p53 mutations in defined structural and functional domains are related to poor clinical outcome in non-small cell lung cancer patients

The prognostic value of p53 status in non-small cell lung cancer has been i nvestigated in 148 patients,vith clinical stage I-IIIB disease. Tumor tissu es were examined for mutations in exons 4-9, with emphasis on defined struc tural and functional domains. Eighty-four mutations mere detected in 83 (54 %) of the patients. Eighty-eight percent of the mutations were within exons 5-8, and 12% of the mutations were within exons 4 and 9, Missense mutation s occurred in 67% of the tumors, and 30% were null mutations (10% stop muta tions, 15% frameshift mutations, and 5% splice site mutations), Patients wi th mutations in p53 had a significantly higher risk for lung cancer-related death and for death from all causes than those with wild-type p53 [hazard ratio (HR) = 2.09 and 95% confidence interval (CI) = 1.20-3.64 and HR = 1.6 9 and 95% CI = 1.06-2.70, respectively], Mutations in p53 related to even s till poorer lung cancer-related prognosis were found at the following locat ions: (a) exon 8 (HR = 3.5; 95% CI, 1.59-7.71)]; (b) the structural domains L2 + L3 (HR = 2.36; 95% CI, 1.18-4.74), and (c) codons involved in zinc bi nding (HR = 11.7; 95% CI, 3.56-38.69), Together, the biologically functiona l group of severe flexible mutants (codons 172, 173, 175, 176, 179, 181, 23 8, 245, and 267) and severe contact mutants (248, 282) were significantly r elated to shorter lung cancer-related survival (HR = 4.16; 95% CI, 1.93-8.9 7), Squamous cell carcinoma was the dominant histological type in tumors in volved in poor prognosis in zinc binding (HR = 3.19; 95% CI, 1.07-9.45), Th ese results indicate that mutations in defined structural and functional do mains of p53 may be useful molecular biological markers for prognosis and t reatment strategy in non-small cell lung cancer patients.