Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population

BackgroundAnaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Patients and MethodsTissue microarray (TMA) was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC) cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC) assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (qRT-PCR), target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.ResultsAmong the tested cases, 2 (0.44%) CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4–ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1). One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.ConclusionsThe incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.背景：间变性淋巴瘤激酶（Anaplastic lymphoma kinase, ALK）重排定义了一类适合激酶靶向抑制治疗的肺癌亚型。本研究旨在探究中国大型消化道癌症患者队列中ALK融合基因的检出率。 患者与方法：从808例消化道癌症病例中构建组织微阵列（Tissue microarray, TMA）样本，其中包括169例食管鳞状细胞癌、182例胃癌以及457例结直肠癌（colorectal cancer, CRC）病例。我们采用全自动免疫组织化学（immunohistochemistry, IHC）检测方法，对所有病例的ALK表达情况进行检测。对免疫组化检测呈阳性的病例，进一步通过荧光原位杂交（fluorescence in situ hybridization, FISH）、实时聚合酶链反应（real-time polymerase chain reaction, qRT-PCR）、目标基因富集测序技术，以确认ALK基因重排并探索新型融合伴侣基因。 结果：在所有受检病例中，共有2例（0.44%）结直肠癌病例经免疫组化与荧光原位杂交检测均呈阳性。经实时聚合酶链反应检测，其中1例免疫组化阳性的结直肠癌病例检出EML4-ALK融合基因。另1例免疫组化阳性的结直肠癌病例经目标基因富集测序发现，ALK与新型伴侣基因血影蛋白β非红细胞1（spectrin beta non-erythrocytic 1, SPTBN1）发生融合。另有1例胃癌病例免疫组化检测呈部分阳性，但经荧光原位杂交与基因测序未检出ALK融合。 结论：中国结直肠癌患者中ALK基因融合的检出率为0.44%，而胃癌与食管鳞状细胞癌患者中未检出ALK融合基因。本次发现的新型SPTBN1-ALK融合基因与其他ALK融合基因，有望成为抗ALK靶向治疗的潜在靶点。