Nondisruptive p53 mutations are associated with shorter survival in advanced non-small-cell lung cancer patients
Menée initialement sur une cohorte de 318 patients atteints d'un cancer du poumon non à petites cellules de stade IIIB-IV (125 sans mutation du gène EGFR, 193 avec mutation), puis validée sur une cohorte de 64 patients avec mutation du gène EGFR, cette étude met en évidence une association entre des mutations non perturbatrices de la structure ou de la fonction de la protéine TP53 et la survie des patients
Purpose: TP53 mutations in early stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.
Experimental design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 stage IIIB-IV NSCLC patients: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as 'disruptive' and 'nondisruptive' according to their predicted degree of disturbance of the p53 protein structure and function.
Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared to 15.6 months for the remaining 97 patients (P=0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months vs. 28.4 months for the remaining 167 patients (P=0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared to 37.8 months for the 53 remaining patients (P=0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.
Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.
Clinical Cancer Research , résumé, 2014