Japanese Foundation for Cancer Research, Tokyo, Japan.
Cancer. 2012 Sep 15;118(18):4427-36. doi: 10.1002/cncr.27391. Epub 2012 Jan 17.
Several promising molecular-targeted drugs are used for advanced renal cancers. However, complete remission is rarely achieved, because none of the drugs targets a key molecule that is specific to the cancer, or is associated with "oncogene addiction" (dependence on one or a few oncogenes for cell survival) of renal cancer. Recently, an anaplastic lymphoma kinase (ALK) fusion, vinculin-ALK, has been reported in pediatric renal cell carcinoma (RCC) cases who have a history of sickle cell trait. In this context, ALK inhibitor therapy would constitute a therapeutic advance, as has previously been demonstrated with lung cancer, inflammatory myofibroblastic tumors, and anaplastic large cell lymphomas.
Anti-ALK immunohistochemistry was used to screen 355 tumor tissues, using the intercalated antibody-enhanced polymer (iAEP) method. The cohort consisted of 255 clear cell RCCs, 32 papillary RCCs, 34 chromophobe RCCs, 6 collecting duct carcinomas, 10 unclassified RCCs, 6 sarcomatoid RCCs, and 12 other tumors.
Two patients (36- and 53-year-old females) were positive for ALK as determined by iAEP immunohistochemistry. Using 5'- rapid amplification of complementary DNA ends, we detected TPM3-ALK and EML4-ALK in these tumors. The results of this study were confirmed by fluorescence in situ hybridization assays. The 2 ALK-positive RCCs were unclassified (mixed features of papillary, mucinous cribriform, and solid patterns with rhabdoid cells) and papillary subtype. They comprised 2.3% of non-clear cell RCCs (2 of 88) and 3.7% of non-clear cell and nonchromophobe RCCs (2 of 54).
The results of this study indicate that ALK fusions also exist in adult RCC cases without uncommon backgrounds. These findings confirm the potential of ALK inhibitor therapy for selected cases of RCC.
有几种有前途的分子靶向药物用于治疗晚期肾癌。然而，完全缓解很少发生，因为没有一种药物针对的是肾癌特有的关键分子，或者与肾癌的“致癌基因成瘾”（依赖一个或几个致癌基因存活）有关。最近，在有镰状细胞特征病史的小儿肾细胞癌（RCC）病例中报道了一种间变性淋巴瘤激酶（ALK）融合，连接蛋白-ALK。在这种情况下，ALK 抑制剂治疗将构成一种治疗进展，正如以前在肺癌、炎症性肌纤维母细胞瘤和间变大细胞淋巴瘤中所证明的那样。
使用插层抗体增强聚合物（iAEP）法对 355 个肿瘤组织进行抗 ALK 免疫组织化学筛选。该队列包括 255 例透明细胞 RCC、32 例乳头状 RCC、34 例嫌色细胞 RCC、6 例集合管癌、10 例未分类 RCC、6 例肉瘤样 RCC 和 12 例其他肿瘤。
两名患者（36 岁和 53 岁女性）通过 iAEP 免疫组织化学检测为 ALK 阳性。使用 5'快速扩增互补 DNA 末端，我们在这些肿瘤中检测到 TPM3-ALK 和 EML4-ALK。荧光原位杂交检测证实了这项研究的结果。这 2 例 ALK 阳性 RCC 为未分类（具有横纹肌样细胞的乳头状、黏液性筛状和实性特征混合）和乳头状亚型。它们占非透明细胞 RCC（88 例中的 2 例）和非透明细胞和非嫌色细胞 RCC（54 例中的 2 例）的 2.3%。
这项研究的结果表明，ALK 融合也存在于没有不常见背景的成人 RCC 病例中。这些发现证实了 ALK 抑制剂治疗对选定的 RCC 病例的潜在作用。
