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. 2022 Apr;7(2):100405.
doi: 10.1016/j.esmoop.2022.100405. Epub 2022 Mar 16.

Characterizing kinase intergenic-breakpoint rearrangements in a large-scale lung cancer population and real-world clinical outcomes

Y Yao  1 , Z Yu  2 , Y Ma  3 , Q Ou  3 , X Wu  3 , D Lu  4 , X Li  5
Affiliations

Characterizing kinase intergenic-breakpoint rearrangements in a large-scale lung cancer population and real-world clinical outcomes

Y Yao et al. ESMO Open. 2022 Apr.

Abstract

Background: Kinase gene fusions are strong driver mutations in neoplasia; however, kinase intergenic-breakpoint rearrangements (IGRs) confound the detection of such fusions and of targeted treatments. We aim to provide an overview of kinase IGRs in a large lung cancer cohort and examine real-world survival outcomes of patients with such fusions.

Methods: Mutational profiles analyzed using targeted next-generation sequencing of 425 cancer-related genes between June 2016 and July 2019 were retrospectively reviewed. Patients' demographic data, clinical characteristics, and survivals were analyzed. RNA sequencing or immunohistochemical assays were carried out to verify chimeric fusion products.

Results: We identified 3411 patients with kinase fusions from a cohort of 30 450 patients with lung cancer, and 624 kinase IGR events were identified in 538 of the 3411 patients. The most frequently identified kinase genes included anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET), ROS proto-oncogene 1 (ROS1), Erb-B2 receptor tyrosine kinase 2/3 (ERBB2/3), and epidermal growth factor receptor (EGFR). Our data showed that most (67%) kinase IGRs occurred on the same chromosome and kinase domains remained intact at the 3'-end. Approximately 3% (19/624) of the kinase IGRs had one genomic breakpoint located in gene promoter regions, including nine fusion events involving ALK, RET, ROS1, EGFR, ERBB2, or fibroblast growth factor receptor 3 (FGFR3). Among the 538 patients with kinase IGRs, 167 (31%) lacked oncogenic driver mutations, among which 28 received targeted therapies in real-world practice. Notably, three ALK IGR patients who harbored no canonical oncogenic aberrations were confirmed with an EML4-ALK chimeric fusion product by RNA sequencing and/or ALK immunohistochemical assays. One patient demonstrated a favorable clinical outcome after 14 months on crizotinib. An additional two patients who had ROS1 IGRs demonstrated a clinical benefit after 13 and 19 months on crizotinib, respectively.

Conclusion: A large real-world lung cancer cohort with kinase IGRs was comprehensively analyzed for their molecular characteristics. The data indicated the potential oncogenic function of kinase IGRs and their outcomes following the administration of targeted therapies.

Keywords: intergenic breakpoints; kinase fusion; lung cancer; real-world survival; targeted next-generation sequencing.

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Conflict of interest statement

Disclosure YM, QO, and XW are employees of Nanjing Geneseeq Technology Inc., Jiangsu, China. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Patient enrollment and inclusion. This flow chart depicts the patients screened and the number of patients included in the analysis. IHC, immunohistochemistry; NGS, next-generation sequencing; PR, partial response; RNA-seq, RNA sequencing; SD, stable disease; TKI, tyrosine kinase inhibitor.
Figure 2
Figure 2
Statistical analysis of the incidence of kinase IGRs and breakpoint locations. (A) Pie chart shows the distribution of kinase genes in a total of 624 kinase IGR events. (B) Proportions of IGRs with intact and non-intact kinase domain are shown in the blue and orange bars on the y-axis. The two breakpoints of IGR located on the same chromosome are colored in green versus yellow for different chromosomes. The number of IGR events with the 10 actionable kinase genes are labeled below in parentheses. IGR, intergenic-breakpoint rearrangement.
Figure 3
Figure 3
Circos plots for the 10 actionable kinase gene IGRs. (A-J) The circos plot for each kinase gene IGR. From outside to inside: track 1 is the chromosome annotation. Track 2 with a light-yellow shade represents the intactness of the kinase domain of the IGR (intact: red bars in the outer layer; non-intact: blue bars in the inner layer). Track 3 shows the intra-chromosomal rearrangements colored in light blue. The green lines in track 4 are the inter-chromosomal IGRs. The IGRs with promoter involvement are colored in orange with the gene promoter labeled. (K) All of the promoter-involved IGRs are shown. The actionable kinase genes are highlighted (ALK: olive green, ERBB2: yellow, EGFR: red, RET: light blue, ROS1: teal, and FGFR3: burgundy) and the rest are colored in green. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ERBB2, Erb-B2 receptor tyrosine kinase 2; FGFR3, fibroblast growth factor receptor 3; RET, RET proto-oncogene; ROS1, ROS proto-oncogene 1.
Figure 4
Figure 4
Concurrent mutational and clinical information analysis of IGRs. (A) Proportion of samples from the entire cohort with only IGR (31%, 167/546), canonical oncogenic driver alterations listed in Figure 4B (61%, 335/546), or other oncogenic driver alterations (8%, 44/546). (B) The proportion of selected oncogenic driver alterations in the entire cohort. The detailed concurrent alterations of (C) treatment-naïve, (D) formally-treated, and (E) treatment information unavailable samples with actionable kinase intergenic fusions are shown by the oncoprint plots. For each category, samples were classified into four subgroups: IGR alone (golden), concurrent with MUT (canonical driver mutation) (green), SV (structure variant) (red), and both MUT and SV (purple). Different alterations are represented in different colors, as shown in the legend. Top annotations include the sample type, cancer subtype, tumor histology, disease stage, and treatment information (if available), as shown in the legend. IGR, intergenic-breakpoint rearrangement; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer.
Figure 5
Figure 5
The treatment history of four patients benefiting from targeted TKI therapy. The treatment history of patient 6 (A), patient 145 (B), patient 32 (D), and patient 11 (E) are shown. ALK-TKIs are indicated by the blue boxes. The arrows with boxes above the timeline indicate the timepoint of NGS with sequencing results (only fusions and oncogenic mutations are shown). (C) The ALK immunohistochemistry result from the primary tissue sample from patient 145 with ×20 magnification. ALK, anaplastic lymphoma kinase; FFPE, formalin-fixed paraffin-embedded; NGS, next-generation sequencing; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.
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