Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas.
Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas.
复制标题
DOI：
10.1186/1471-2407-12-569
复制
发表时间：
2012-12-04
期刊：
影响因子：
3.8
通讯作者：
Pinto LF
中科院分区：
文献类型：
--
作者：
Gonzaga IM;Soares-Lima SC;de Santos PT;Blanco TC;de Reis BS;Quintella DC;de Oliveira IM;de Faria PA;Kruel CD;Andreollo NA;de Simão TA;Pinto LF
食管鳞状细胞癌 (ESCC) 的 5 年生存率低于 10%，表明改善其治疗的紧迫性。表皮生长因子受体的改变与许多肿瘤的恶性转化密切相关，最近成功的靶向治疗已针对这些分子。因此，在本研究中，我们分析了食管鳞癌患者中EGFR和HER2的表达，并评估了EGFR突变谱以及KRAS和BRAF热点突变的存在。我们进行了 RT-qPCR、免疫组织化学和荧光原位杂交来确定 ESCC 患者中 EGFR 和 HER2 的表达，并进行了直接测序和 PCR-RFLP 进行突变和多态性分析。我们的结果显示，与周围组织相比，肿瘤中 EGFR mRNA 表达增加 (p <0.05)，11% 的病例在肿瘤和配对的邻近粘膜之间存在至少四倍的差异。仅 4% 的病例出现 EGFR 蛋白过度表达。肿瘤和邻近粘膜之间 HER2 mRNA 的中值表达没有差异。尽管如此，与配对的对应基因相比，7% 的肿瘤的该基因表达量至少高出 25 倍。免疫组织化学分析显示，21% 的肿瘤呈 HER2 阳性（评分为 2+ 和 3+），尽管只有 3+ 的肿瘤呈现出该基因的扩增。对 EGFR（外显子 18-21）、KRAS（密码子 12 和 13）和 BRAF (V600E) 的突变分析显示，在分析的近 100 名患者中，这些基因的任何热点均没有突变。 2.1% 的患者中 EGFR 在密码子 836 (C>T) 处呈现同义多态性，79.2% 的患者在密码子 787 (G>A) 处呈现同义多态性。最后的多态性也在 304 名健康对照中进行了评估，与 ESCC 患者相比，其频率相似 (73.7%)。不到 10% 的患者没有 EGFR、KRAS 和 BRAF 突变，且 EGFR 和 HER2 过度表达，表明该信号通路仅在一小部分 ESCC 患者中发生改变。 HER 受体靶向治疗可能仅对一小部分 ESCC 患者有效。
Esophageal squamous cell carcinoma (ESCC) shows a 5-year survival rate below 10%, demonstrating the urgency in improving its treatment. Alterations in epidermal growth factor receptors are closely related to malignancy transformation in a number of tumors and recent successful targeted therapies have been directed to these molecules. Therefore, in this study, we analyzed the expression of EGFR and HER2 and evaluated EGFR mutation profile as well as the presence of mutations in hotspots of KRAS and BRAF in ESCC patients. We performed RT-qPCR, immunohistochemistry and Fluorescent in situ hybridization to determine EGFR and HER2 expression in ESCC patients, and direct sequencing and PCR-RFLP for mutations and polymorphism analysis. Our results showed an increased EGFR mRNA expression in tumors compared to surrounding tissue (p <0.05), with 11% of the cases presenting at least a four-fold difference between tumor and paired adjacent mucosa. EGFR protein overexpression was present only in 4% of the cases. The median expression of HER2 mRNA was not different between tumors and adjacent mucosa. Still, 7% of the tumors presented at least a 25-fold higher expression of this gene when compared to its paired counterpart. Immunohistochemical analysis revealed that 21% of the tumors were positive for HER2 (scores 2+ and 3+), although only 3+ tumors presented amplification of this gene. Mutation analysis for EGFR (exons 18-21), KRAS (codons 12 and 13) and BRAF (V600E) showed no mutations in any of the hotspots of these genes in almost 100 patients analyzed. EGFR presented synonymous polymorphisms at codon 836 (C>T) in 2.1% of the patients, and at codon 787 (G>A) in 79.2% of the cases. This last polymorphism was also evaluated in 304 healthy controls, which presented a similar frequency (73.7%) in comparison with ESCC patients. The absence of mutations of EGFR, KRAS and BRAF as well as the overexpression of EGFR and HER2 in less than 10% of the patients suggest that this signaling pathway is altered in only a small proportion of patients with ESCC. HER receptors target therapies may have the potential to be effective in only a minor fraction of patients with ESCC.
登录
查看更多内容
影响因子：
51.1
作者：
Pirker, Robert;Pereira, Jose R.;O'Byrne, Kenneth J.
通讯作者：
O'Byrne, Kenneth J.
影响因子：
3.7
作者：
Morgan S;Grandis JR
通讯作者：
Grandis JR
影响因子：
3.7
作者：
Italiano, Antoine;Follana, Philippe;Francois, Eric
通讯作者：
Francois, Eric
影响因子：
11.2
作者：
Kim, Seok-Hyun;Nakagawa, Hiroshi;El-Deiry, Wafik S.
通讯作者：
El-Deiry, Wafik S.
影响因子：
11.5
作者：
Croxtall, Jamie D.;McKeage, Kate
通讯作者：
McKeage, Kate