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[1600] EGFR Gene Amplification Is Invariably Associated with Exon 19 Deletion in Non-Small Cell Lung Carcinoma

LM Sholl, AJ Iafrate, B Yeap, A Holmes, YP Chou, MT Wu, YG Goan, L Su, PA Jänne, DC Christiani, LR Chirieac. Brigham and Womens Hospital, Boston; Massachusetts General Hospital, Boston; Dana Farber Cancer Institute, Boston; Kaohsiung Veteran General Hospital, Kaohsiung, Taiwan; Harvard School of Public Health, Boston

Background: A subset of non-small cell lung carcinomas (NSCLC) contain an activated form of the epidermal growth factor receptor (EGFR) secondary to mutations in the kinase domain (exons 18 to 21) and/or gene amplification. Deletions in exon 19 and the L858R substitution in exon 21 each account for 40-50% of mutations. Gene amplification occurs in approximately 15% of cases. To date, no studies have examined the correlation between mutation type and amplification status. We hypothesized that there is a preferential association of EGFR gene amplification with selected types of EGFR mutations.
Design: Paraffin-embedded NSCLC specimens from 79 non-smoking Chinese women in Taiwan treated by surgery alone were examined for gene copy number by FISH and scored according to published criteria as gene amplified, high polysomy, low polysomy, or disomic. EGFR kinase domain mutations were detected by PCR-capillary sequencing. Mutant and wild type alleles were quantified in a subset of exon 19 deletion cases (n=37) and L858R mutation cases (n=9) by QPCR.
Results: FISH analysis revealed that 9 cases (11%) were gene amplified, 25 cases (32%) had high polysomy, 20 cases (25%) had low polysomy, and 25 cases (32%) were disomic. The exon 19 deletion mutation was present in 100% of cases with gene amplification; the exon 19 deletion was found in 56%, 55%, and 44% of high polysomy, low polysomy, and disomic cases, respectively (Fishers exact test; p=0.009). The non-amplified categories contained a heterogenous mix of WT, missense- and insertion- mutation cases. Preferential amplification of the mutant allele occurred exclusively in the cases with exon 19 deletion and more frequently in the gene amplified cases (6 of 7; 86%) as compared to the non-amplified cases (6 of 39; 15%).
Conclusions: Our amplification-mutation correlation study reveals that there is a molecularly distinct subset of NSCLC that harbors EGFR gene amplification and the exon 19 deletion mutation. Amplification occurs preferentially on the mutated allele in cases with gene amplification by FISH. Our findings may have significant implications for selection of patients with NSCLC for treatment with tyrosine kinase inhibitors.
Category: Pulmonary

Monday, March 3, 2008

Poster # 224, Monday Morning