Oyama Takeru, Okamoto Koichi, Nakamura Ritsuko, Tajiri Ryosuke, Ikeda Hiroko, Ninomiya Itasu, Ooi Akishi
Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.
Department of Gastroenterologic Surgery, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.
Pathol Int. 2015 Nov;65(11):608-13. doi: 10.1111/pin.12344. Epub 2015 Aug 28.
EGFR and ERBB2 belong to the EGFR gene family. In esophageal squamous cell carcinomas (SCCs), amplification of EGFR or ERBB2 is usually mutually exclusive. EGFR amplification occurs in approximately 15% of SCCs, ERBB2 occurs in less than 5%. Here, we report the co-amplification of EGFR and ERBB2 in an ulcerative and infiltrating-type SCC that measured approximately 4.2 × 2.7 × 1.2 cm with a superficial lesion occurring in the thoracic esophagus of a 72-year-old man. Multiplex ligation-dependent probe amplification using representative tumor sections showed gain of CCND1 and coincident amplification of ERBB2 or EGFR or neither. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor comprised three cancer-cell populations: well-differentiated SCC with high-level ERBB2 amplification and ERBB2 overexpression, more infiltrative poorly-differentiated SCC with high-level EGFR amplification and EGFR overexpression, and poorly-differentiated SCC lacking any ERBB2 or EGFR abnormality. These three populations each had low-level CCND1 amplification and nuclear cyclin D1 overexpression. This histological topology and gene amplification combinations suggested that genetic instability first produced CCND1 amplification, and then ERBB2 or EGFR gene amplification occurred. It is further speculated that during cancer progression and clonal selection indecisive predominance of either clone caused the rare co-amplification of ERBB2 and EGFR in a single chimeric tumor.
表皮生长因子受体（EGFR）和人表皮生长因子受体2（ERBB2）属于EGFR基因家族。在食管鳞状细胞癌（SCC）中，EGFR或ERBB2的扩增通常是相互排斥的。EGFR扩增发生在约15%的SCC中，ERBB2扩增发生在不到5%的SCC中。在此，我们报告了一名72岁男性胸段食管溃疡性浸润型SCC中EGFR和ERBB2的共扩增，该肿瘤大小约为4.2×2.7×1.2 cm，表面有病变。使用代表性肿瘤切片进行多重连接依赖探针扩增显示细胞周期蛋白D1（CCND1）增加，同时伴有ERBB2或EGFR扩增或两者均无扩增。免疫组织化学和荧光原位杂交显示，该肿瘤由三种癌细胞群体组成：具有高水平ERBB2扩增和ERBB2过表达的高分化SCC、具有高水平EGFR扩增和EGFR过表达的浸润性更强的低分化SCC、以及缺乏任何ERBB2或EGFR异常的低分化SCC。这三种群体均有低水平的CCND1扩增和细胞核周期蛋白D1过表达。这种组织学拓扑结构和基因扩增组合表明，遗传不稳定性首先导致CCND1扩增，随后发生ERBB2或EGFR基因扩增。进一步推测，在癌症进展和克隆选择过程中，任一克隆的不确定优势导致了在单个嵌合肿瘤中罕见的ERBB2和EGFR共扩增。
