{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:38:40Z","timestamp":1792730320186,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The South-Eastern Norway Regional Health Authority","award":["2022020"],"award-info":[{"award-number":["2022020"]}]},{"name":"The Research fund Vestfold Hospital Trust","award":["198223"],"award-info":[{"award-number":["198223"]}]},{"name":"Research fund, Department of Pathology, Vestfold Hospital Trust"},{"name":"South-Eastern Norway Regional Health Authority","award":["2018049"],"award-info":[{"award-number":["2018049"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Exp Metastasis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lung cancer remains a major cause of cancer-related mortality, including among patients diagnosed with potentially curable disease. Current decisions regarding perioperative treatment and follow-up rely on a limited number of established prognostic factors. Further knowledge is needed regarding the clinical, histopathological, and molecular factors associated with subsequent metastatic disease, particularly brain metastasis (BM), which is associated with poor prognosis. We investigated these factors in a large cohort of patients with surgically resected stage I\u2013III lung cancer followed for more than five years. BM was associated with higher pathological tumour and lymph-node stage and younger age at surgery. Lung adenocarcinoma was associated with a higher risk of BM than lung squamous cell carcinoma. Several molecular alterations were associated with metastatic disease or BM, including\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations in lung adenocarcinoma and\n                    <jats:italic>NFE2L2<\/jats:italic>\n                    mutations in lung squamous cell carcinoma. Additional associations involving specific\n                    <jats:italic>EGFR<\/jats:italic>\n                    and\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutation subtypes and rarer alterations were observed, but were based on small numbers of cases and should be considered exploratory. Several of the associated genes are involved in the RAS\/MAPK, PI3K\/AKT\/mTOR, or NRF2-related pathways. However, pathway activation and causality could not be established in this observational study. These findings support further investigation of clinical, histopathological, and molecular factors associated with metastatic progression after surgical resection. Validation in larger, independent, stage-stratified and contemporary cohorts with comprehensive treatment data is required before the identified molecular alterations can be considered for clinical risk stratification or surveillance.\n                  <\/jats:p>","DOI":"10.1007\/s10585-026-10444-8","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:11:54Z","timestamp":1792728714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular, histopathological, and clinical risk factors for overall metastatic disease and brain metastases in surgically resected stage I\u2013III lung cancer"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7930-9153","authenticated-orcid":false,"given":"Anne Pernille Harlem","family":"Dyrbekk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3133-5503","authenticated-orcid":false,"given":"P\u00e5l","family":"Suhrke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4169-0157","authenticated-orcid":false,"given":"Marianne Odnakk","family":"Ludahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0687-424X","authenticated-orcid":false,"given":"Nermin","family":"Zecic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9680-6329","authenticated-orcid":false,"given":"Joakim Oliu","family":"Moe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1246-3048","authenticated-orcid":false,"given":"Inger Johanne Zwicky","family":"Eide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2025-4062","authenticated-orcid":false,"given":"Marius","family":"Lund-Iversen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-8391","authenticated-orcid":false,"given":"Odd Terje","family":"Brustugun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"10444_CR1","unstructured":"Cancer Registry of Norway (2025) Cancer in Norway 2024: Cancer incidence, mortality, survival and prevalence in Norway. https:\/\/www.fhi.no\/en\/publ\/2025\/cancer-in-norway-2024\/. Accessed 05 Oct 