title: Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer.
abstract: Next to EGFR mutation, EGFR gene copy number evaluated by fluorescence in situ hybridization (FISH) emerged as a potential predictive marker for sensitivity to EGFR tyrosine kinase inhibitors, although controversial data exist. As the diagnostic accuracy of predictive biomarkers can be substantially limited by regional differences within tumors, heterogeneity of EGFR gene copy gain in NSCLC was assessed in this study. For this purpose, a novel tissue microarray (TMA) based analysis platform was developed. TMAs were constructed containing 8 different tissue cylinders from 144 primary NSCLCs. From 62 of these patients additional nodal metastases were sampled. EGFR gene copy number and EGFR expression was analyzed by FISH and immunohistochemistry according to the suggested guidelines. 13 (9.0%) of the 144 evaluated tumors showed EGFR amplification and 37 (25.7%) tumors high polysomy in at least one tumor area. In 7 (53.8%) of 13 amplified cases the analysis of different tumor areas revealed subclones without EGFR gene copy gain next to subclones with amplification. All of the 36 evaluable tumors with high polysomy showed heterogeneity of EGFR gene copy number with areas negative for gene copy gain within the individual tumors. Heterogeneity of EGFR gene copy gain in lung cancer challenges the concept of using small biopsies for the analysis of EGFR FISH status. EGFR gene copy number is highly heterogeneous within individual NSCLCs and this finding might well be a reason for the controversial clinical data existing regarding responsiveness to anti-EGFR therapy.
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. t.grob@uke.de
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Grob
authors.forename: Tobias
authors.initials: T
authors.lastname: Hoenig
authors.forename: Till S
authors.initials: TS
authors.lastname: Clauditz
authors.forename: Djordje
authors.initials: D
authors.lastname: Atanackovic
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Koenig
authors.forename: Yogesh K
authors.initials: YK
authors.lastname: Vashist
authors.forename: Hans
authors.initials: H
authors.lastname: Klose
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C512478:EGFR protein, human; D066246:ErbB Receptors