{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:20:32Z","timestamp":1792045232620,"version":"4.4.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UVMMC Department of Pathology and Laboratory Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/carcin\/bgab104","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T19:48:52Z","timestamp":1635277732000},"page":"1428-1438","source":"Crossref","is-referenced-by-count":17,"title":["Functional assessment of somatic <i>STK11<\/i> variants identified in primary human non-small cell lung cancers"],"prefix":"10.1093","volume":"42","author":[{"given":"Liam L","family":"Donnelly","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler C","family":"Hogan","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean M","family":"Lenahan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopika","family":"Nandagopal","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna G","family":"Eaton","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meagan A","family":"Lebeau","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai L","family":"McCann","sequence":"additional","affiliation":[{"name":"University of Vermont, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey M","family":"Sarausky","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J","family":"Hampel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret P","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoletta","family":"Sidiropoulos","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"},{"name":"University of Vermont Cancer Center, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Deming","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA"},{"name":"University of Vermont Cancer Center, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5821-6187","authenticated-orcid":false,"given":"David J","family":"Seward","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA"},{"name":"University of Vermont Cancer Center, Burlington, VT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"2022010505441372600_CIT0001","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA. 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Lung Cancer Res.,"},{"key":"2022010505441372600_CIT0008","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12943-018-0864-3","article-title":"Biomarkers for predicting efficacy of PD-1\/PD-L1 inhibitors","volume":"17","author":"Yi","year":"2018","journal-title":"Mol. Cancer,"},{"key":"2022010505441372600_CIT0009","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nature06030","article-title":"LKB1 modulates lung cancer differentiation and metastasis","volume":"448","author":"Ji","year":"2007","journal-title":"Nature,"},{"key":"2022010505441372600_CIT0010","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/2159-8290.CD-18-0099","article-title":"STK11\/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discov.,"},{"key":"2022010505441372600_CIT0011","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1158\/0008-5472.CAN-15-1439","article-title":"STK11\/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment","volume":"76","author":"Koyama","year":"2016","journal-title":"Cancer Res.,"},{"key":"2022010505441372600_CIT0012","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1158\/1078-0432.CCR-14-3112","article-title":"Immunohistochemical loss of LKB1 is a biomarker for more aggressive biology in KRAS-mutant lung adenocarcinoma","volume":"21","author":"Calles","year":"2015","journal-title":"Clin. 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Genet.,"},{"key":"2022010505441372600_CIT0016","first-page":"3659","article-title":"Inactivation of LKB1\/STK11 is a common event in adenocarcinomas of the lung","volume":"62","author":"Sanchez-Cespedes","year":"2002","journal-title":"Cancer Res.,"},{"key":"2022010505441372600_CIT0017","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.lungcan.2019.01.003","article-title":"Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11","volume":"130","author":"La Fleur","year":"2019","journal-title":"Lung Cancer,"},{"issue":"Pt 26","key":"2022010505441372600_CIT0018","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.1242\/jcs.01571","article-title":"Analysis of the LKB1-STRAD-MO25 complex","volume":"117","author":"Boudeau","year":"2004","journal-title":"J. Cell Sci.,"},{"key":"2022010505441372600_CIT0019","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1126\/science.1178377","article-title":"Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation","volume":"326","author":"Zeqiraj","year":"2009","journal-title":"Science,"},{"key":"2022010505441372600_CIT0020","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/sj.emboj.7600110","article-title":"LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK\/PAR-1","volume":"23","author":"Lizcano","year":"2004","journal-title":"EMBO J.,"},{"key":"2022010505441372600_CIT0021","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1038\/onc.2012.431","article-title":"LKB1 tumor suppressor regulates AMP kinase\/mTOR-independent cell growth and proliferation via the phosphorylation of Yap","volume":"32","author":"Nguyen","year":"2013","journal-title":"Oncogene,"},{"key":"2022010505441372600_CIT0022","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1093\/carcin\/22.8.1257","article-title":"Aberrant cell cycle checkpoint function in transformed hepatocytes and WB-F344 hepatic epithelial stem-like cells","volume":"22","author":"Kaufmann","year":"2001","journal-title":"Carcinogenesis,"},{"key":"2022010505441372600_CIT0023","doi-asserted-by":"crossref","first-page":"10701","DOI":"10.1158\/0008-5472.CAN-06-0999","article-title":"LKB1 is recruited to the p21\/WAF1 promoter by p53 to mediate transcriptional activation","volume":"66","author":"Zeng","year":"2006","journal-title":"Cancer Res.,"},{"key":"2022010505441372600_CIT0024","first-page":"1291","article-title":"Liver kinase B1\/adenosine monophosphate-activated protein kinase signaling axis induces p21\/WAF1 expression in a p53-dependent