2026"},{"key":"10444_CR2","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.jncc.2025.01.003","volume":"5","author":"Y Ji","year":"2025","unstructured":"Ji Y, Zhang Y, Liu S, Li J, Jin Q, Wu J, Duan H, Liu X, Yang L, Huang Y (2025) The epidemiological landscape of lung cancer: current status, temporal trend and future projections based on the latest estimates from GLOBOCAN 2022. J Natl Cancer Cent 5:278\u2013286. https:\/\/doi.org\/10.1016\/j.jncc.2025.01.003","journal-title":"J Natl Cancer Cent"},{"key":"10444_CR3","unstructured":"Norwegian Institute of Public Health; Cancer Registry of Norway (2025) \u00c5rsrapport 2024 med resultater og forbedringstiltak fra Nasjonalt kvalitetsregister for lungekreft. https:\/\/www.fhi.no\/contentassets\/b19a8ea7ddb74efc92ad44cf16d74c5d\/arsrapport-2024-nasjonalt-kvalitetsregister-for-lungekreft.pdf. Accessed 02 Oct 2026"},{"key":"10444_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14061400","volume":"14","author":"S Garinet","year":"2022","unstructured":"Garinet S, Wang P, Mansuet-Lupo A, Fournel L, Wislez M, Blons H (2022) Updated prognostic factors in localized NSCLC. Cancers 14:1400. https:\/\/doi.org\/10.3390\/cancers14061400","journal-title":"Cancers"},{"key":"10444_CR5","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.nec.2020.06.001","volume":"31","author":"P Sacks","year":"2020","unstructured":"Sacks P, Rahman M (2020) Epidemiology of brain metastases. Neurosurg Clin N Am 31:481\u2013488. https:\/\/doi.org\/10.1016\/j.nec.2020.06.001","journal-title":"Neurosurg Clin N Am"},{"key":"10444_CR6","doi-asserted-by":"publisher","DOI":"10.1201\/9780203852569","volume-title":"The biology of cancer","author":"RA Weinberg","year":"2006","unstructured":"Weinberg RA (2006) The biology of cancer. WW Norton & Company, New York"},{"key":"10444_CR7","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1056\/NEJMoa1916623","volume":"383","author":"N Howlader","year":"2020","unstructured":"Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, Mariotto AB, Lowy DR, Feuer EJ (2020) The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 383:640\u2013649. https:\/\/doi.org\/10.1056\/NEJMoa1916623","journal-title":"N Engl J Med"},{"key":"10444_CR8","doi-asserted-by":"publisher","first-page":"943","DOI":"10.2147\/cmar.S187317","volume":"11","author":"T Lu","year":"2019","unstructured":"Lu T, Yang X, Huang Y, Zhao M, Li M, Ma K, Yin J, Zhan C, Wang Q (2019) Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res 11:943\u2013953. https:\/\/doi.org\/10.2147\/cmar.S187317","journal-title":"Cancer Manag Res"},{"key":"10444_CR9","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/j.annonc.2025.08.003","volume":"36","author":"A Zer","year":"2025","unstructured":"Zer A, Ahn MJ, Barlesi F, Bubendorf L, De Ruysscher D, Garrido P, Gautschi O, Hendriks LE, J\u00e4nne PA, Kerr KM, Mascaux C et al (2025) Early and locally advanced non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 36:1245\u20131262. https:\/\/doi.org\/10.1016\/j.annonc.2025.08.003","journal-title":"Ann Oncol"},{"key":"10444_CR10","unstructured":"Helsedirektoratet (2025) Lungekreft, mesoteliom og thymom: handlingsprogram. https:\/\/www.helsedirektoratet.no\/retningslinjer\/lungekreft-mesoteliom-og-thymom-handlingsprogram\/innledning#revisjon-mai-2025. Accessed 02 October 2026"},{"key":"10444_CR11","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1093\/oncolo\/oyac094","volume":"27","author":"RSP Huang","year":"2022","unstructured":"Huang RSP, Harries L, Decker B, Hiemenz MC, Murugesan K, Creeden J, Tolba K, Stabile LP, Ramkissoon SH, Burns TF, Ross JS (2022) Clinicopathologic and genomic landscape of non-small cell lung cancer brain metastases. Oncologist 27:839\u2013848. https:\/\/doi.org\/10.1093\/oncolo\/oyac094","journal-title":"Oncologist"},{"key":"10444_CR12","volume-title":"WHO classification of tumours of the lung, pleura, thymus and heart","author":"WD Travis","year":"2015","unstructured":"Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) WHO classification of tumours of the lung, pleura, thymus and heart, 4th edition. International Agency for Research on Cancer (IARC), Lyon","edition":"4th edition"},{"key":"10444_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104401","volume":"200","author":"A La Salvia","year":"2024","unstructured":"La Salvia A, Meyer ML, Hirsch FR, Kerr KM, Landi L, Tsao MS, Cappuzzo F (2024) Rediscovering