Molecular characterization of genomic breakpoints of <i>ALK</i> rearrangements in non‐small cell lung cancer

Wang, Zizong; Han, Yushuai; Tao, Hou‐Quan; Xu, Maochao; Liu, Zhengchuang; Zhu, Jianhua; Li, Wei; Ma, Jie; Liu, Zhifang; Wang, Weiran; Ma, Tonghui

doi:10.1002/1878-0261.13348

Cited by 4 publications

(4 citation statements)

References 56 publications

(60 reference statements)

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“…These conflicting results highlight the importance of validation assays such as RNA NGS for cases harbouring genomic intergenic‐breakpoint ROS1 rearrangements, to ensure the generation of an active chimeric protein. Moreover, unlike most of ALK and RET rare rearrangements which transformed into canonical fusions [ 22 , 23 ]. The two rare fusions in this study, CCDC6‐ROS1 and MYO5C ‐ ROS1 , were entirely consistent at the DNA and RNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Zhou

Zhang

et al. 2023

Molecular Oncology

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ROS proto‐oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are a crucial therapeutic target in non‐small cell lung cancer (NSCLC). However, there is limited comprehensive analysis of the molecular patterns of ROS1 fusions. This study aimed to address this gap by analyzing 135 ROS1 fusions from 134 Chinese NSCLC patients using next‐generation sequencing (NGS). The fusions were categorized into common and uncommon based on their incidence. Our study revealed, for the first time, a unique distribution preference of breakpoints within ROS1, with common fusions occurring in introns 31–33 and uncommon fusions occurring in introns 34 and 35. Additionally, we identified previously unknown breakpoints within intron 28 of ROS1. Furthermore, we identified a close association between the distribution patterns of fusion partners and breakpoints on ROS1, providing important insights into the molecular landscape of ROS1 fusions. We also confirmed the presence of inconsistent breakpoints in ROS1 fusions between DNA‐based next‐generation sequencing (DNA NGS) and RNA‐based NGS (RNA NGS) through rigorous validation methods. These inconsistencies were attributed to alternative splicing resulting in out‐of‐frame or exonic ROS1 fusions. These findings significantly contribute to our understanding of the molecular characteristics of ROS1 fusions, which have implications for panel design and the treatment of NSCLC patients with ROS1 rearrangements.

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Section: Discussionmentioning

confidence: 99%

“…Here, ALK, ROS1, and RET fusion-positive cancer patients from the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, CELL 2022) were used as the compared cohort [21]. The information of ALK and RET fusions in our cohort could be found in previous publications [22,23].…”

Section: Patients and Samplesmentioning

confidence: 99%

Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Zhou

Zhang

et al. 2023

Molecular Oncology

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“…The EML4-ALK fusion consists of the basal domain encoded by the EML4 gene and the kinase region encoded by the ALK gene [39]. To date, numerous distinct ALK fusion partners, including EML4, Kinesin family member 5B (KIF5B), Kinesin Light Chain 1 (KLC1), and Translocated promoter region, nuclear basket protein (TPR), have been identified [40]. Among ALK-rearranged NSCLC, both the fusion partner and the EML4-ALK fusion variants have been considered candidate modifiers of transforming potential and response biomarkers to ALK-TKIs [41].…”

Section: Alk-tkismentioning

confidence: 99%

“…Interestingly, it has been suggested that individual genomic breakpoints of EML4 and ALK may have a different impact on the response to ALK-TKIs [40,52]. Nevertheless, a negative impact of TP53 mutations on PFS and OS, regardless of the EML4-ALK variant type (1 or 3a/b), was shown [45,44].…”

Section: Alk-tkismentioning

confidence: 99%

Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update

Moes-Sosnowska,

Szpechcinski,

Chorostowska-Wynimko

2024

TUB

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The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS proto-oncogene 1 (ROS1), has improved patients’ prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53) gene is one of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC.

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Clinical relevance and druggability of sole reciprocal kinase fusions: A large‐scale study

Feng,

Ma,

Wang

et al. 2024

Cancer Medicine

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BackgroundBuilding on our prior work that RNA alternative splicing modulates the druggability of kinase fusions, this study probes the clinical significance of sole reciprocal fusions. These rare genomic arrangements, despite lacking kinase domains at the DNA level, demonstrated potential RNA‐level druggability in sporadic cases from our prior research.MethodsUtilizing the large‐scale multicenter approach, we performed RNA sequencing and clinical follow‐up to evaluate a broad spectrum of kinase fusions, including ALK, ROS1, RET, BRAF, NTRK, MET, NRG1, and EGFR, in 1943 patients.ResultsOur findings revealed 51 instances (2.57%) of sole reciprocal fusions, predominantly in lung (57%), colorectal (14%), and glioma (10%) cancers. Comparative analysis with an MSKCC cohort confirmed the prevalence in diverse cancer types and identified unique fusion partners and chromosomal locales. Cross‐validation through RNA‐NGS and FISH authenticated the existence of functional kinase domains in subsets including ALK, ROS1, RET, and BRAF, which correlated with positive clinical responses to targeted kinase inhibitors (KIs). Conversely, fusions involving EGFR, NRG1, and NTRK1/2/3 generated nonfunctional transcripts, suggesting the need for alternative therapeutic interventions.ConclusionThis inaugural multicenter study introduces a novel algorithm for detecting and treating sole reciprocal fusions in advanced cancers, expanding the patient population potentially amenable to KIs.

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Molecular characterization of genomic breakpoints of ALK rearrangements in non‐small cell lung cancer

Cited by 4 publications

References 56 publications

Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update

Clinical relevance and druggability of sole reciprocal kinase fusions: A large‐scale study

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