manner","volume":"16","author":"Ma","year":"2018","journal-title":"Oncol. Lett.,"},{"key":"2022010505441372600_CIT0025","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/hmg\/11.13.1497","article-title":"Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1\/CIP1)","volume":"11","author":"Tiainen","year":"2002","journal-title":"Hum. Mol. Genet.,"},{"key":"2022010505441372600_CIT0026","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1038\/onc.2011.19","article-title":"A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation","volume":"30","author":"Hou","year":"2011","journal-title":"Oncogene,"},{"key":"2022010505441372600_CIT0027","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s12881-018-0626-5","article-title":"The altered activity of P53 signaling pathway by STK11 gene mutations and its cancer phenotype in Peutz-Jeghers syndrome","volume":"19","author":"Jiang","year":"2018","journal-title":"BMC Med. Genet.,"},{"key":"2022010505441372600_CIT0028","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S1097-2765(01)00258-1","article-title":"The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death","volume":"7","author":"Karuman","year":"2001","journal-title":"Mol. Cell,"},{"key":"2022010505441372600_CIT0029","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1093\/ndt\/gfn229","article-title":"Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman\u2019s syndrome","volume":"23","author":"Riveira-Munoz","year":"2008","journal-title":"Nephrol. Dial. Transplant,"},{"key":"2022010505441372600_CIT0030","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/(SICI)1098-1004(1998)12:3<153::AID-HUMU3>3.0.CO;2-I","article-title":"Information analysis of human splice site mutations","volume":"12","author":"Rogan","year":"1998","journal-title":"Hum. Mutat.,"},{"key":"2022010505441372600_CIT0031","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/humu.22624","article-title":"Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions","volume":"35","author":"Sharma","year":"2014","journal-title":"Hum. Mutat.,"},{"key":"2022010505441372600_CIT0032","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.gpb.2013.01.008","article-title":"Interpretation, stratification and evidence for sequence variants affecting mRNA splicing in complete human genome sequences","volume":"11","author":"Shirley","year":"2013","journal-title":"Genom. Proteom. 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Mutat.,"},{"key":"2022010505441372600_CIT0037","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nbt.3481","article-title":"Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA","volume":"34","author":"Richardson","year":"2016","journal-title":"Nat. Biotechnol.,"},{"key":"2022010505441372600_CIT0038","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1038\/s41598-018-38189-9","article-title":"New insights into the pathogenicity of non-synonymous variants through multi-level analysis","volume":"9","author":"Sun","year":"2019","journal-title":"Sci. Rep.,"},{"key":"2022010505441372600_CIT0039","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1086\/302159","article-title":"Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity","volume":"63","author":"Mehenni","year":"1998","journal-title":"Am. J. Hum. Genet.,"},{"key":"2022010505441372600_CIT0040","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1038\/s41467-020-15573-6","article-title":"p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival","volume":"11","author":"Deng","year":"2020","journal-title":"Nat. Commun.,"},{"key":"2022010505441372600_CIT0041","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.clinre.2010.11.008","article-title":"A novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers syndrome patient significantly diminished p53 activity","volume":"35","author":"Liu","year":"2011","journal-title":"Clin. Res. Hepatol. Gastroenterol.,"},{"key":"2022010505441372600_CIT0042","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov.,"},{"key":"2022010505441372600_CIT0043","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1158\/1078-0432.CCR-06-0083","article-title":"Frequency and spectrum of cancers in the Peutz-Jeghers syndrome","volume":"12","author":"Hearle","year":"2006","journal-title":"Clin. Cancer Res.,"},{"key":"2022010505441372600_CIT0044","doi-asserted-by":"crossref","first-page":"16426","DOI":"10.1038\/s41598-019-52308-0","article-title":"Prediction of deleterious non-synonymous SNPs of human STK11 gene by combining algorithms, molecular docking, and molecular dynamics simulation","volume":"9","author":"Islam","year":"2019","journal-title":"Sci. Rep.,"},{"key":"2022010505441372600_CIT0045","doi-asserted-by":"crossref","first-page":"17663","DOI":"10.1074\/jbc.M112.444620","article-title":"LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence","volume":"288","author":"Kline","year":"2013","journal-title":"J. Biol. Chem.,"},{"key":"2022010505441372600_CIT0046","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1091\/mbc.E15-08-0569","article-title":"LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion","volume":"27","author":"Konen","year":"2016","journal-title":"Mol. Biol. Cell,"},{"key":"2022010505441372600_CIT0047","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1093\/hmg\/ddi139","article-title":"Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity","volume":"14","author":"Forcet","year":"2005","journal-title":"Hum. Mol. Genet.,"}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgab104\/41291102\/bgab104.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/42\/12\/1428\/42071474\/bgab104.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/42\/12\/1428\/42071474\/bgab104.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T05:45:01Z","timestamp":1641361501000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/42\/12\/1428\/6431898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,19]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,11,19]]},"published-print":{"date-parts":[[2021,12,31]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgab104","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,1]]},"published":{"date-parts":[[2021,11,19]]}}}