immunohistochemistry in lung cancer. Crit Rev Oncol Hematol 200:104401. https:\/\/doi.org\/10.1016\/j.critrevonc.2024.104401","journal-title":"Crit Rev Oncol Hematol"},{"key":"10444_CR14","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s13000-015-0395-9","volume":"10","author":"M Lund-Iversen","year":"2015","unstructured":"Lund-Iversen M, Gr\u00f8holt KK, Helland \u00c5, Borgen E, Brustugun OT (2015) NUT expression in primary lung tumours. Diagn Pathol 10:156\u2013156. https:\/\/doi.org\/10.1186\/s13000-015-0395-9","journal-title":"Diagn Pathol"},{"key":"10444_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03099-x","volume":"9","author":"J George","year":"2018","unstructured":"George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, M\u00fcller C, Dahmen I, Delhomme TM, Ardin M et al (2018) Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9:1048. https:\/\/doi.org\/10.1038\/s41467-018-03099-x","journal-title":"Nat Commun"},{"key":"10444_CR16","unstructured":"Norwegian Institute of Public Health Norwegian Cause of Death Registry (2026) https:\/\/www.fhi.no\/en\/ch\/cause-of-death-registry\/. Accessed 02 Oct 2026"},{"key":"10444_CR17","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13000-023-01357-1","volume":"18","author":"APH Dyrbekk","year":"2023","unstructured":"Dyrbekk APH, Warsame AA, Suhrke P, Ludahl MO, Moe JO, Eide IJZ, Lund-Iversen M, Brustugun OT (2023) Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer. Diagn Pathol 18:70. https:\/\/doi.org\/10.1186\/s13000-023-01357-1","journal-title":"Diagn Pathol"},{"key":"10444_CR18","doi-asserted-by":"publisher","unstructured":"Dyrbekk APH, Warsame AA, Suhrke P, Ludahl MO, Zecic N, Moe JO, Lund-Iversen M, Brustugun OT (2024) Evaluation of NTRK expression and fusions in a large cohort of early-stage lung cancer. Clin Exp Med 24:10. https:\/\/doi.org\/10.1007\/s10238-023-01273-","DOI":"10.1007\/s10238-023-01273-"},{"key":"10444_CR19","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1038\/s41591-020-0969-2","volume":"26","author":"D Tamborero","year":"2020","unstructured":"Tamborero D, Dienstmann R, Rachid MH, Boekel J, Baird R, Bra\u00f1a I, De Petris L, Yachnin J, Massard C, Opdam FL, Schlenk R et al (2020) Support systems to guide clinical decision-making in precision oncology: the Cancer Core Europe Molecular Tumor Board Portal. Nat Med 26:992\u2013994. https:\/\/doi.org\/10.1038\/s41591-020-0969-2","journal-title":"Nat Med"},{"key":"10444_CR20","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.jmoldx.2016.10.002","volume":"19","author":"MM Li","year":"2017","unstructured":"Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, Tsimberidou AM, Vnencak-Jones CL, Wolff DJ, Younes A, Nikiforova MN (2017) Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 19:4\u201323. https:\/\/doi.org\/10.1016\/j.jmoldx.2016.10.002","journal-title":"J Mol Diagn"},{"key":"10444_CR21","unstructured":"StataCorp LCC (2023) Stata statistical software: release 18"},{"key":"10444_CR22","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1148\/radiol.2423051707","volume":"242","author":"A Mujoomdar","year":"2007","unstructured":"Mujoomdar A, Austin JH, Malhotra R, Powell CA, Pearson GD, Shiau MC, Raftopoulos H (2007) Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 242:882\u2013888. https:\/\/doi.org\/10.1148\/radiol.2423051707","journal-title":"Radiology"},{"key":"10444_CR23","doi-asserted-by":"publisher","first-page":"479","DOI":"10.21037\/jtd-23-1435","volume":"16","author":"X Xu","year":"2024","unstructured":"Xu X, Chen G, Fan S, Zhang Q, Huang W, Chen J, Ji W, Ma J, He J (2024) Risk factors for brain metastases in locally advanced non-small cell lung cancer patients treated with radical radiotherapy. J Thorac Dis 16:479\u2013490. https:\/\/doi.org\/10.21037\/jtd-23-1435","journal-title":"J Thorac Dis"},{"key":"10444_CR24","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/s1556-0864(15)31569-0","volume":"1","author":"AA Shi","year":"2006","unstructured":"Shi AA, Digumarthy SR, Temel JS, Halpern EF, Kuester LB, Aquino SL (2006) Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol 1:205\u2013210. https:\/\/doi.org\/10.1016\/s1556-0864(15)31569-0","journal-title":"J Thorac Oncol"},{"key":"10444_CR25","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1097\/cej.0000000000000790","volume":"32","author":"Y Hao","year":"2023","unstructured":"Hao Y, Li G (2023) Risk and prognostic factors of brain metastasis in lung cancer patients: a surveillance, epidemiology, and end results population-based cohort study. Eur J Cancer Prev 32:498\u2013511. https:\/\/doi.org\/10.1097\/cej.0000000000000790","journal-title":"Eur J Cancer Prev"},{"key":"10444_CR26","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2024-087181","volume":"15","author":"X Wan","year":"2025","unstructured":"Wan X, Mo H, Chen J, Zhou Q, Qiu S, Zou Y, Wu W, Tang Q, Wang S (2025) Risk factors for brain metastasis in lung cancer: an umbrella review of systematic reviews and meta-analyses. BMJ Open 15:e087181. https:\/\/doi.org\/10.1136\/bmjopen-2024-087181","journal-title":"BMJ Open"},{"key":"10444_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/jgo.18.00216","volume":"5","author":"AM Suidan","year":"2019","unstructured":"Suidan AM, Roisman L, Belilovski Rozenblum A, Ilouze M, Dudnik E, Zer A, Peled N (2019) Lung cancer in young patients: higher rate of driver mutations and brain involvement, but better survival. J Glob Oncol 5:1\u20138. https:\/\/doi.org\/10.1200\/jgo.18.00216","journal-title":"J Glob Oncol"},{"key":"10444_CR28","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1200\/jco.2015.62.0138","volume":"34","author":"KL Johung","year":"2016","unstructured":"Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K et al (2016) Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol 34:123\u2013129. https:\/\/doi.org\/10.1200\/jco.2015.62.0138","journal-title":"J Clin Oncol"},{"key":"10444_CR29","doi-asserted-by":"publisher","first-page":"3773","DOI":"10.1200\/jco.20.01255","volume":"38","author":"PW Sperduto","year":"2020","unstructured":"Sperduto PW, Mesko S, Li J, Cagney D, Aizer A, Lin NU, Nesbit E, Kruser TJ, Chan J, Braunstein S, Lee J et al (2020) Survival in patients with brain metastases: summary report on the updated diagnosis-specific graded prognostic assessment and definition of the eligibility quotient. J Clin Oncol 38:3773\u20133784. https:\/\/doi.org\/10.1200\/jco.20.01255","journal-title":"J Clin Oncol"},{"key":"10444_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01347-1","volume":"8","author":"H Wang","year":"2023","unstructured":"Wang H, Guo M, Wei H, Chen Y (2023) Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct Target Ther 8:92. https:\/\/doi.org\/10.1038\/s41392-023-01347-1","journal-title":"Signal Transduct Target Ther"},{"key":"10444_CR31","doi-asserted-by":"publisher","first-page":"705","DOI":"10.3892\/mco.2016.1057","volume":"5","author":"J Gu","year":"2016","unstructured":"Gu J, Zhou Y, Huang L, Ou W, Wu J, Li S, Xu J, Feng J, Liu B (2016) TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: evidence from a meta-analysis. Mol Clin Oncol 5:705\u2013713. https:\/\/doi.org\/10.3892\/mco.2016.1057","journal-title":"Mol Clin Oncol"},{"key":"10444_CR32","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jtho.2021.08.764","volume":"17","author":"MM Saleh","year":"2022","unstructured":"Saleh MM, Scheffler M, Merkelbach-Bruse S, Scheel AH, Ulmer B, Wolf J, Buettner R (2022) Comprehensive analysis of TP53 and KEAP1 mutations and their impact on survival in localized- and advanced-stage NSCLC. J Thorac Oncol 17:76\u201388. https:\/\/doi.org\/10.1016\/j.jtho.2021.08.764","journal-title":"J Thorac Oncol"},{"key":"10444_CR33","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1200\/jco.2012.48.1390","volume":"31","author":"FA Shepherd","year":"2013","unstructured":"Shepherd FA, Domerg C, Hainaut P, J\u00e4nne PA, Pignon JP, Graziano S, Douillard JY, Brambilla E, Le Chevalier T, Seymour L, Bourredjem A et al (2013) Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 31:2173\u20132181. https:\/\/doi.org\/10.1200\/jco.2012.48.1390","journal-title":"J Clin Oncol"},{"key":"10444_CR34","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1097\/jto.0000000000000266","volume":"9","author":"B Izar","year":"2014","unstructured":"Izar B, Zhou H, Heist RS, Azzoli CG, Muzikansky A, Scribner EE, Bernardo LA, Dias-Santagata D, Iafrate AJ, Lanuti M (2014) The prognostic impact of KRAS, its codon and amino acid specific mutations, on survival in resected stage I lung adenocarcinoma. J Thorac Oncol 9:1363\u20131369. https:\/\/doi.org\/10.1097\/jto.0000000000000266","journal-title":"J Thorac Oncol"},{"key":"10444_CR35","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/jto.0000000000000432","volume":"10","author":"HA