Abstract
Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22-21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
Highlights
The multi-targeted anaplastic lymphoma kinase (ALK) inhibitor crizotinib has demonstrated significant improvement in progression-free survival (PFS) over chemotherapy as both first-line or second-line treatment of ALK-rearranged non-small cell lung cancer (NSCLC) [1, 2] and has firmly established that ALK rearrangement is a targetable driver mutation in NSCLC
One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK fluorescence in situ hybridization (FISH) and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by comprehensive genomic profiling (CGP)
One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK
Summary
The multi-targeted anaplastic lymphoma kinase (ALK) inhibitor crizotinib has demonstrated significant improvement in progression-free survival (PFS) over chemotherapy as both first-line or second-line treatment of ALK-rearranged non-small cell lung cancer (NSCLC) [1, 2] and has firmly established that ALK rearrangement is a targetable driver mutation in NSCLC. ALK breakapart fluorescence in situ (FISH) was until recently the only companion diagnostic assay approved by the US Food and Drug Administration (FDA) for the detection of ALK rearrangement [3]. ALK immunohistochemistry (IHC) has been shown to be sensitive and specific and cost effective to screen for ALK rearrangement in NSCLC [7]. Given that both ALK and ROS1 rearrangements have been identified in CRC [5] and we have previously identified ROS1 rearrangement in GC [8], we performed a screening study for ALK rearrangement in GC and CRC using ALK IHC
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