Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer

• Published in: International journal of cancer Vol. 133; no. 4; pp. 898 - 907
• Main Authors: Pros, Eva, Lantuejoul, Sylvie, Sanchez‐Verde, Lydia, Castillo, Sandra D, Bonastre, Ester, Suarez‐Gauthier, Ana, Conde, Esther, Cigudosa, Juan C, Lopez‐Rios, Fernando, Torres‐Lanzas, Juan, Castellví, Josep, Cajal, Santiago Ramon y, Brambilla, Elisabeth, Sanchez‐Cespedes, Montse
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15-08-2013; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Gene Amplification; Gene expression; Gene Expression Profiling; growth factor receptors; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung cancer; Lung Neoplasms - genetics; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Pneumology; Real-Time Polymerase Chain Reaction; Receptors, Growth Factor - genetics; Receptors, Growth Factor - metabolism; RNA, Messenger - genetics; therapeutic marker; Tumors; Tumors of the respiratory system and mediastinum; Lung disease; Respiratory disease; Lung cancer; Biological marker; Malignant tumor; Medical screening; Gene amplification; Growth factor receptor; Cancerology; Treatment; growth factor receptors; Bronchus disease; therapeutic marker; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28090

Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately. One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK, FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real‐time quantitative RT‐PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to 6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always coamplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target. Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK, MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho‐S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre‐select tumors for testing. Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments.
What's new?
Targeting growth factor receptors is a good way to treat cancer, in the right patients. Therefore, it's important to be able to identify patients with alterations in relevant GFRs. One way they get activated is by gene amplification, but it can be tricky to establish whether amplification has taken place. This study provides the first comprehensive analysis of gene copy number and gene expression alteration in non‐small cell lung carcinoma (NSCLC). By combining the analyses of alterations at the DNA, mRNA, and protein levels for certain growth factors in a panel of 300 NSCLC, the authors were able to identify those tumors that carry gene amplifications. These new results establish parameters for gene amplification that will be useful for routine screening.