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

Yao, Yu; Yu, Zhiqing; Ma, Yafeng; Ou, Qiuxiang; Wu, Xue; Lü, Duo; Li, X.

doi:10.1016/j.esmoop.2022.100405

Cited by 3 publications

(4 citation statements)

References 42 publications

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“…In our study, there were only 3 patients harboring multiple ALK fusions with concurrent 5'- ALK fusions, and most of them harbored two or three coexisting 3'- ALK fusions, which might account for the different prognoses compared to patients harboring nonreciprocal/reciprocal ALK fusions. Furthermore, there were 6 patients harboring multiple ALK fusions coexisting with intergenic ALK fusions, which might also predict good response to ALK-TKIs therapy, because previous study found that intergenic-breakpoint rearrangement of ALK had favorable clinical outcomes and there may be a complicated splicing mechanism which could transcribe intergenic-breakpoint rearrangements into functional chimeric RNAs ( 33 ). However, the mechanism of the better response in patients with multiple ALK fusions is still unknown, and tumors with multiple ALK fusions are likely to be more reliant on the ALK signaling pathway, thus ALK-TKIs would be more effective in this condition ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors

Wei,

Zhang,

Wang

et al. 2023

Transl Lung Cancer Res

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Background Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase ( ALK ) fusions may benefit from ALK-tyrosine kinase inhibitors (ALK-TKIs). However, few studies have analyzed the clinical outcome in patients harboring multiple ALK fusions, including double or triple ALK fusions. Here, our study aimed to analyze the impact of harboring multiple ALK fusions on the efficacy of receiving ALK-TKIs in NSCLC patients. Methods A total of 125 patients with ALK -rearranged NSCLC detected by targeted capture DNA-based next-generation sequencing (NGS) at West China Hospital were enrolled. The literature on patients harboring multiple ALK fusions was systematically reviewed. The clinical response to ALK-TKIs was evaluated according to ALK fusion patterns in 62 patients: 56 from our center and 6 from the literature. Results Among the 125 patients, a single canonical echinoderm microtubule-associated protein-like 4 ( EML4 )- ALK fusion was detected in 65.6% (82/125), a single non- EML4-ALK fusion was detected in 13.6% (17/125), and multiple ALK fusions were detected in 20.8% (26/125). Among the 62 patients with ALK fusion treated with ALK-TKIs, the median progression-free survival (PFS) was significantly longer in patients with multiple ALK fusions than in those with a single ALK fusion (26.9 vs. 11.2 months, P=0.009), irrespective of brain metastasis, type of TKI drug, and treatment lines. The multiple ALK fusion group also tended to have a longer overall survival (OS) (P=0.26). Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK -positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI): 0.229–1.049]. Conclusions Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.

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Section: Discussionmentioning

confidence: 99%

Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors

Wei,

Zhang,

Wang

et al. 2023

Transl Lung Cancer Res

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“…On the other hand, RNA-based approach would depend on the quality of the sample but has a unique advantage in detecting functional fusion events as compared to DNA-based methods. For example, it has been shown that a considerable portion of rare or IGR fusion events as detected by DNA-based sequencing approach are common fusion genes at the RNA level 24,25 . In our study, we confirmed our DNA-based finding in a case with a rare HLA-DRB1-MET fusion who had responded to crizotinib by using targeted RNA sequencing.…”

Section: Discussionmentioning

confidence: 99%

Landscape of potentially targetable receptor tyrosine kinase fusions in diverse cancers by DNA-based profiling

Wang

Lü

et al. 2022

npj Precis. Onc.

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Recurrent fusions of receptor tyrosine kinases (RTKs) are often driving events in tumorigenesis that carry important diagnostic value and are potentially targetable by the increasing number of tyrosine kinase inhibitors (TKIs). Here, we characterized the spectrum of 1324 RTK fusions with intact kinase domains in solid tumors by DNA-based high-throughput sequencing. Overall, the prevalence of RTK fusions were 4.7%, with variable frequencies and diverse genomic structures and fusion partners across cancer types. Cancer types, such as thyroid cancers, urological cancers and neuroendocrine tumors are selective in the RTK fusions they carry, while others exhibit highly complex spectra of fusion events. Notably, most RTKs were promiscuous in terms of the partner genes they recombine with. A large proportion of RTK fusions had one of the breakpoints localized to intergenic regions. Comprehensive genomic profiling revealed differences in co-mutational patterns pre- and post-TKI treatments across various RTK fusions. At baseline, multiple cases were detected with co-occurring RTK fusions or concomitant oncogenic mutations in driver genes, such as KRAS and EGFR. Following TKI resistance, we observed differences in potential on- and off-target resistance mutations among fusion variants. For example, the EML4-ALK v3 variant displayed more complex on-target resistance mechanisms, which might explain the reduced survival outcome compared with the v1 variant. Finally, we identified two lung cancer patients with MET+ and NTRK1+ tumors, respectively, who responded well to crizotinib treatment. Taken together, our findings demonstrate the diagnostic and prognostic values of screening for RTK fusions using DNA-based sequencing in solid tumors.

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“…However, previous studies have demonstrated a good performance of the same targeted panel as used in this study for detecting structural variance. Yao, Y et al reported the ALK intergenic‐breakpoint rearrangement (IGR) detection in a large retrospective lung cancer cohort, and the authors have successfully validated the expression of all ALK rare IGRs using either RNA‐seq or IHC staining 20 . Another study identified 27 known and novel ALK fusions which were all validated by either FISH or IHC staining 21 .…”

Section: Characteristics Cohort N = 17mentioning

confidence: 99%

“…Yao, Y et al reported the ALK intergenic‐breakpoint rearrangement (IGR) detection in a large retrospective lung cancer cohort, and the authors have successfully validated the expression of all ALK rare IGRs using either RNA‐seq or IHC staining. 20 Another study identified 27 known and novel ALK fusions which were all validated by either FISH or IHC staining. 21 Nonetheless, further studies to validate the expression and functions of these novel EGFR ‐LFDs are warranted.…”

mentioning

confidence: 99%

Pan‐cancer molecular analysis of EGFR large fragment deletion in the Asian population

Guo

Yu³

et al. 2023

Cancer Medicine

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Background: Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR-LFD have not been studied in the Asian cancer population.Method: Here we retrospectively analyzed the targeted sequencing data from a large cancer database.Results: EGFR-LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR-LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal-level and arm-level CNV in this cohort. EGFR exon2-17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. Conclusion:Our study provided valuable insights into the distribution and molecular characteristics of EGFR-LFD, hoping to shed light on the treatment management for EGFR-LFD carriers.

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

Cited by 3 publications

References 42 publications

Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors

Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors

Landscape of potentially targetable receptor tyrosine kinase fusions in diverse cancers by DNA-based profiling

Pan‐cancer molecular analysis of EGFR large fragment deletion in the Asian population

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