Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Clin Cancer Res. 2013 Aug 1;19(15):4273-81. doi: 10.1158/1078-0432.CCR-13-0318. Epub 2013 May 31.
Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers.
We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib.
Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing.
Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.
间变性淋巴瘤激酶（ALK）基因重排定义了非小细胞肺癌（NSCLC）的一个独特分子亚群。最近，一些病例报告和小系列报告显示，在克唑替尼初治和耐药的 NSCLC 中，ALK 重排可与其他致癌驱动基因重叠。
我们回顾了 1683 例 NSCLC 患者的临床基因分型数据，并研究了 ALK 阳性 NSCLC 患者中同时存在 EGFR 或 KRAS 突变的发生率。我们还检查了 34 例接受克唑替尼耐药后 ALK 阳性 NSCLC 患者的活检标本。
筛选出 301 例（17.8%）EGFR 突变、465 例（27.6%）KRAS 突变和 75 例（4.4%）ALK 重排。EGFR 突变和 ALK 重排是相互排斥的。4 例 KRAS 突变患者的 ALK FISH 模式异常，最常见的是孤立的 5'绿色探针。3 例有足够的组织进行 ALK 免疫组化确认，均为 ALK 表达阴性。在接受克唑替尼耐药的 ALK 阳性 NSCLC 患者中，29 例（100%）重复活检标本的 ALK FISH 阳性。在 34 例中有 7 例（20.6%）观察到 ALK 激酶结构域的继发性突变和 ALK 基因扩增，有 3 例（10.3%）观察到 ALK 基因扩增。在 25 例有足够组织进行检测的克唑替尼耐药、ALK 阳性患者中，均未发现 EGFR 或 KRAS 突变。
在一个大型西方患者人群中，功能性 ALK 重排与 EGFR 和 KRAS 突变是相互排斥的。在对克唑替尼耐药的 ALK 阳性癌症中也观察到这种无重叠现象。