Yu","year":"2015","unstructured":"Yu HA, Sima CS, Shen R, Kass S, Gainor J, Shaw A, Hames M, Iams W, Aston J, Lovly CM, Horn L et al (2015) Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas. J Thorac Oncol 10:431\u2013437. https:\/\/doi.org\/10.1097\/jto.0000000000000432","journal-title":"J Thorac Oncol"},{"key":"10444_CR36","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.ebiom.2019.02.049","volume":"41","author":"H Adderley","year":"2019","unstructured":"Adderley H, Blackhall FH, Lindsay CR (2019) KRAS-mutant non-small cell lung cancer: converging small molecules and immune checkpoint inhibition. EBioMedicine 41:711\u2013716. https:\/\/doi.org\/10.1016\/j.ebiom.2019.02.049","journal-title":"EBioMedicine"},{"key":"10444_CR37","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.873532","volume":"12","author":"A Khadse","year":"2022","unstructured":"Khadse A, Haakensen VD, Silwal-Pandit L, Hamfjord J, Micke P, Botling J, Brustugun OT, Lingj\u00e6rde OC, Helland \u00c5, Kure EH (2022) Prognostic significance of the loss of heterozygosity of KRAS in early-stage lung adenocarcinoma. Front Oncol 12:873532. https:\/\/doi.org\/10.3389\/fonc.2022.873532","journal-title":"Front Oncol"},{"key":"10444_CR38","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.cllc.2023.05.002","volume":"24","author":"J Isaksson","year":"2023","unstructured":"Isaksson J, Berglund A, Louie K, Will\u00e9n L, Hamidian A, Edsj\u00f6 A, Enlund F, Planck M, Vikstr\u00f6m A, Johansson M, Hallqvist A et al (2023) KRAS G12C mutant non-small cell lung cancer linked to female sex and high risk of CNS metastasis: population-based demographics and survival data from the National Swedish Lung Cancer Registry. Clin Lung Cancer 24:507\u2013518. https:\/\/doi.org\/10.1016\/j.cllc.2023.05.002","journal-title":"Clin Lung Cancer"},{"key":"10444_CR39","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1177\/03008916251343724","volume":"111","author":"J Zhang","year":"2025","unstructured":"Zhang J, Luo Z, Xie Z, Huang J, Lin H, Pan H, Chen L, Wu C, Wu L, Zhou Y, Zheng J et al (2025) Association between EGFR mutation types and incidence of brain metastases in postoperative patients with stage I\u2013III NSCLC. Tumori 111:200\u2013209. https:\/\/doi.org\/10.1177\/03008916251343724","journal-title":"Tumori"},{"key":"10444_CR40","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1056\/NEJMoa2304594","volume":"389","author":"M Tsuboi","year":"2023","unstructured":"Tsuboi M, Herbst RS, John T, Kato T, Majem M, Groh\u00e9 C, Wang J, Goldman JW, Lu S, Su W-C, de Marinis F et al (2023) Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 389:137\u2013147. https:\/\/doi.org\/10.1056\/NEJMoa2304594","journal-title":"N Engl J Med"},{"key":"10444_CR41","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1158\/1078-0432.Ccr-14-2124","volume":"21","author":"ME Arcila","year":"2015","unstructured":"Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, Kris MG, Solit DB, Ladanyi M (2015) MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin Cancer Res 21:1935\u20131943. https:\/\/doi.org\/10.1158\/1078-0432.Ccr-14-2124","journal-title":"Clin Cancer Res"},{"key":"10444_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2024.100839","volume":"38","author":"VD de Jager","year":"2024","unstructured":"de Jager VD, Timens W, Bayle A, Botling J, Brcic L, B\u00fcttner R, Fernandes MGO, Havel L, Hochmair M, Hofman P, Janssens A et al (2024) Future perspective for the application of predictive biomarker testing in advanced stage non-small cell lung cancer. Lancet Reg Health Eur 38:100839. https:\/\/doi.org\/10.1016\/j.lanepe.2024.100839","journal-title":"Lancet Reg Health Eur"},{"key":"10444_CR43","doi-asserted-by":"publisher","DOI":"10.1200\/po.22.00382","volume":"6","author":"ML Cheng","year":"2022","unstructured":"Cheng ML, Lee JK, Kumar R, Klein H, Raskina K, Schrock AB, Michael KS, Mazor T, Cerami E, Oxnard GR, Liu D et al (2022) Response to MEK inhibitor therapy in MAP2K1 (MEK1) K57N non-small-cell lung cancer and genomic landscape of MAP2K1 mutations in non-small-cell lung cancer. JCO Precis Oncol 6:e2200382. https:\/\/doi.org\/10.1200\/po.22.00382","journal-title":"JCO Precis Oncol"},{"key":"10444_CR44","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1158\/2159-8290.Cd-18-0385","volume":"8","author":"D Jia","year":"2018","unstructured":"Jia