دورية أكاديمية
أعرض في EDS

Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers.

التفاصيل البيبلوغرافية
العنوان: Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers.
المؤلفون: Donnelly LL; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Hogan TC; Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA., Lenahan SM; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Nandagopal G; Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA., Eaton JG; Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA., Lebeau MA; Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA., McCann CL; University of Vermont, Burlington, VT, USA., Sarausky HM; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Hampel KJ; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Armstrong JD; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Cameron MP; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA., Sidiropoulos N; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.; University of Vermont Cancer Center, Burlington, VT, USA., Deming P; Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA.; University of Vermont Cancer Center, Burlington, VT, USA., Seward DJ; Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.; University of Vermont Cancer Center, Burlington, VT, USA.
المصدر: Carcinogenesis [Carcinogenesis] 2021 Dec 31; Vol. 42 (12), pp. 1428-1438.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Irl Press At Oxford University Press Country of Publication: England NLM ID: 8008055 Publication Model: Print Cited Medium: Internet ISSN: 1460-2180 (Electronic) Linking ISSN: 01433334 NLM ISO Abbreviation: Carcinogenesis Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Irl Press At Oxford University Press
Original Publication: [New York, IRL Press]
مواضيع طبية MeSH: Mutation*, AMP-Activated Protein Kinase Kinases/*genetics , Carcinoma, Non-Small-Cell Lung/*genetics , Lung Neoplasms/*genetics, AMP-Activated Protein Kinase Kinases/metabolism ; Alternative Splicing ; Biomarkers, Tumor ; CRISPR-Cas Systems ; Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/mortality ; DNA Mutational Analysis ; Disease Susceptibility ; Gene Editing ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Humans ; Lung Neoplasms/diagnosis ; Lung Neoplasms/mortality ; Mutagenesis, Site-Directed ; Mutation, Missense ; Phosphorylation ; Prognosis ; RNA Splice Sites
مستخلص: Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.
(© The Author(s) 2021. Published by Oxford University Press.)
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معلومات مُعتمدة: Department of Pathology and Laboratory Medicine; Department of Biomedical and Health Sciences; UVMMC Department of Pathology and Laboratory Medicine
المشرفين على المادة: 0 (Biomarkers, Tumor)
0 (RNA Splice Sites)
EC 2.7.11.1 (STK11 protein, human)
EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
تواريخ الأحداث: Date Created: 20211201 Date Completed: 20220221 Latest Revision: 20220221
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8727739
DOI: 10.1093/carcin/bgab104
PMID: 34849607
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2180
DOI:10.1093/carcin/bgab104