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Masica DL , Li S , Douville C , Manola J , Ferris RL , Burtness B , Forastiere AA , Koch WM , Chung CH , Karchin R
Predicting survival in head and neck squamous cell carcinoma from TP53 mutation
Hum Genet. 2015 May;134(5) :497-507
PMID: 25108461    PMCID: PMC4324386    URL: http://www.ncbi.nlm.nih.gov/pubmed/25108461
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Abstract
For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient's mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as "disruptive" or "non-disruptive". For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.
Notes
Masica, David L Li, Shuli Douville, Christopher Manola, Judith Ferris, Robert L Burtness, Barbara Forastiere, Arlene A Koch, Wayne M Chung, Christine H Karchin, Rachel ENG T32 GM007057/GM/NIGMS NIH HHS/ P30 CA006973/CA/NCI NIH HHS/ U10 CA021115/CA/NCI NIH HHS/ U10 CA180820/CA/NCI NIH HHS/ U10 CA180794/CA/NCI NIH HHS/ Comparative Study Evaluation Studies Germany 2014/08/12 06:00 Hum Genet. 2015 May;134(5):497-507. doi: 10.1007/s00439-014-1470-0. Epub 2014 Aug 10.