The transcriptional landscape and mutational profile of lung adenocarcinoma

Seo, Jeong Sun; Ju, Young Seok; Lee, Won Chul; Shin, Jong Yeon; Lee, Jake June-Koo; Bleazard, Thomas; Lee, Jun-Ho; Jung, Yoo Jin; Kim, Jung Oh; Shin, Jung Young; Yu, Saet Byeol; Kim, Jihye; Lee, Eung Ryoung; Kang, Chang Hyun; Park, In Kyu; Rhee, Hwanseok; Lee, Se‐Hoon; Kim, Jong‐Il; Kang, Jin Hyoung; Kim, Young Tae

doi:10.1101/gr.145144.112

Cited by 533 publications

(438 citation statements)

References 51 publications

(63 reference statements)

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“…This exclusivity of lung adenocarcinoma driver alterations has been observed previously and is confi rmed in this large cohort of lung adenocarcinoma specimens. Tumors with MET ex14 alterations rarely harbored the other known drivers of lung adenocarcinoma, as has been previously observed in other cohorts (23)(24)(25)(26), supporting the role of MET ex14 alterations as oncogenic driver mutations. We also observed that mutations in KRAS , EGFR , ERBB2 , and MET each frequently co-occurred with copy-number amplifi cation of the same gene, highlighting the cumulative effect of gene activation by both mutation and amplifi cation.…”

Section: Resultssupporting

confidence: 82%

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

et al. 2015

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Focal amplifi cation and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 ( MET ex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profi les from 38,028 patients to identify 221 cases with MET ex14 mutations (0.6%), including 126 distinct sequence variants. MET ex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring MET ex14 alterations. We also report three new patient cases with MET ex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of MET ex14 mutations indicates that diagnostic testing via comprehensive genomic profi ling is necessary for detection in a clinical setting. SIGNIFICANCE:Here we report the identifi cation of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro . Patients whose tumors harbored these alterations derived meaningful clinical benefi t from MET inhibitors. Collectively, these data support the role of MET ex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefi t from MET inhibitors. Cancer Discov; 5(8);

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Section: Resultssupporting

confidence: 82%

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

et al. 2015

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“…To date, MET exon 14 oncogenic alterations have been reported in approximately the 4% of lung cancer (25)(26)(27). According to the Cancer Genome Atlas (TCGA) project, the 4.3% of lung adenocarcinoma harbors DNA alterations with MET exon 14 skipping, confirmed by RNA analysis (28).…”

Section: Lung Cancermentioning

confidence: 99%

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Pilotto¹,

Gkountakos²,

Carbognin³

et al. 2017

Ann. Transl. Med.

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Abstract:The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

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“…ROS1 is fused to one of a number of genes in lung cancers, including CD74, SLC34A2, EZR, LRIG3, SDC4, TPM3, FIG (also known as GOPC), CCDC6, and KDELR2. [4][5][6][7][9][10][11][12] In these fusions, the 3 0 region of ROS1 encoding its kinase domain is fused to the 5 0 region of the respective partner gene. The fusion encodes a chimeric protein with constitutive kinase activity that initiates oncogenic intracellular signal transduction cascades.…”

mentioning

confidence: 99%

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

et al. 2014

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The recent discovery and characterization of an oncogenic ROS1 gene fusion in a subset of lung cancers has raised significant clinical interest because small molecule inhibitors may be effective to these tumors. As lung cancers with ROS1 rearrangements comprise only 1-3% of lung adenocarcinomas, patients with such tumors must be identified to gain optimal benefit from molecular therapy. Recently, immunohistochemical analyses using a novel anti-ROS1 rabbit monoclonal antibody (D4D6) have shown promise for accurate identification of ROS1-rearranged cancers. To validate this finding, we compared the immunostaining results of tissue microarrays (TMAs) containing 17 ROS1-rearranged and 253 ROS1-non-rearranged lung carcinomas. All 17 ROS1-rearranged cancers showed ROS1 immunoreactivity mostly in a diffuse and moderate-to-strong manner with an H-score range of 5-300 (median, 260). In contrast, 69% of ROS1-non-rearranged cancers lacked detectable immunoreactivity, whereas the remaining 31% showed reactivity mainly in a weak or focal manner. The H-score for the entire ROS1-non-rearranged group ranged from 0 to 240 (median, 0). The difference in H-score between the two cohorts was statistically significant, and the H-score cutoff (Z150) allowed optimal discrimination (94% sensitivity and 98% specificity). Similar but slightly less-specific performance was achieved using the extent of diffuse (Z75%) staining or Z2 þ staining intensity as cutoffs. CD74-ROS1 and EZR-ROS1 fusions were significantly associated with at least focal globular immunoreactivity and plasma membranous accentuation, respectively, and these patterns were specific to ROS1-rearranged cases. Although full-length ROS1 is expressed in some ROS1-non-rearranged cases, we showed that establishment of an optimal set of interpretative criteria makes ROS1 immunohistochemistry a valuable method to rapidly and accurately screen lung cancer patients for appropriate molecular therapy.

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The transcriptional landscape and mutational profile of lung adenocarcinoma

Cited by 533 publications

References 51 publications

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

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