D, Augert A, Kim DW, Eastwood E, Wu N, Ibrahim AH, Kim KB, Dunn CT, Pillai SPS, Gazdar AF, Bolouri H et al (2018) Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition. Cancer Discov 8:1422\u20131437. https:\/\/doi.org\/10.1158\/2159-8290.Cd-18-0385","journal-title":"Cancer Discov"},{"issue":"9","key":"10444_CR45","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1634\/theoncologist.2019-0846","volume":"25","author":"B Laderian","year":"2020","unstructured":"Laderian B, Mundi P, Fojo T, Bates E (2020) Emerging therapeutic implications of STK11 mutation: case series. Oncologist 25(9):733\u2013737. https:\/\/doi.org\/10.1634\/theoncologist.2019-0846","journal-title":"Oncologist"},{"key":"10444_CR46","doi-asserted-by":"publisher","first-page":"427","DOI":"10.5732\/cjc.013.10086","volume":"32","author":"W Zhou","year":"2013","unstructured":"Zhou W, Marcus AI, Vertino PM (2013) Dysregulation of mTOR activity through LKB1 inactivation. Chin J Cancer 32:427\u2013433. https:\/\/doi.org\/10.5732\/cjc.013.10086","journal-title":"Chin J Cancer"},{"key":"10444_CR47","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1158\/2159-8290.Cd-18-0099","volume":"8","author":"F Skoulidis","year":"2018","unstructured":"Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, Schrock AB, Hartmaier RJ, Trabucco SE, Gay L, Ali SM et al (2018) STK11\/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822\u2013835. https:\/\/doi.org\/10.1158\/2159-8290.Cd-18-0099","journal-title":"Cancer Discov"},{"key":"10444_CR48","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ejca.2021.08.011","volume":"157","author":"A Di Federico","year":"2021","unstructured":"Di Federico A, De Giglio A, Parisi C, Gelsomino F (2021) STK11\/LKB1 and KEAP1 mutations in non-small cell lung cancer: prognostic rather than predictive? Eur J Cancer 157:108\u2013113. https:\/\/doi.org\/10.1016\/j.ejca.2021.08.011","journal-title":"Eur J Cancer"},{"key":"10444_CR49","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1089\/ars.2020.8024","volume":"33","author":"K Smolkova","year":"2020","unstructured":"Smolkova K, Miko E, Kovacs T, Leguina-Ruzzi A, Sipos A, Bai P (2020) Nuclear factor erythroid 2-related factor 2 in regulating cancer metabolism. Antioxid Redox Signal 33:966\u2013997. https:\/\/doi.org\/10.1089\/ars.2020.8024","journal-title":"Antioxid Redox Signal"},{"key":"10444_CR50","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.ccell.2018.03.022","volume":"34","author":"M Rojo de la Vega","year":"2018","unstructured":"Rojo de la Vega M, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34:21\u201343. https:\/\/doi.org\/10.1016\/j.ccell.2018.03.022","journal-title":"Cancer Cell"},{"issue":"4348\u20134371","key":"10444_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.07.016","volume":"184","author":"S Satpathy","year":"2021","unstructured":"Satpathy S, Krug K, Jean Beltran PM, Savage SR, Petralia F, Kumar-Sinha C, Dou Y, Reva B, Kane MH, Avanessian SC, Vasaikar SV et al (2021) A proteogenomic portrait of lung squamous cell carcinoma. Cell 184(4348\u20134371):e40. https:\/\/doi.org\/10.1016\/j.cell.2021.07.016","journal-title":"Cell"},{"key":"10444_CR52","doi-asserted-by":"publisher","DOI":"10.3390\/cells10081879","volume":"10","author":"M Sanchez-Ortega","year":"2021","unstructured":"Sanchez-Ortega M, Carrera AC, Garrido A (2021) Role of NRF2 in lung cancer. Cells 10:1879. https:\/\/doi.org\/10.3390\/cells10081879","journal-title":"Cells"},{"key":"10444_CR53","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101302","volume":"4","author":"J Duan","year":"2023","unstructured":"Duan J, Zhang Y, Chen R, Liang L, Huo Y, Lu S, Zhao J, Hu C, Sun Y, Yang K, Chen M et al (2023) Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma. Cell Rep Med 4:101302. https:\/\/doi.org\/10.1016\/j.xcrm.2023.101302","journal-title":"Cell Rep Med"},{"key":"10444_CR54","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1158\/1078-0432.CCR-20-1985","volume":"27","author":"A Singh","year":"2021","unstructured":"Singh A, Daemen A, Nickles D, Jeon SM, Foreman O, Sudini K, Gnad F, Lajoie S, Gour N, Mitzner W, Chatterjee S et al (2021) NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin Cancer Res 27:877\u2013888. https:\/\/doi.org\/10.1158\/1078-0432.CCR-20-1985","journal-title":"Clin Cancer Res"},{"key":"10444_CR55","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.3390\/ijms25042044","volume":"25","author":"J