Novel LTK fusions based on NGS sequencing data in Chinese patients with solid tumors.

3144 Background: Leukocyte receptor tyrosine kinase ( LTK) gene has the same kinase domain (PTKc_ALK_LTK) as ALK, and could functionally response to ALK inhibitors such as lorlatinib. Previous study reported that CLIP1-LTK fusion was a novel oncogenic driver mutation in lung cancer (occur in 0.4% of non-small cell lung cancer), which was sensitive to the ALK tyrosine kinase inhibitor lorlatinib. So far, LTK fusion has been rarely reported. Methods: A total of 11 Chinese solid tumor patients were reviewed, including 6 cases of LTK positive rearrangements in DNA and 5 cases of LTK positive fusion in RNA. FFPE samples were collected for NGS-based 450 cancer gene panel detection in both DNA and RNA level, and matched blood samples were used as normal control to filter out germline mutations. LTK fusions were analyzed by OrigiFus algorithm. Results: We found 6 patients with LTK rearrangements by DNA-based NGS detection, including lung adenocarcinoma, colorectal cancer, stomach cancer, spindle cell sarcoma of small intestine, adenocarcinoma of the pancreas, and cancer of unknown primary, and 5 soft tissue sarcoma patients with RPAP1 E25- LTK E2 fusions by RNA-based NGS detection. We analyzed the patterns of partner genes and breakpoints of the 6 LTK rearrangements. The partner genes included NUSAP1 (n=2), NDUFAF1 (n=1), LOC105370802 (n=1), EHD4 (n=1), and AGBL1 (n=1). All these partner genes were located on the same chromosome as LTK, rather than CLIP1, which was identified as a translocation. The breakpoints on LTK included exon20 (n=2), intron1 (n=2), exon6 (n=1), and exon10 (n=1). Five of the 6 fusions consisted of a complete PTKc_ALK_LTK domain. Among the 6 LTK rearrangements, LTK E20- NUSAP1 E2 was predicted as a fusion. Interestingly, this clinical real-world sample also harbored a classic NTRK1 fusion, LMNA E2- NTRK1 E11. The other NUSAP1- LTK was predicted to have a transcript of 3’-3’, but one of the breakpoints was observed at LTK exon6, which could be located at the kinase domain, so the possibility of eventual fusion cannot be excluded. The two NUSAP1-LTK fusions were found in a stomach tumor and a soft tissue sarcoma, respectively. One non-small-cell lung cancer (NSCLC) patient had a breakpoint detected on LTK exon10, which is the same as the exon of CLIP1- LTK reported. Conclusions: This study revealed novel LTK fusions/rearrangements and their cancer distribution in Chinese patients with solid tumors. We gave the details of these fusions/rearrangements which enrich our understanding of the LTK fusion. Although the small number of cases, our analysis promoted the attention on LTK and its potential value of drug research and clinical treatment in pan-cancer.