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Open Access Highly Accessed Research article

Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma

Hélène Blons123*, Karine Pallier12, Delphine Le Corre12, Claire Danel4, Maxime Tremblay-Gravel12, Claude Houdayer5, Elizabeth Fabre-Guillevin6, Marc Riquet27, Philippe Dessen8 and Pierre Laurent-Puig123*

Author Affiliations

1 UMR-S775, INSERM, Paris, F-75006, France

2 Université Paris Descartes, Paris, F-75006, France

3 Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75015, France

4 Department of Pathology, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75015, France

5 Department of Molecular Oncology, Institut Curie, Paris, F-75005, France

6 Department of Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75015, France

7 Department of Thoracic Surgery, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75015, France

8 Department of Informatics, Institut Gustave Roussy, Villejuif, F-94905, France

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BMC Medical Genomics 2008, 1:25  doi:10.1186/1755-8794-1-25

Published: 12 June 2008

Abstract

Background

Lung cancer with EGFR mutation was shown to be a specific clinical entity. In order to better understand the biology behind this disease we used a genome wide characterization of loss of heterozygosity and amplification by Single Nucleotide Polymorphism (SNP) Array analysis to point out chromosome segments linked to EGFR mutations. To do so, we compared genetic profiles between EGFR mutated adenocarcinomas (ADC) and KRAS mutated ADC from 24 women with localized lung cancer.

Results

Patterns of alterations were different between EGFR and KRAS mutated tumors and specific chromosomes alterations were linked to the EGFR mutated group. Indeed chromosome regions 14q21.3 (p = 0.027), 7p21.3-p21.2 (p = 0.032), 7p21.3 (p = 0.042) and 7p21.2-7p15.3 (p = 0.043) were found significantly amplified in EGFR mutated tumors. Within those regions 3 genes are of special interest ITGB8, HDAC9 and TWIST1. Moreover, homozygous deletions at CDKN2A and LOH at RB1 were identified in EGFR mutated tumors. We therefore tested the existence of a link between EGFR mutation, CDKN2A homozygous deletion and cyclin amplification in a larger series of tumors. Indeed, in a series of non-small-cell lung carcinoma (n = 98) we showed that homozygous deletions at CDKN2A were linked to EGFR mutations and absence of smoking whereas cyclin amplifications (CCNE1 and CCND1) were associated to TP53 mutations and smoking habit.

Conclusion

All together, our results show that genome wide patterns of alteration differ between EGFR and KRAS mutated lung ADC, describe two models of oncogenic cooperation involving either EGFR mutation and CDKN2A deletion or cyclin amplification and TP53 inactivating mutations and identified new chromosome regions at 7p and 14q associated to EGFR mutations in lung cancer.