Mutation of TP53 and Alteration of p14arf Expression in EGFR- and KRAS-Mutated Lung Adenocarcinomas

The p14(arf) protein activates growth suppression by p53 in response to oncogene activation. In a series of 96 lung adenocarcinomas, disruption of the p53/p14(arf) pathway (TP53 mutation or decreased p14arf expression, or both) is observed in 18 of 31 EGFR-mutated (58.1%) and 9 of 13 KRAS-mutated (69.2%) cases, suggesting that inactivation of this pathway is common but not systematic in relation to oncogene activation. Background: In lung adenocarcinoma, inactivation of the tumor suppressor p53 may abrogate a safeguard mechanism preventing the development of tumors with activating mutations in EGFR or KRAS. To assess this hypothesis, we analyzed TP53 mutations and downregulation of p14(arf), a negative regulator of p53 activated by oncogenic signals, in a retrospective series of 96 patients with primary adenocarcinoma of the lung. Patients and Methods: Mutations in TP53 (exons 4-9), KRAS (exon 1), and EGFR (exons 18-21) were identified by direct sequencing of DNA from formalin-fixed, paraffin-embedded resected tumors. Expression of p14arf was semiquantitatively evaluated by immunohistochemical analysis. Results: TP53, KRAS, and EGFR mutations were detected in 42 of 93 (45.2%), 15 of 95 (15.8%), and 31 of 90 (34.4%) cases, respectively. Low p14arf expression was observed in 19 of 91 cases (20.9%). Disruption of the p53/p14arf pathway (defined as TP53 mutation or decreased p14arf expression, or both) was observed in 18 of 31 EGFR-mutated (58.1%) tumors and in 9 of 13 KRAS-mutated (69.2%) tumors. Conclusion: Inactivation of the p53/p14arf pathway is common but not systematic in EGFR-or KRAS-mutated lung adenocarcinomas. Our work highlights the need to better investigate the association between EGFR and KRAS mutations and alterations in tumor suppressor pathways.