Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020

Ou, Sai‐Hong Ignatius; Zhu, Viola W.

doi:10.1016/j.jtocrr.2020.100037

Cited by 32 publications

(45 citation statements)

References 39 publications

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“…Several studies have focused on exploring the efficacy of TKIs among ALK, ROS1, and RET fusions with different partners and breakpoints. 10,35,36 We have previously found that patients with CD74-ROS1 fusion identified by DNA NGS who received first-line crizotinib have a longer PFS than patients with non-CD74-ROS1 fusion, 13 whereas Li et al 37 have observed diametrically opposite results. Moreover, at least 21 EML4-ALK variants have been described on the basis of breakpoint location, and these variants may be associated with clinical responses to TKIs.…”

Section: Discussionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

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Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.Methods: NSCLCs were analyzed by DNA NGS, targetspecific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.Results: In total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non-EML4-ALK, non-CD74/EZR/TPM3/SDC4-ROS1, and non-KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n ¼ 31) who received first-line crizotinib exhibited shorter median progressionfree survival than those with canonical ALK fusion (n ¼ 53, 8.4 mo versus 12.0 mo, p ¼ 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p ¼ 0.185).Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.

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Section: Discussionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

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“…At the moment, ROS1 fusions have identified with 55 different partners genes in different cancer types, including more than 20 fusion partners in NSCLC. The CD74-ROS1, EZR-ROS1, SDC4-ROS1 and SLC34A2-ROS1 fusion represent the most common rearrangements[ 58 ]. All resultant fusion proteins retain an intact ROS1 intracellular kinase domain which, as a result of the rearrangement, becomes constitutively activated.…”

Section: Ros1mentioning

confidence: 99%

Oncogenic driver mutations in non-small cell lung cancer: Past, present and future

Chevallier

Borgeaud

Addeo

et al. 2021

WJCO

157

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Lung cancer, of which non-small lung cancer is the most common subtype, represents the leading cause of cancer related-death worldwide. It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis. In recent years, more of these so-called oncogenic drivers have been identified, and a better understanding of their biology has allowed the development new targeted agents. This review aims to provide an update about the current landscape of driver mutation in non-small-cell lung cancer. Alterations in Kirsten rat sarcoma, epidermal growth factor receptor, MET, anaplastic lymphoma kinase, c-ROS oncogene 1, v-raf murine sarcoma viral oncogene homolog B, neurotrophic receptor tyrosine kinase, human epidermal growth factor 2, neuregulin-1 and rearranged during transfection are discussed, as well as agents targeting these alterations. Current standards of treatment as well as promising future strategies are presented. Currently, more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer, highlighting the importance of actively searching for these mutations. Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms, and to define the best treatment strategy and therapeutic sequence.

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“…The identification of multiple fusion partners [4] and the variants is not just important for ALK+ NSCLC but also for other receptor tyrosine kinase fusion positive NSCLC or solid tumors. For instance, among patients with ROS1+ or RET+ NSCLC [61,62], CD74-ROS1 may predispose patients with higher risk of CNS metastasis and a shorter PFS when treated with crizotinib [63] and KIF5B-RET+ NSCLC may be more resistant to multi-target RET kinase inhibitors [64,65]. This will require constant reminders that not just the knowledge of EML4-ALK variants but 5' fusion partners in ALK+ NSCLC [66] which is beyond the scope of this review is important in determining biological properties including but not limited to subcellular localization potentially activating different signaling pathways, transcriptional activation level from the promoter region of different 5' fusion genes partner, and protein stability leading to differential response to ALK TKI therapy.…”

Section: Conclusion Remarksmentioning

confidence: 99%

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020

Cited by 32 publications

References 39 publications

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Oncogenic driver mutations in non-small cell lung cancer: Past, present and future

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

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