Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241, West Huai Hai Road, Xv Hui District, Shanghai, 200030, China.
Mol Diagn Ther. 2019 Jun;23(3):395-405. doi: 10.1007/s40291-019-00389-y.
The clinicopathological features and genomic rearrangements of anaplastic lymphoma kinase (ALK) fusion cases have not been fully identified.
Our objective was to explore the status of ALK in non-small-cell lung cancer (NSCLC) specimens, to explore the relationships between ALK status and clinicopathological features and to identify genomic rearrangements via capture-based next-generation sequencing (NGS).
We tested 9889 NSCLC specimens for ALK status using the Ventana anti-ALK (D5F3) antibody. Clinicopathological features were analyzed and genomic rearrangements identified using capture-based NGS in 76 ALK-positive cases.
In total, 485 specimens (4.90%) tested positive for ALK. The positivity rate was higher for adenocarcinoma samples than for non-adenocarcinoma samples (6.03 vs. 1.47%; p < 0.001) and for biopsies/cell blocks than for surgical specimens (7.00 vs. 4.16%; p < 0.001). Patient age, patient sex, specimen type, specimen histotype, and patient smoking history were all significantly correlated with ALK status. Genomic rearrangements were detected in 98.68% (75/76) of the ALK-positive samples; 89.33% (67/75) carried the canonical EML4-ALK, and the remaining samples carried only noncanonical ALK rearrangements. Four of these noncanonical ALK fusion samples were identified as carrying EML4-ALK transcripts at the RNA level. A novel fusion variant, SRD5A2-ALK, was revealed.
Younger patients with NSCLC, especially those aged < 30 years, were more likely to test positive for ALK. Positive ALK test results were more common in patients with invasive mucinous adenocarcinoma and solid-predominant invasive adenocarcinoma than in patients with other histotypes. Samples that carried only noncanonical ALK rearrangements may also have carried the canonical EML4-ALK, which was not detected by capture-based NGS. EML4-ALK transcripts might result from rare splicing mechanisms without genomic rearrangements.
间变性淋巴瘤激酶（ALK）融合病例的临床病理特征和基因组重排尚未完全确定。
本研究旨在探讨非小细胞肺癌（NSCLC）标本中 ALK 的状态，探讨 ALK 状态与临床病理特征的关系，并通过基于捕获的下一代测序（NGS）鉴定基因组重排。
我们使用 Ventana 抗-ALK（D5F3）抗体检测了 9889 例 NSCLC 标本的 ALK 状态。对 76 例 ALK 阳性病例进行基于捕获的 NGS 分析，以确定临床病理特征和基因组重排。
共有 485 例（4.90%）标本检测出 ALK 阳性。腺癌标本的阳性率高于非腺癌标本（6.03%比 1.47%；p<0.001），活检/细胞块的阳性率高于手术标本（7.00%比 4.16%；p<0.001）。患者年龄、患者性别、标本类型、标本组织学类型和患者吸烟史均与 ALK 状态显著相关。在 98.68%（75/76）的 ALK 阳性样本中检测到基因组重排；89.33%（67/75）携带经典的 EML4-ALK，其余样本仅携带非经典的 ALK 重排。这些非经典的 ALK 融合样本中有 4 个在 RNA 水平上被鉴定为携带 EML4-ALK 转录本。揭示了一种新的融合变体 SRD5A2-ALK。
年轻的 NSCLC 患者，尤其是年龄<30 岁的患者，更有可能检测到 ALK 阳性。ALK 阳性检测结果在侵袭性黏液性腺癌和以实体为主的侵袭性腺癌患者中比在其他组织学类型的患者中更为常见。仅携带非经典 ALK 重排的样本也可能携带经典的 EML4-ALK，但未被基于捕获的 NGS 检测到。EML4-ALK 转录本可能是由于罕见的剪接机制而没有基因组重排导致的。
