Genomic landscape and therapeutic implications of Anaplastic Lymphoma Kinase fusion-positive colorectal cancer

Abstract

Abstract Background Anaplastic lymphoma kinase (ALK) fusions are established oncogenic drivers and therapeutic targets in multiple malignancies, including non-small cell lung cancer, but are rare in colorectal cancer (CRC). Although ALK fusions in CRC have been associated with sensitivity to ALK inhibitors, their broader genomic context remains incompletely defined. We aimed to characterize the prevalence, clinicogenomic features, and therapeutic implications of ALK fusions in advanced CRC. Materials and Methods Comprehensive genomic profiling using hybrid capture-based next-generation sequencing was performed on 56 206 advanced CRC tumors to identify alterations, including ALK fusions. Microsatellite instability (MSI)/mismatch repair (MMR) status, tumor mutational burden (TMB), genomic ancestry, COSMIC trinucleotide signatures, and homologous recombination deficiency (HRD) signatures were derived from sequencing data. PD-L1 expression was assessed by immunohistochemistry. Results ALK fusions were identified in 63 tumors (0.1%). Compared with ALK fusion-negative CRC, ALK fusion-positive (ALKfus+) tumors demonstrated enrichment for MSI-high/MMR-deficient status and high TMB, with numerically higher PD-L1 expression. In contrast, canonical CRC driver alterations were markedly depleted, including KRAS, APC, and PIK3CA mutations. Conclusions ALK fusions define a rare but biologically distinct subset of CRC characterized by frequent MSI-high/MMR-deficient status and a unique genomic landscape. These findings support comprehensive genomic profiling to identify ALK fusions in CRC, which may inform the use of ALK-directed therapies, and highlight the frequent co-occurrence of MSI-high disease within this subgroup.