Abstract
Approximately 3–7% of non-small cell lung cancers harbor an anaplastic lymphoma kinase (ALK) gene fusion, constituting a new molecular subtype of lung cancer that responds to crizotinib, an ALK inhibitor. Although previous studies have evaluated ALK-rearranged lung cancers, the comprehensive analysis of lung cancer in Chinese has not well assessed. Herein, we identified 44 cases of ALK-rearranged samples by fluorescent in-situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction (RT-PCR) in a large number of surgically resected lung cancers. All 44 ALK-rearranged lung cancers were adenocarcinomas, with 2 cases having additional focal squamous components. The goal was to analyse the clinicopathological features of ALK-rearranged lung adenocarcinomas. Our data showed that a cribriform structure, prominent extracellular mucus and any type of mucous cell pattern may be either sensitive or specific to predict an ALK rearrangement. We used FISH as the standard detection method. We compared the ALK rearrangement accuracy of FISH, RT-PCR and IHC. RT-PCR could define both the ALK fusion partner and the fusion variant, but seemed unable to detect all translocations involving the ALK gene. It is noteworthy that IHC using the D5F3 antibody (Cell Signaling Technology) showed higher sensitivity and specificity than the ALK1 antibody (Dako). Therefore, we conclude that IHC remains a cost-effective and efficient technique for diagnosing ALK rearrangements and that D5F3 can be the optimal screening antibody in clinical practice.
Highlights
Lung cancer remains the leading cause of cancer-related death in the world
A fusion gene that joins the echinoderm microtubule-associated protein-like 4 (EML4) gene with the anaplastic lymphoma kinase (ALK) gene was found in a subset of non-small-cell lung carcinomas (NSCLCs) in 2007 [1]
We previously demonstrated that 90% of lung adenocarcinomas from never-smokers harbored mutually exclusive oncogenic mutations in just four genes (EGFR, KRAS, HER2 and ALK) [8]
Summary
Lung cancer remains the leading cause of cancer-related death in the world. The clinical importance of the molecular phenotype of lung cancer lies mainly in its therapeutic implications since different subtypes may respond to different target treatments. A fusion gene that joins the echinoderm microtubule-associated protein-like 4 (EML4) gene with the anaplastic lymphoma kinase (ALK) gene was found in a subset of non-small-cell lung carcinomas (NSCLCs) in 2007 [1]. This fusion occurred due to chromosomal inversion or translocation on chromosome 2p, resulting in formation of the EML4-ALK fusion gene. Despite the relatively low frequency of the EML4-ALK fusion, ALK-rearranged lung cancer is a unique molecular subgroup with a high sensitivity to ALK inhibitors, and is mutually exclusive from other well-known oncogenic mutations involving EGFR or KRAS [2,3,4,5]. To better understand ALK-rearranged lung cancers, it is important to characterize their clinicopathologic features. We compared clinicopathological features of the ALK-positive group with common driver mutation, and with pannegative group, seeking to assess whether there were distinctive clinicopathological features associated with ALK rearrangement cohort
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