Wen","year":"2024","unstructured":"Wen J, Yu JZ, Liu C, Ould Ismail AAO, Ma W (2024) Exploring the molecular tumor microenvironment and translational biomarkers in brain metastases of non-small-cell lung cancer. Int J Mol Sci 25:2044. https:\/\/doi.org\/10.3390\/ijms25042044","journal-title":"Int J Mol Sci"},{"key":"10444_CR56","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.880077","volume":"12","author":"W Shen","year":"2022","unstructured":"Shen W, Zhou Q, Peng C, Li J, Yuan Q, Zhu H, Zhao M, Jiang X, Liu W, Ren C (2022) FBXW7 and the hallmarks of cancer: underlying mechanisms and prospective strategies. Front Oncol 12:880077. https:\/\/doi.org\/10.3389\/fonc.2022.880077","journal-title":"Front Oncol"},{"key":"10444_CR57","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1158\/1541-7786.Mcr-22-0474","volume":"21","author":"T Xie","year":"2023","unstructured":"Xie T, Liu Z, Li Y, Wang S, Zhai Y, Teng F, Hao X, Wang Y, Wang H, Zhang X, Wu X et al (2023) Evolutionary characteristics and immunologic divergence of lung and brain metastasis lesions in NSCLC. Mol Cancer Res 21:374\u2013385. https:\/\/doi.org\/10.1158\/1541-7786.Mcr-22-0474","journal-title":"Mol Cancer Res"},{"key":"10444_CR58","doi-asserted-by":"publisher","DOI":"10.1093\/ejcts\/ezae217","author":"RS Werner","year":"2024","unstructured":"Werner RS, Rechsteiner M, Moch H, Curioni-Fontecedro A, Weller M, Weiss T, Regli L, Le Rhun E, Mairinger F, Opitz I, Soltermann A (2024) Genetic profiles of oligometastatic non-small-cell lung cancer and corresponding brain metastases. Eur J Cardiothorac Surg. https:\/\/doi.org\/10.1093\/ejcts\/ezae217","journal-title":"Eur J Cardiothorac Surg"},{"key":"10444_CR59","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/s41588-020-0592-7","volume":"52","author":"DJH Shih","year":"2020","unstructured":"Shih DJH, Nayyar N, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, Bertalan M, Kaplan A, D\u2019Andrea MR, Chukwueke U, Ippen FM et al (2020) Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet 52:371\u2013377. https:\/\/doi.org\/10.1038\/s41588-020-0592-7","journal-title":"Nat Genet"},{"key":"10444_CR60","doi-asserted-by":"publisher","first-page":"3535","DOI":"10.1002\/cncr.32372","volume":"125","author":"H Wang","year":"2019","unstructured":"Wang H, Ou Q, Li D, Qin T, Bao H, Hou X, Wang K, Wang F, Deng Q, Liang J, Zheng W et al (2019) Genes associated with increased brain metastasis risk in non-small cell lung cancer: comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036). Cancer 125:3535\u20133544. https:\/\/doi.org\/10.1002\/cncr.32372","journal-title":"Cancer"},{"key":"10444_CR61","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1186\/s13059-020-02175-0","volume":"21","author":"WC Lee","year":"2020","unstructured":"Lee WC, Reuben A, Hu X, McGranahan N, Chen R, Jalali A, Negrao MV, Hubert SM, Tang C, Wu CC, Lucas AS et al (2020) Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity. Genome Biol 21:271. https:\/\/doi.org\/10.1186\/s13059-020-02175-0","journal-title":"Genome Biol"},{"key":"10444_CR62","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdad145","volume":"5","author":"LJ Andrews","year":"2023","unstructured":"Andrews LJ, Thornton ZA, Saleh R, Dawson S, Short SC, Daly R, Higgins JPT, Davies P, Kurian KM (2023) Genomic landscape and actionable mutations of brain metastases derived from non-small cell lung cancer: a systematic review. Neuro-Oncol Adv 5:vdad145. https:\/\/doi.org\/10.1093\/noajnl\/vdad145","journal-title":"Neuro-Oncol Adv"},{"key":"10444_CR63","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-017-0109-3","volume":"11","author":"C Philpott","year":"2017","unstructured":"Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M (2017) The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics 11:13. https:\/\/doi.org\/10.1186\/s40246-017-0109-3","journal-title":"Hum Genomics"},{"key":"10444_CR64","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/s41393-018-0214-8","volume":"56","author":"LA Harvey","year":"2018","unstructured":"Harvey LA (2018) Nearly significant if only\u2026. Spinal Cord 56:1017\u20131017. https:\/\/doi.org\/10.1038\/s41393-018-0214-8","journal-title":"Spinal Cord"},{"key":"10444_CR65","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/d41586-019-00857-9","volume":"567","author":"V