Centonza Antonella, Mazza Tommaso, Trombetta Domenico, Sparaneo Angelo, Petrizzelli Francesco, Castellana Stefano, Centra Flavia, Fabrizio Federico Pio, Di Micco Concetta Martina, Benso Federica, Tabbò Fabrizio, Righi Luisella, Merlini Alessandra, Graziano Paolo, Muscarella Lucia Anna
Unit of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy.
Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy.
J Pers Med. 2024 Jun 21;14(7):670. doi: 10.3390/jpm14070670.
Anaplastic lymphoma kinase (ALK) fusions account for 5-7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments.
间变性淋巴瘤激酶（ALK）融合在非小细胞肺癌（NSCLC）患者中占5%-7%，在过去几年中，针对此类患者的治疗方法有了显著进展。然而，对靶向治疗的反应仍然存在异质性，部分原因是迄今为止报道了许多不同的ALK融合变体。也发现了罕见的融合变体，但它们在影响对ALK抑制剂（ALKis）反应中的作用仍未得到充分阐明。对一名低分化腺癌患者的肺活检样本进行了组织和蛋白质水平的实验室研究以及下一代测序（NGS）的分子分析。使用ColabFold软件v1.5.5的计算机预测模型对嵌合异常ALK蛋白的整个结构进行建模和预测。在此，我们报告一例病例，一名60岁的既往吸烟者，被诊断为NSCLC并发生ALK易位。他接受了第一代、第二代和第三代ALK蛋白抑制剂（ALKis）治疗，显示出约4年的临床获益。免疫组化分析和组织活检的分子检查表明ALK呈阳性染色，且存在一种新的基因融合变体，涉及具有钙调蛋白同源性和卷曲螺旋结构域1样（SPECC1L）基因的精子抗原，外显子7有一个未报道的断点。使用锚定多重PCR（AMP）-NGS技术鉴定了新的SPECCL1::ALK融合，并预测在所得嵌合蛋白的羧基末端区域保留Pkinase_Tyr结构域。据我们所知，这是首例携带SPECC1L外显子7融合断点的ALK阳性NSCLC患者，也是少数关于与SPECC1L::ALK融合相关临床结果的报告之一。这种新鉴定的融合变体在计算机上假设的生物学作用证实了观察到的对多种ALKis的临床反应。分子研究结果还强化了基于AMP的NGS技术作为一种有价值工具的实用性，可用于识别可能与患者对不同ALKis治疗结果变异性相关的罕见染色体事件。
