A transforming <i>KIF5B</i> and <i>RET</i> gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing

Ju, Young Seok; Lee, Won Chul; Shin, Jong Yeon; Lee, Seungbok; Bleazard, Thomas; Won, Jae Kyung; Kim, Young Tae; Kim, Jong‐Il; Kang, Jin Hyoung; Seo, Jeong Sun

doi:10.1101/gr.133645.111

Cited by 437 publications

(359 citation statements)

References 42 publications

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“…To date, several cancer genome sequencing studies have discovered RET fusions in B1-2% of lung cancer. [10][11][12][13] RET fusions were the potential therapeutic targets of multitargeted kinase inhibitors, vandetanib, sunitinib, and sorafenib. [11][12][13] Importantly, RET rearrangement is mutually exclusive with aberrations in EGFR, KRAS, ALK, HER2, and BRAF in lung cancer.…”

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confidence: 99%

Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

et al. 2015

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The success of crizotinib in ALK-positive patients has elicited efforts to find new oncogenic fusions in lung cancer. These efforts have led to the discovery of novel oncogenic fusion genes such as ROS1 and RET. However, the molecular and clinicopathologic characteristics associated with RET or ROS1 fusion, compared with ALK fusion-positive lung cancer, remain unclear. We accordingly analyzed the clinicopathologic characteristics of RET-and ROS1-fusion-positive lung adenocarcinomas. We further performed immunohistochemistry and fluorescence in situ hybridization analysis (FISH) in 15 cases of RET and 9 cases of ROS1 fusion tumors by identified NanoString's nCounter screening. RET fusion-positive patients were younger in age, never-smokers, and in early T stage; ROS1 fusion-positive patients had a higher number of never-smokers compared with patients with quintuple-negative (EGFR À /KRAS À /ALK À /ROS1 À /RET À ) lung adenocarcinoma. Histologically, RET and ROS1 fusion tumors share the solid signet-ring cell and mucinous cribriform pattern, as previously mentioned in the histology of ALK fusion tumors. Therefore, it can be presumed that fusion gene-associated lung adenocarcinomas share similar histologic features. In immunohistochemistry, the majority of 15 RET and 9 ROS1 fusion-positive cases showed positivity of more than moderate intensity and cytoplasmic staining for RET and ROS1 proteins, respectively. In FISH, the majority of RET and ROS1 rearrangement showed two signal patterns such as one fusion signal and two separated green and orange signals (1F1G1O) and an isolated 3 0 green signal pattern (1F1G). Our study has provided not only characteristics of fusion gene-associated histologic features but also a proposal for a future screening strategy that will enable clinicians to select cases needed to be checked for ROS1 and RET rearrangements based on clinicohistologic features.

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confidence: 99%

Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

et al. 2015

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“…Germline and somatic gain-of-function RET mutations are known to predispose to multiple endocrine neoplasia type 2 and sporadic medullary thyroid cancer, respectively, whereas somatic RET gene fusions account for the majority of radiation-induced and sporadic papillary thyroid cancers. In 2011, investigators from Seoul identified a fusion gene involving RET partnered with KIF5B in a young never smoker with lung adenocarcinoma (42). RET rearrangements have since been identified in approximately 1 to 2% of patients with adenocarcinoma or adenosquamous carcinoma of the lung.…”

Section: Ret Fusionsmentioning

confidence: 99%

The Impact of Genomic Changes on Treatment of Lung Cancer

Cardarella

Johnson

2013

Am J Respir Crit Care Med

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The remarkable success of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in patients with EGFR mutations and ALK rearrangements, respectively, introduced the era of targeted therapy in advanced non-small cell lung cancer (NSCLC), shifting treatment from platinum-based combination chemotherapy to molecularly tailored therapy. Recent genomic studies in lung adenocarcinoma identified other potential therapeutic targets, including ROS1 rearrangements, RET fusions, MET amplification, and activating mutations in BRAF, HER2, and KRAS in frequencies exceeding 1%. Lung cancers that harbor these genomic changes can potentially be targeted with agents approved for other indications or under clinical development. The need to generate increasing amounts of genomic information should prompt health-care providers to be mindful of the amounts of tissue needed for these assays when planning diagnostic procedures. In this review, we summarize oncogenic drivers in NSCLC that can be currently detected, highlight their potential therapeutic implications, and discuss practical considerations for successful application of tumor genotyping in clinical decision making.Keywords: lung cancer; cancer genomics; molecular targeted therapy Lung cancer remains the leading cause of cancer-related mortality in the United States and worldwide. Approximately 85% of patients are diagnosed with non-small cell lung cancer (NSCLC), and most present with advanced disease that is not amenable to curative therapy. For these patients, cytotoxic chemotherapy offers modest prolongation in survival. Over the past 2 decades, modifications of chemotherapy combinations, the addition of monoclonal antibodies, including bevacizumab and cetuximab, and the incorporation of histologic subtype into treatment decisions have added incrementally to the survival of patients with advanced NSCLC. However, therapeutic outcomes appear to have reached a plateau, with response rates of 20 to 35% and median survival of 8 to 12 months (1-3). Recently, clinical and laboratory research have led to a better understanding of the molecular pathogenesis that causes lung cancer. The ongoing research of patients with NSCLC and their tumors has demonstrated that NSCLC can be further defined at the molecular level by the identification and characterization of oncogenic drivers that occur in genes critical to cellular proliferation and survival, leading to aberrant activation of signaling proteins that induce sustained growth of the lung cancer cells. These advances in the molecular pathogenesis of NSCLC have prompted investigators to systematically characterize lung cancers for these oncogenic drivers and treat with appropriate targeted therapies. A cohort of patients can now be prospectively identified who have significantly improved outcomes with such therapies, with median survival in excess of 2 years, necessitating the routine identification of these genomically defined patient subsets. In this perspective, we review oncogenic ...

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“…RET means that it will "rearrange during transfection"; the DNA of RET was first discovered rearranged in a 3T3 fibroblast cell line and transfection took place after it. Recently, RET rearrangements were discovered in NSCLC by using different screening strategies from cancer and normal tissue which originated from a lung cancer patient, in whom there were no driver mutation or fusion, who had no smoking history, and whose family has no tumor history [53]. KIF5B is a new chimeric fusion transcript, which was originally discovered as a new driver mutation in NSCLC by four independent research groups simultaneously.…”

Section: Retmentioning

confidence: 99%

The development of potential targets in the treatment of non-small cell lung cancer

Zhang

Lin

2016

Open Life Sciences

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The oncogenic driver mutations have been found that not only have potential sensitivity to epidermal growth factor receptor but also can inhibit anaplastic lymphoma kinase tyrosine kinase; more and more interest has been evoked in discovering additional targets to non-small cell lung cancer (NSCLC). Recently, many novel underlying oncogenic gene alterations have been identified, such as HER2 insertions, BRAF mutations, PIK3 mutations, FGFR1 amplifications, DDR2 mutations, KRAS mutations, MET amplification, ROS1 rearrangements, ALK rearrangements, and RET rearrangements. In this review, we will discuss the discovery of these potential targets and the application of each in NSCLC and of small molecular inhibitors on these potential targets.

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A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing

Cited by 437 publications

References 42 publications

Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

The Impact of Genomic Changes on Treatment of Lung Cancer

The development of potential targets in the treatment of non-small cell lung cancer

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