Workshops

Clustered Genomic Alterations in Chromosome 7p Dictate Outcomes and Targeted Treatment Responses of Lung Adenocarcinoma with EGFR-activating Mutations

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2011-06-22
13:30:00 - 14:20:00

308 , Mathematics Research Center Building (ori. New Math. Bldg.)



Purpose

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are proved more effective for lung adenocarcinoma patients with EGFR-activating mutation than wild-type, the former group still has about 30% non-responders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek for molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to the EGFR-activating mutant patients.

Patients and Methods

We first investigated the molecular differences between EGFR mutant and EGFR wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues, Then we used an independent group of 114 patients to validate the clinical relevance of copy number alterations (CNAs) in predicting the overall and the disease-free survivals. Finally, focusing on 23 EGFR-mutant patients receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs.

Results

We identified chromosome regions with differential CNAs between the EGFR-activating mutant and EGFR wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted the overall and the disease-free survivals for EGFR-activating mutant patients, but not wild-type. Importantly, simultaneous presence of more genes with increased CNA in this cluster correlated with less favorable response to EGFR-TKIs in EGFR-activating mutant patients.

Conclusion

Our results shed light on why among patients with EGFR mutation; responses to the EGFR-TKIs are heterogeneous. They may lead to a better patient management for EGFR-mutant patients.