Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability.
Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability.
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DOI：
10.1158/1078-0432.ccr-08-1282
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发表时间：
2009-07-15
期刊：
影响因子：
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通讯作者：
Malkhosyan SR
中科院分区：
文献类型：
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作者：
Baranovskaya S;Martin Y;Alonso S;Pisarchuk KL;Falchetti M;Dai Y;Khaldoyanidi S;Krajewski S;Novikova I;Sidorenko YS;Perucho M;Malkhosyan SR
表皮生长因子受体（EGFR）在几种肿瘤类型中过表达，其表达受5′端微卫星重复序列（CA）n长度的影响：重复序列越长，表达越低。二核苷酸重复序列在具有微卫星不稳定性的肿瘤中积累插入/缺失类型的突变。我们设计了这项研究来评估EGFR（CA）n中这些突变的发生及其在微卫星不稳定性阳性结肠和胃肿瘤癌变中的相关性。我们分析了55例结直肠癌和14例胃癌微卫星不稳定性阳性癌的体内EGFR（CA）n突变频率，以及微卫星不稳定性阳性结肠肿瘤细胞系LS 174的单细胞克隆培养物的体外EGFR（CA）n突变频率。通过荧光激活细胞分选仪分析具有不同重复长度的单细胞克隆培养物的EGFR细胞表面表达。EGFR（CA）n突变与KRAS、BRAF和p53突变之间进行相关性分析。与单细胞克隆培养相比，其表现出更高的缺失率比插入，大多数EGFR（CA）n突变在结肠和胃肿瘤中的插入。在单细胞克隆培养中，EGFR（CA）n越长，EGFR细胞表面表达越低。在结肠癌中，重复序列的延长与KRAS和BRAF突变呈负相关，但与p53无关。肿瘤中EGFR（CA）n的延长不能用这种重复序列有利于插入而不是缺失的内在特性来解释。相反，在微卫星不稳定性阳性肿瘤中发生重复延长的选择，导致EGFR下调。这些发现表明，在微卫星不稳定性阳性肿瘤中，目前靶向EGFR过表达的治疗可能没有效果或与预期效果相反。
The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5′-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability – positive colon and gastric tumors. We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability – positive cancers, and in vitro in single-cell clone cultures of microsatellite instability – positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53. Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53. The EGFR(CA)n elongation observedin tumors cannot be explained by anintrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability – positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability – positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.