title: Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers.
abstract: In a subset of lung adenocarcinomas, the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. For this study, we selected 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, and low and high polysomy (100% versus 54%, P = 0.009). EGFR amplification occurred invariably on the mutated and not the wild-type allele (median mutated/wild-type ratios 14.0 versus 0.33, P = 0.003), was associated with solid histology (P = 0.008), and advanced clinical stage (P = 0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival, 16 versus 31 months, P = 0.01) and when adjusted for stage (P = 0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and show distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Holmes-Tisch
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chou
authors.forename: Ming-Tsang
authors.initials: MT
authors.lastname: Wu
authors.forename: Yih-Gang
authors.initials: YG
authors.lastname: Goan
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Elisa
authors.initials: E
authors.lastname: Benedettini
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking / Q000235:genetics*; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins