Al-Saad Samer, Richardsen Elin, Kilvaer Thomas K, Donnem Tom, Andersen Sigve, Khanehkenari Mehrdad, Bremnes Roy M, Busund Lill-Tove
Institute of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.
Department of Clinical Pathology, University Hospital of Northern Norway, Tromso, Norway.
PLoS One. 2017 Jul 25;12(7):e0181527. doi: 10.1371/journal.pone.0181527. eCollection 2017.
To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.
Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.
In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).
MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.
比较银原位杂交（SISH）和免疫组织化学（IHC）检测MET和IGF1R改变的疗效，并研究其发生率和预后意义。还研究了MET受体表达、MET基因改变与两种最常见的EGFR基因突变之间可能的相关性。
对326例非小细胞肺癌（NSCLC）患者的I至IIIA期肿瘤进行免疫组织化学检测，以检测MET和IGF-1的蛋白表达。在石蜡包埋、福尔马林固定的材料中，通过SISH将其细胞质表达与MET和IGF1R基因的基因拷贝数进行比较。与两种常见EGFR突变的免疫组织化学表达及临床病理变量进行相关性分析。采用单因素和多因素生存分析来评估所检测标志物的预后疗效。
在单因素分析中，高细胞质MET表达在腺癌患者中显示出显著的负性预后效应（p = 0.026）。MET基因与7号染色体的比例是一个显著的正性预后标志物（p = 0.005），可能仅归因于7号染色体多倍体的高度负性预后意义（p = 0.002）。高IGF1R基因拷贝数是所有NSCLC患者的负性预后标志物（p = 0.037）。在多因素分析中，肿瘤细胞中7号染色体多倍体与预后不良显著且独立相关（p = 0.011）。在腺癌患者中，高细胞质MET表达是一个独立的负性预后标志物（p = 0.013）。在男性患者中，高IGF1R基因拷贝数与15号染色体计数的比例与预后不良显著且独立相关（p = 0.018）。
与SISH相比，MET蛋白表达提供了更优的预后信息。7号染色体多倍体是NSCLC患者的独立负性预后因素。这一发现对于通过SISH检测位于7号染色体上的基因具有重要意义。高IGF1R基因拷贝数与15号染色体计数的比例是原发性NSCLC男性患者生存较差的独立预测指标。
