Genomic landscaping of receptor tyrosine kinase ALK with highly frequent rearrangements in cancers

Anaplastic lymphoma kinase (ALK) fusion tyrosine kinases (TKs) are commonly found in various cancers and are considered as promising targets for therapy due to their intricate biological processes. However, the reasons for the higher frequency of ALKs fusion compared to other TKs are not well elucidated. Physicochemical properties, secondary and tertiary structures, and phylogenetic trees, along with protein sequence alignments of receptor tyrosine kinases (RTKs) and ALK fused partner genes, were examined using the resources provided by the National Center for Biotechnology Information (NCBI) and the Catalogue of Somatic Mutations in Cancer (COSMIC). Sequence alignments were performed to identify common sequences between partner genes and search for common breakpoints within the COSMIC database. ALK is a large, unstable, acidic protein with similarly conservation among RTKs. ALK fusion partners are mostly acidic, unstable proteins, mostly consisting of α-helices and random coil. However, EML4 and NPM1 are the most frequently occurring partner genes and have their own unique structural characteristics. By functional domain analysis, we found that the functions of the first half of the ALK partner gene (the part fused to ALK) are mostly focused on signaling. ALK is identified as a large hydrophilic protein，exhibits a higher proportion of random coils. Compared to other RTKs, ALK has fewer structural domains (PTKC_ALK_LTK domain). Pairwise comparison with fusion partner genes revealed a conserved sequence predicted to have structural stability and act as a common binding site for nucleases. Exon 20 of ALK is a fusion frequent site according to COSMIC database analysis. The structural instability of ALK and partner genes, coupled with the inherent variability of breakpoint sequences, leads to the formation of potent kinase-activated oncogenes, which play a critical role in tumorigenesis. While the occurrence of ALK fusions with partner genes is random, specific combinations lead to the generation of oncogenes.