Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Cancer Res Treat. 2020 Jan;52(1):74-84. doi: 10.4143/crt.2019.062. Epub 2019 May 8.
The purpose of this study was to reveal the clinicopathological characteristics and prognostic implications associated with fibroblast growth factor receptor 1 (FGFR1) amplification in colorectal cancers (CRCs).
We measured the copy number of FGFR1 by droplet digital polymerase chain reaction (ddPCR), and analyzed the FGFR1 expression by immunohistochemistry, in 764 surgically resected CRCs (SNUH2007 dataset, 384 CRCs; SNUH Folfox dataset, 380 CRCs).
CRCs with ≥ 3.3 copies of the FGFR1 gene were classified as FGFR1 amplified. FGFR1 amplification was found in 10 of the 384 CRCs (2.6%) in the SNUH2007 dataset, and in 28 of the 380 CRCs (7.4%) in the SNUH Folfox dataset. In the SNUH2007 dataset, there was no association between the FGFR1 copy number status and sex, gross appearance, stage, or differentiation. High FGFR1 expression was associated with female sex and KRAS mutation. At the molecular level, FGFR1 amplification was mutually exclusive with BRAF mutation, microsatellite instability, and MLH1 methylation, in both SNUH2007 and SNUH Folfox datasets. Survival analysis revealed that FGFR1 amplification was associated with significantly worse clinical outcome compared with no FGFR1 amplification, in both SNUH2007 and SNUH Folfox datasets. Within the SNUH2007 dataset, CRC patients with high FGFR1 expression had an inferior progression-free survival compared with those with low FGFR1 expression. The FGFR inhibitor, PD173074, repressed the proliferation of a CRC cell line overexpressing FGFR1, but not of cells with FGFR1 amplification.
FGFR1 amplification measured by ddPCR can be a prognostic indicator of poor clinical outcome in patients with CRCs.
本研究旨在揭示结直肠癌（CRC）中纤维母细胞生长因子受体 1（FGFR1）扩增的临床病理特征和预后意义。
我们通过液滴数字聚合酶链反应（ddPCR）测量 FGFR1 的拷贝数，并通过免疫组织化学分析 FGFR1 的表达，共分析了 764 例手术切除的 CRC（SNUH2007 数据集 384 例；SNUH Folfox 数据集 380 例）。
将 FGFR1 基因的拷贝数≥3.3 倍的 CRC 归类为 FGFR1 扩增。在 SNUH2007 数据集中，有 384 例 CRC 中有 10 例（2.6%）存在 FGFR1 扩增，而在 SNUH Folfox 数据集中，有 380 例 CRC 中有 28 例（7.4%）存在 FGFR1 扩增。在 SNUH2007 数据集中，FGFR1 拷贝数状态与性别、大体外观、分期或分化无关。高 FGFR1 表达与女性和 KRAS 突变有关。在分子水平上，FGFR1 扩增与 BRAF 突变、微卫星不稳定性和 MLH1 甲基化在 SNUH2007 和 SNUH Folfox 数据集中均相互排斥。生存分析显示，与 FGFR1 无扩增相比，FGFR1 扩增与 SNUH2007 和 SNUH Folfox 数据集中的临床结局显著较差相关。在 SNUH2007 数据集中，高 FGFR1 表达的 CRC 患者无进展生存期劣于低 FGFR1 表达的患者。FGFR 抑制剂 PD173074 抑制了 FGFR1 过表达的 CRC 细胞系的增殖，但对 FGFR1 扩增的细胞没有抑制作用。
ddPCR 测量的 FGFR1 扩增可作为 CRC 患者临床结局不良的预后指标。
