title: Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation.
abstract: In lung cancer, an association was made between drastic clinical response to epidermal growth factor receptor (EGFR) inhibitors and the presence of somatic mutations within the tyrosine kinase domain of the EGFR. In some cases, patients with partial response or disease stabilization do not always have EGFR-mutated tumors. To go further in the characterization of the EGF pathway, we screened EGFR, ERBB2, ERBB3, KRAS, BRAF, and PIK3CA for mutations in 2 groups of White patients with nonsmall cell lung cancer (45 cancers from women and 46 cancers from men). Associations between TP53 mutations, clinicopathologic parameters, and EGF pathway molecular alterations were analyzed. All mutations were exclusive and essentially found in EGFR and KRAS. We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis. On the contrary, KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation. These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. The identification of BAC features in ADC helps clustering patients that are more likely to fit the EGFR-mutated group.
authors.affiliation: Department of Biochemistry, Hôpital Européen Georges Pompidou, Université Paris V, 75015 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Corre
authors.forename: Marc
authors.initials: M
authors.lastname: Riquet
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fabre-Guilevin
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Claire
authors.initials: C
authors.lastname: Danel
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging
chemical_list: D004273:DNA, Neoplasm; D066246:ErbB Receptors