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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
The landscape of kinase domain duplication in Chinese lung cancer patients
Di Wu1, Yuancai Xie2, Chang'e Jin1
1Department of Respiratory Medicine, Shenzhen People's Hospital, Shenzhen, China.
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)-naïve. 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.
Insights
Large genomic rearrangements (LGRs) and kinase domain duplications (KDDs) occur in Chinese lung cancer patients. KDDs were found in 0.23% of patients, primarily involving EGFR, and were comparable across lung cancer subtypes.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Kinase domain duplication (KDD) is a genomic rearrangement affecting protein kinase genes.
- KDD in lung cancer driver genes is oncogenic in non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To investigate the spectrum of KDD in classic driver genes among Chinese lung cancer patients.
- To analyze KDD prevalence in patients lacking common driver mutations and tyrosine kinase inhibitor (TKI)-naïve status.
Main Methods:
- Retrospective enrollment of 10,525 Chinese lung cancer patients.
- Exclusion of patients with classic driver mutations and TKI-naïve status.
- Capture-based targeted sequencing and in-house analysis scripts for LGR and KDD identification.
Main Results:
- Prevalence of 0.41% for LGR and 0.23% for KDD identified in the cohort.
- Canonical EGFR-KDD (exons 18-25) was most common (19/24 KDD cases).
- KDD and LGR prevalence were comparable between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
Conclusions:
- LGR and KDD occur at low frequencies (0.41% and 0.23%) in this TKI-naïve Chinese lung cancer cohort.
- EGFR-KDD is the predominant KDD type, while non-KDD LGRs show broader gene distribution.
- The study highlights the importance of investigating LGRs and KDDs in lung cancer, irrespective of common driver mutations.
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