Amrhein","year":"2019","unstructured":"Amrhein V, Greenland S, McShane B (2019) Scientists rise up against statistical significance. Nature 567:305\u2013307. https:\/\/doi.org\/10.1038\/d41586-019-00857-9","journal-title":"Nature"},{"key":"10444_CR66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0020124","volume":"2","author":"JP Ioannidis","year":"2005","unstructured":"Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2:e124. https:\/\/doi.org\/10.1371\/journal.pmed.0020124","journal-title":"PLoS Med"},{"key":"10444_CR67","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature13385","volume":"511","author":"Cancer Genome Atlas Research Network","year":"2014","unstructured":"Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543\u2013550. https:\/\/doi.org\/10.1038\/nature13385","journal-title":"Nature"},{"key":"10444_CR68","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/s41591-024-03286-y","volume":"31","author":"JA Zuccato","year":"2025","unstructured":"Zuccato JA, Mamatjan Y, Nassiri F, Ajisebutu A, Liu JC, Muazzam A, Singh O, Zhang W, Voisin M, Mirhadi S, Suppiah S et al (2025) Prediction of brain metastasis development with DNA methylation signatures. Nat Med 31:116\u2013125. https:\/\/doi.org\/10.1038\/s41591-024-03286-y","journal-title":"Nat Med"},{"key":"10444_CR69","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010193","author":"G Tsakonas","year":"2022","unstructured":"Tsakonas G, Koulouris A, Kazmierczak D, Botling J, Ortiz-Villalon C, Nord H, Lindskog M, Sandelin M, Micke P, Hydbring P, Ekman S (2022) Matched analyses of brain metastases versus primary non-small cell lung cancer reveal a unique microRNA signature. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms24010193","journal-title":"Int J Mol Sci"},{"key":"10444_CR70","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.ejca.2020.03.014","volume":"132","author":"G Tsakonas","year":"2020","unstructured":"Tsakonas G, Lewensohn R, Botling J, Ortiz-Villalon C, Micke P, Friesland S, Nord H, Lindskog M, Sandelin M, Hydbring P, Ekman S (2020) An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer. Eur J Cancer 132:24\u201334. https:\/\/doi.org\/10.1016\/j.ejca.2020.03.014","journal-title":"Eur J Cancer"},{"key":"10444_CR71","volume-title":"Thoracic tumours (Internet)","author":"WHO Classification of Tumours Editorial Board","year":"2021","unstructured":"WHO Classification of Tumours Editorial Board (2021) Thoracic tumours (Internet). International Agency for Research on Cancer, Lyon"},{"key":"10444_CR72","unstructured":"Norwegian Institute of Public Health; Cancer Registry of Norway (2015) \u00c5rsrapport 2013\u20132014: Nasjonalt kvalitetsregister for lungekreft. https:\/\/www.fhi.no\/globalassets\/publikasjoner-og-rapporter\/arsrapporter\/publisert-2015\/aarsrapport_2014_lungekreft.pdf. Accessed 02 Oct 2026"},{"key":"10444_CR73","unstructured":"Norwegian Institute of Public Health (2023) Utbredelse av r\u00f8yking i Norge. https:\/\/www.fhi.no\/le\/royking\/tobakkinorge\/bruk-av-tobakk\/utbredelse-av-royking-i-norge\/. Accessed 02 Oct 2026"}],"container-title":["Clinical &amp; Experimental Metastasis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-026-10444-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10585-026-10444-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-026-10444-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:11:57Z","timestamp":1792728717000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10585-026-10444-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,23]]},"references-count":73,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10444"],"URL":"https:\/\/doi.org\/10.1007\/s10585-026-10444-8","relation":{},"ISSN":["1573-7276"],"issn-type":[{"value":"1573-7276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,23]]},"assertion":[{"value":"15 September 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. The Regional Ethics Committee of South-Eastern Norway (REK) approved the study, number 2009\/1904, S-06402b.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Study participants submitted informed consent, and data were anonymized for the analyses.","order":3,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The patients were informed about future publications in the informed consent, and that the data\/results would be anonymized.","order":4,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"61"}}