: David M
authors: DM
authors: Neskey
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Abdullah A
authors: AA
authors: Osman
authors: Department of Otolaryngology Head and Neck Surgery, Albert Einstein School of Medicine, Yeshiva University, New York, New York.
authors: Thomas J
authors: TJ
authors: Ow
authors: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors: Panagiotis
authors: P
authors: Katsonis
authors: Department of Statistics, Rice University, Houston, Texas.
authors: Thomas
authors: T
authors: McDonald
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Stephanie C
authors: SC
authors: Hicks
authors: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors: Teng-Kuei
authors: TK
authors: Hsu
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Curtis R
authors: CR
authors: Pickering
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Alexandra
authors: A
authors: Ward
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Ameeta
authors: A
authors: Patel
authors: Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.
authors: John S
authors: JS
authors: Yordy
authors: Department of Thoracic Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Heath D
authors: HD
authors: Skinner
authors: Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Uma
authors: U
authors: Giri
authors: Department of Otolaryngology-Head and Neck Surgery, Yokahama University, Yokahama, Japan.
authors: Daisuke
authors: D
authors: Sano
authors: Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas. Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.
authors: Michael D
authors: MD
authors: Story
authors: Department of Head and Neck Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Beth M
authors: BM
authors: Beadle
authors: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Adel K
authors: AK
authors: El-Naggar
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Merrill S
authors: MS
authors: Kies
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: William N
authors: WN
authors: William
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Carlos
authors: C
authors: Caulin
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Mitchell
authors: M
authors: Frederick
authors: Department of Statistics, Rice University, Houston, Texas.
authors: Marek
authors: M
authors: Kimmel
authors: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. jmyers@mdanderson.org.
authors: Jeffrey N
authors: JN
authors: Myers
authors: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors: Olivier
authors: O
authors: Lichtarge
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D023281:Genomics; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D009154:Mutation; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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