4434

Several chromosomal regions are recurrently amplified or deleted in lung tumors, but little is known about the underlying genes, which could be important mediators in tumor formation or progression. High-copy number alterations are mostly associated with a profound change in the expression of the target genes within the amplicon. In this study we wanted therefore to investigate in more detail narrow region high level amplifications of early stage pulmonary adenocarcinomas where the underlying oncogenes have not yet been described. Array CGH (30 000 oligos) was performed on tumor specimens from 30 untreated patients with an early stage lung adenocarcinoma (pT1-pT3, M0). All of the 30 analyzed tumor samples showed changes in their copy numbers, 11 contained high level amplifications (<10Mbp) at 22 different loci. In several cases the tumor contained several narrow high level amplification implicating own mechanisms causing high-level amplifications in contrast to single copy gains and losses found in the other tumors. In most cases the amplicon was only present in 1 case, except for 8p11.21 (3 cases), 12p11.22 (2 cases) 12q15 (3 cases), and 14q12 (2 cases). Four regions harbouring well known lung cancer related oncogenes, cMYC (8q24.21), FGFR1 (8p11.21), ERBB2 (17q12), CDK4 (12q14.1) and MDM2 (12q15) were found among the 11 amplicons. Other previously often described narrow amplicons included 3q25.1, 11q35, 19q13.12 and 22q11.21. Two cases had a narrow 7.5 Mbp amplicon at 14q13.3-q21.1. Two of the overexpressed and amplified genes within the minimally altered region (TITF1 and FOXA1) were found highly interesting, as both have been previously associated with lung morphogenesis and are discussed for influence on the pattern of lymph node involvement, survival and metastasis in lung cancer. Immunohistochemical (IHC) analysis of 56 tumor samples on a tissue microarray showed that TITF1 was expressed at a high level in 37.5 % of lung tumors. FOXA1 was expressed at a high level in 48.2 % of lung tumors. A FISH validation is currently ongoing for investigating the correlation between gene copy number and protein expression of both TITF1 and FOXA1. Amplification and overexpression of FOXA1 and TITF1 in lung adenocarcinomas would suggest a potential oncogenic role for these genes in tumorigenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA