{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:50:55Z","timestamp":1790776255935,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2019,2,19]],"date-time":"2019-02-19T00:00:00Z","timestamp":1550534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"German Federal Ministry of Education and Research"},{"name":"Kompetenzverbund Strahlenforschung","award":["FKZ 02NUK026"],"award-info":[{"award-number":["FKZ 02NUK026"]}]},{"name":"European Research Council Starting Independent Investigator","award":["260524"],"award-info":[{"award-number":["260524"]}]},{"name":"Proof of Concept Grants","award":["679345"],"award-info":[{"award-number":["679345"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>KRAS mutations of lung adenocarcinoma (LADC) are associated with smoking but little is known on other exposure-oncogene associations. Hypothesizing that different inciting agents may cause different driver mutations, we aimed to identify distinct molecular pathways to LADC, applying two entirely different approaches. First, we examined clinicopathologic features and genomic signatures of environmental exposures in the large LADC Campbell data set. Second, we designed a molecular mechanistic risk model of LADC (M3LADC) that links environmental exposure to incidence risk by mathematically emulating the disease process. This model was applied to incidence data of Japanese atom-bomb survivors which contains information on radiation and smoking exposure. Grouping the clinical data by driver mutations revealed two main distinct molecular pathways to LADC: one unique to transmembrane receptor-mutant patients that displayed robust signatures of radiation exposure and one shared between submembrane transducer-mutant patients and patients with no evident driver mutation that carried the signature of smoking. Consistently, best fit of the incidence data was achieved with a M3LADC with two pathways: in one LADC risk increased with radiation exposure and in the other with cigarette consumption. We conclude there are two main molecular pathways to LADC associated with different environmental exposures. Future molecular measurements in lung cancer tissue of atom-bomb survivors may allow to further test quantitatively the M3LADC-predicted link of radiation to transmembrane receptor mutations. Moreover, the developed molecular mechanistic model showed that for low doses, as relevant e.g. for medical imaging, smokers have the same radiation risk compared with never smokers.<\/jats:p>","DOI":"10.1093\/carcin\/bgz036","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T15:09:48Z","timestamp":1550502588000},"page":"1240-1250","source":"Crossref","is-referenced-by-count":27,"title":["Risk of lung adenocarcinoma from smoking and radiation arises in distinct molecular pathways"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6598-5352","authenticated-orcid":false,"given":"Noemi","family":"Castelletti","sequence":"first","affiliation":[{"name":"Institute of Radiation Medicine (IRM), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Bavaria, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Christian","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine (IRM), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Bavaria, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristoforo","family":"Simonetto","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine (IRM), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Bavaria, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoji","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Biostatistics Center, Kurume University, Asahi-machi, Kurume, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"K\u00fcchenhoff","sequence":"additional","affiliation":[{"name":"Department of Statistics, Ludwig-Maximilian University (LMU) Munich, Munich, Bavaria, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios T","family":"Stathopoulos","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine; University of Patras; Rio, Achaia, Greece"},{"name":"Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilian University (LMU) and Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,2,19]]},"reference":[{"key":"2019101711285768400_CIT0001","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1001\/jamaoncol.2016.5688","article-title":"Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 Cancer Groups, 1990 to 2015: a systematic analysis for the global burden of disease study","volume":"3","author":"Fitzmaurice","year":"2017","journal-title":"JAMA Oncol."},{"key":"2019101711285768400_CIT0002","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. 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