MAP Kinase Overexpressed in Never-Smokers With Lung Cancer

November 1, 2006

In a study investigating possible molecular abnormalities in nonsmokers with lung adenocarcinoma, a team of French researchers has found that never-smokers significantly overexpress the MAP (mitogen activated protein) kinases P38 and JNK (c-Jun N-terminal kinase), compared with smokers.

ISTANBUL, Turkey--In a studyinvestigating possible molecular abnormalitiesin nonsmokers with lung adenocarcinoma,a team of French researchershas found that never-smokers significantlyoverexpress the MAP (mitogenactivated protein) kinases P38 and JNK(c-Jun N-terminal kinase), comparedwith smokers.

Lead author Giannis Mountzios, MD,of the Institut Gustave Roussy, Villejuif,France, reported the findings at the 31stCongress of the European Society forMedical Oncology (ESMO) (Late BreakingAbstract 7).

"We chose this type cancer becausewe know from large epidemiologicalstudies that a significant proportion ofnonsmokers, and especially women, developit," Dr. Mountzios said. "Wewanted to determine if there was a specificmolecular profile that differentiatesthe development of lung adenocarcinomain people who have never smoked."

He and his colleagues focused on immunohistochemicalevaluation of severalkey downstream mediators of cytoplasmicand nuclear signaling transduction differthatare known to be associated with lungoncogenesis. Using microarray technologyon previously collected tissue samplesfrom 188 chemonaive patients withoperable lung adenocarcinoma, they assessedexpression of P38, JNK, ERK(extracellular signal-regulated kinase),STAT3 (signal transducer and activatorof transcription 3), PKB (protein kinaseB, or AKT), and the DNA-repair geneERCC1 (excision repair complementcomplex one). The researchers recordedexpression levels in smokers vs neversmokers;the prognostic value of eachmarker was evaluated by correlatingexpression profiles with correspondingclinical parameters.

Strong P38, JNK Overexpression
The team, supervised by Jean CharlesSoria, MD, PhD, and Pierre Fouret, MD,PhD, from the Departments of Medicineand Translational Research, respectively,at Institut Gustave Roussy, found thatnever-smokers vs smokers had significantoverexpression of P38 (P < .001)and JNK (P = .012), "and, for P38 inparticular, this difference was significantindependent of clinicalparameters known to affect the expressionof these molecules," Dr.Mountzios said. Expression of P38in never-smokers was 10-foldhigher than in smokers with lungadenocarcinoma.

In univariate (but not multivariate)analyses, P38 and STAT3expression levels were predictiveof overall survival. In addition,there was some indication thatERK expression might be an independentpredictor of disease-freesurvival in patients with lungadenocarcinoma.

"These results suggest that lungadenocarcinoma may be a different disease in molecular terms insmokers and nonsmokers," Dr.Mountzios said.

He speculated that the processof carcinogenesis in never-smokersmight involve a preexistingmolecular abnormality that needsto be clarified with methods usinggenetic material. "Althoughthese results are not directly applicableto the clinical setting, theydo provide a better understandingof the molecular biology ofthe disease. This could enable researchersto identify more specifictherapeutic targets that are activatedin lung adenocarcinoma patientsin relation to their smokingstatus," he said.