胃癌中的FGFR2蛋白水平过表达预示基因扩增,且H指数高提示预后不良

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胃癌中的FGFR2蛋白水平过表达预示基因扩增，且H指数高提示预后不良

译者:张兴艳【眠空2015】新疆医科大学第一附属医院

摘要

FGFR2基因扩增以及由此导致的FGFR2蛋白过表达在胃癌中较少见，而且开发一个精确的、可广泛用于大规模筛选可能对FGFR抑制剂治疗有效的患者很有意义。

我们首先利用一种特异性抗体FPR2-D通过免疫组织化学法筛选了312例已知FGFR2b拷贝数异常的胃癌患者。然后对1574胃癌患者标本构建的组织微阵列进行了免疫组织化学检测。

筛选出来的病例通过FISH检测了FGFR2扩增。此外，我们在88例配对的原发和转移性胃癌中检测了FGFR2的过表达。在第一个队列中，FGFR2b免疫组织化学结果与拷贝数异常及FISH有较好的相关性(r = 0.79，r = 1.0)。1974例胃癌中有73例FGFR2b过表达（阳性率4%）。免疫组织化学结果和FISH结果一致性非常高;所有免疫组化2+、3+的病例都确定有FGFR2扩增。

配对的原发和转移性胃癌中，转移性胃癌中阳性例数及阳性率明显高于原发性胃癌(分别为8%、3%和75%、47%; P<0.001).FGFR2b高表达与弥漫性胃癌亚型及高N分期明显相关（ P=0.01、 P=0.01) 。H值≥150及FGFR2b过表达是影响总生存期的独立预后因素，风险比为1.836(95%置信区间,1.034 -3.261;P = 0.038)。FGFR2b免疫组织化学阳性与其扩增有密切关系。

鉴于FGFR2在胃癌中扩增的的低频性，免疫组织化学是一个准确检测FGFR2扩增的筛查方案，而且原发性和转移性胃癌组织都应该检测FGFR2扩增，以筛选出可用FGFR2抑制剂治疗的胃癌患者。

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival.

Ahn S,Lee J,Hong M,Kim ST,Park SH,Choi MG,Lee JH,Sohn TS,Bae JM,Kim S,Jung SH,Kang WK,Kim KM

Modern Pathology； Aug 2016; 29 (9): 1004 - 1113:1095-103 

Abstract

FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important.

We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH.

In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. 

In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; P<0.001). 

FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score ≥150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. 

Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors.