Degree Of Intratumoral Heterogeneity Research Articles

Abstract NSCLC is the cancer with highest death rate; it is typically diagnosed at a late stage and has limited therapeutic options. FGFR signaling is a potential oncogenic driver in many cancers, including NSCLC. In this study we evaluated the copy number variations (CNVs) of FGFR1 and FGFR2 by dual color FISH in specimens from 139 NSCLC patients (78 SCC, 46 ADC, 15 other). CNVs were observed for both FGF receptors. However, FGFR1 was more frequently affected by CNV than FGFR2 (45% vs. 17%). Only a small fraction of patients exhibited CNV of both receptors. In general, the level of gene amplification was higher for FGFR1 as compared with FGFR2. Interestingly, FGFR2 CNV exhibited a high degree of intra-tumor heterogeneity. FGFR1 gene dose elevations were observed due to gene locus amplification (27%) as well as polysomy of chromosome 8 (17%). The degree of gene locus amplification was classified from low (gene ratio 1.5 – 2.5) to high (&gt;4.5). An analysis of the two most common histologies (i.e. Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC)) indicated that gene locus amplifications were more frequent in SCC (38%) as compared with ADC (7%), while polysomy of chromosome 8 was observed at similar rates (18-19%). Lack of FGFR1 rearrangements was confirmed using a break-apart FISH probe. FGFR2 gene dose elevations show gene locus amplifications and polysomy of chromosome 10. Locus amplifications of FGFR2 were observed in 11% of SCC, but were not found in ADC. Similar rates for polysomy of FGFR1were observed in SCC (7%) and ADC (5%). Overall, gene dose elevation of FGFR1 and FGFR2 were found more frequently in SCC. Of higher relevance is the fraction of patients with gene dose elevation due to gene locus amplification. Approximately 40% of the SCC patients possess gene locus amplification of at least one of the two probed FGF-receptors. However, only ∼9% of the SCC patients have both loci amplified. In conclusion here we present for the first time evidence for a potential genetic addiction of NSCLC, specifically on FGFR1 gene locus amplification. Therefore targeting FGFR in combination with proper patient stratification, may be an attractive opportunity to develop improved clinical options for treatment of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4177. doi:10.1158/1538-7445.AM2011-4177

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