The Landscape Of Kinase Domain Duplication In Chinese Lung Cancer Patients

Background: Kinase domain duplication (KDD) is a special type of large genomic rearrangement (LGR), occurring in the kinase domain of protein kinase genes. KDD of some lung cancer driver genes, such as EGFR-KDD, has been identified and implicated to be oncogenic in non-small cell lung cancer (NSCLC). The present study aims to interrogate the spectrum of KDD occurring on classic driver genes in Chinese lung cancer patients without the presence of classic lung cancer driver mutations.Methods: We retrospectively enrolled 10,525 Chinese lung cancer patients who met the following inclusion criteria; (I) do not carry classic lung cancer driver mutations in any of the 8 driver genes and (II) tyrosine kinase inhibitor (TKI)-naive. Capture-based targeted sequencing was performed on tissue or plasma samples. LGR and KDD were identified by using in-house analysis scripts. The prevalence and distribution of LGR and KDD in our cohort were analyzed.Results: The median age of the cohort was 64 years with 68.7% being male. Among all patients, 23.2% and 51.8% were diagnosed with stage III and IV disease respectively. We identified 43 cases (0.41%) harboring LGR in one of the driver genes (EGFR/ERBB2/ALK/RET/ROS1/MET/BRAF), with 24 (0.23%) patients harboring KDD. Of the patients harboring KDD, a majority (n=19) harbored canonical EGFR-KDD involving exons 18-25, whilst one patient harbored duplications of EGFR exons 18-26. There were three MET-KDD patients; in two, the alteration occurred in exons 15-21 and in one, the alteration occurred in exons 3-21. One patient harbored RET-KDD involving exons 12-18. KDD showed a comparable prevalence in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (0.33% vs. 0.11%, P=0.118). Nineteen non-KDD LGRs, spanning six genes including EGFR (n=6), MET (n=3), ALK (n=4), ROS1 (n=2), ERBB2 (n=2) and BRAF (n=2), were found, each occurring in one patient. The prevalence of LGR in LUADs and LUSCs was comparable (0.55% vs. 0.38%, P=0.452).Conclusions: We observed a prevalence of 0.41% and 0.23% for LGR and KDD, respectively. Twenty-four different LGR alterations, including 5 KDDs and 19 non-KDD LGRs, were observed. KDDs mainly occurred in EGFR involving exons 18-25 and non-KDD LGRs were distributed more randomly. The prevalence of LGR/KDD in LUSCs and LUADs was comparable.