Mutation of TP53 and Alteration of p14^arf Expression in EGFR- and KRAS-Mutated Lung Adenocarcinomas

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• 作者：Alexis B. Cortot ; Mohamad Younes ; Ghislaine Martel-Planche ; Benoit Guibert ; Sylvie Isaac ; Pierre-Jean Souquet ; Fr茅d茅ric Commo ; Philippe Girard ; Pierre Fouret ; Elisabeth Brambilla ; Pierre Hainaut ; Jean-Charles Soria
• 关键词：EGFR ; KRAS ; Lung adenocarcinoma ; p53 ; p14arf
• 刊名：Clinical Lung Cancer
• 出版年：March, 2014
• 年：2014
• 卷：15
• 期：2
• 页码：124-130
• 全文大小：437 K

文摘

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 p14^arf 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 p14^arf expression was observed in 19 of 91 cases (20.9%). Disruption of the p53/p14^arf pathway (defined as TP53 mutation or decreased p14^arf 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/p14^arf 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.