FGFR1 expression.

<p>FGFR1 expression.</p

<i>FGFR1</i> Amplification Is Often Homogeneous and Strongly Linked to the Squamous Cell Carcinoma Subtype in Esophageal Carcinoma

<div><p>Background and Aims</p><p>Amplification of the <i>fibroblast growth factor receptor 1</i> (<i>FGFR1</i>) is believed to predict response to multi-kinase inhibitors targeting <i>FGFR1</i>. Esophageal cancer is an aggressive disease, for which novel targeted therapies are highly warranted.</p><p>Methods</p><p>This study was designed to investigate the prevalence and clinical significance of <i>FGFR1</i> amplification in a tissue microarray containing 346 adenocarcinomas and 254 squamous cell carcinomas of the esophagus, using dual-labeling fluorescence <i>in situ</i> hybridization (FISH) analysis.</p><p>Results</p><p><i>FGFR1</i> amplification, defined as a ratio of <i>FGFR1</i>:centromere 8 copy numbers ≥ 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p<0.0001). There was no association between <i>FGFR1</i> amplification and tumor phenotype or clinical outcome. To study potential heterogeneity of <i>FGFR1</i> amplification, all available tumor blocks from 23 <i>FGFR1</i> amplified tumors were analyzed on conventional large sections. This analysis revealed complete homogeneity of <i>FGFR1</i> amplification in 20 (86.9%) primary tumors and in all available lymph node metastases. Remarkably, <i>FGFR1</i> amplification was also seen in dysplasia adjacent to tumor in 6 of 9 patients with <i>FGFR1</i> amplified primary cancers.</p><p>Conclusions</p><p>In conclusion, <i>FGFR1</i> amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers. The high homogeneity of <i>FGFR1</i> amplification suggests that patients with <i>FGFR1</i> amplified esophageal cancers may particularly benefit from anti-<i>FGFR1</i> therapies and prompt for clinical studies in this tumor type.</p></div

Homogeneity/Heterogeneity analysis of <i>FGFR1</i> amplified tumors.

<p>*average copy number counted in 20 cell nuclei,</p><p>**Homogeneity/Heterogeneity, PT: primary tumor, LN: lymph node, Dys: dysplasia</p><p>Homogeneity/Heterogeneity analysis of <i>FGFR1</i> amplified tumors.</p

Raw Survival of ESCC patients.

<p>Red line: no <i>FGFR1</i> amplified tumor patients. Blue line: <i>FGFR1</i> amplified tumor patients.</p

FISH analysis in ESCC patients.

<p>Green signals represent the <i>FGFR1</i> gene while red signals correspond to the centromere of chromosome 8. (A) high-level amplification of <i>FGFR1</i> showing 10–20 gene signals and 2–4 centromere signals with a ratio of 6.16. (B) Heterogeneous amplification of <i>FGFR1</i> as indicated by presence of two distinct cancer areas with FGFR1 amplification and without FGFR1 amplification. These two areas are separated by the dotted line. (C) Normal <i>FGFR1</i> gene and centromere 8 signals.</p

<i>FGFR1</i> ampification in ESCC and EADC.

<p><i>FGFR1</i> ampification in ESCC and EADC.</p

Esophageal Carcinoma—Array.

<p>Esophageal Carcinoma—Array.</p