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  • 1.
    Bergqvist, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Christensen, H. Nordahl
    Wiklund, F.
    Bergström, S.
    Characteristics and Long-Term OS of Non-Small Cell Lung Cancer Patients Receiving EGFR Tyrosine Kinase Inhibitor Treatment2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S419-S419Article in journal (Other academic)
    Abstract [en]

    Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are important therapeutic agents in treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. However, long-term follow-up and knowledge of clinical factors and TKI treatment patterns, which may be associated with longer OS, remains unclear. Using nationwide registry data, the aim was to investigate survival, prognostic factors for OS, and first line TKI treatment pattern of stage IIIB/IV NSCLC patients in Sweden.

    Method: In this cohort study, data on all patients diagnosed with stage IIIB-IV NSCLC during 2010—2015 from the nationwide Cancer Registry of Sweden were linked with data on dispensed EGFR-TKI drugs, comorbidity, and mortality data from Swedish national health registries. OS was defined as the interval from date of diagnosis until date of death. Survival rates were estimated using the Kaplan-Meier method. Assessment of predictive factors for OS was performed in multivariable Cox regression.

    Result: Of 9,992 stage IIIB/IV NSCLC patients (mean age 70 years, female 49%), 1419 (14%) received first-line TKI treatment. Overall, 59% of TKI treated patients (median age 68 years) were female, 44% had at least one comorbidity, 85% had adenocarcinoma, and 89% were stage IV. Median follow-up time was 15 months and median OS was 16 months; 1- and 3-years survival rates were 62% and 15%, respectively. Predictors of longer OS were younger age at diagnosis, adenocarcinoma, less advanced clinical stage, and less comorbid disease. Furthermore, patients included in the end of the period had a longer OS compared to earlier. TKI treatment switching/re-challenging, as well as prolonged TKI treatment, also predicted longer OS.

    Conclusion: This is the first nationwide study on NSCLC patients receiving first-line EGFR TKIs in routine clinical practice in Sweden. In addition to the reported prolonged TKI treatment length and TKI switching/re-challenging during the observation period, improvements and extension of EGFR testing targeting the appropriate NSCLC patient population may further have contributed to the observed relatively long overall survival.

  • 2.
    Cheng, Chao
    et al.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Hong, Wei
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    Li, Yafang
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Xiao, Xiangjun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    McKay, James
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Han, Younghun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Byun, Jinyoung
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Peng, Bo
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Albanes, Demetrios
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Lam, Stephen
    Department of Integrative Oncology, University of British Columbia, BC, Vancouver, Canada.
    Tardon, Adonina
    Public Health Department, University of Oviedo, ISPA and CIBERESP, Asturias, Spain.
    Chen, Chu
    Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Landi, Maria T.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Risch, Angela
    Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
    Christiani, David C.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States.
    Rennert, Gad
    Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    University of Kentucky, Markey Cancer Center, Kentucky, Lexington, United States.
    Goodman, Gary
    Swedish Cancer Institute, WA, Seattle, United States.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Davies, Michael P.A.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Texas, Houston, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Texas, Houston, United States.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Liu, Geoffrey
    University Health Network- The Princess Margaret Cancer Centre, California, Toronto, United States.
    Hung, Rayjean J.
    Luenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
    Andrew, Angeline S.
    Department of Epidemiology, Dartmouth College, New Hampshire, Hanover, United States; Department of Community and Family Medicine, Dartmouth College, New Hampshire, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Zhu, Meng
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zienolddiny, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Cox, Angela
    Academic Unit of Clinical Oncology University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, PA, Pittsburgh, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Li, Yong
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlova, Olga
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlov, Ivan
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Mosaic chromosomal alterations are associated with increased lung cancer risk: insight from the INTEGRAL-ILCCO cohort analysis2023In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380Article in journal (Refereed)
    Abstract [en]

    Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.

  • 3.
    Gulyas, Miklos
    et al.
    Uppsala, Sweden.
    Mattsson, Johanna S. M.
    Uppsala, Sweden.
    Lindgren, Andrea
    Linkoping, Sweden.
    Sederholm, Christer
    Linkoping, Sweden.
    Ek, Lars
    Lund, Sweden.
    Lamberg, Kristina
    Uppsala, Sweden.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Holmberg, Erik
    Gothenburg, Sweden.
    Micke, Patrick
    Uppsala, Sweden.
    Bergman, Bengt
    Gothenburg, Sweden.
    COX-2 Expression Does Not Predict Outcome of Celecoxib in Addition to Standard Chemotherapy in Advanced Non-Small Cell Lung Cancer2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S541-S542Article in journal (Other academic)
  • 4. Hung, Rayjean J.
    et al.
    Spitz, Margaret R.
    Houlston, Richard S.
    Schwartz, Ann G.
    Field, John K.
    Ying, Jun
    Li, Yafang
    Han, Younghun
    Ji, Xuemei
    Chen, Wei
    Wu, Xifeng
    Gorlov, Ivan P.
    Na, Jie
    de Andrade, Mariza
    Liu, Geoffrey
    Brhane, Yonathan
    Diao, Nancy
    Wenzlaff, Angela
    Davies, Michael P. A.
    Liloglou, Triantafillos
    Timofeeva, Maria
    Muley, Thomas
    Rennert, Hedy
    Saliba, Walid
    Ryan, Brid M.
    Bowman, Elise
    Barros-Dios, Juan-Miguel
    Perez-Rios, Monica
    Morgenstern, Hal
    Zienolddiny, Shanbeh
    Skaug, Vidar
    Ugolini, Donatella
    Bonassi, Stefano
    van der Heijden, Erik H. F. M.
    Tardon, Adonina
    Bojesen, Stig E.
    Landi, Maria Teresa
    Johansson, Mattias
    Bickeboeller, Heike
    Arnold, Susanne
    Le Marchand, Loic
    Melander, Olle
    Andrew, Angeline
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Caporaso, Neil
    Teare, M. Dawn
    Schabath, Matthew B.
    Aldrich, Melinda C.
    Kiemeney, Lambertus A.
    Wichmann, H-Erich
    Lazarus, Philip
    Mayordomo, Jose
    Neri, Monica
    Haugen, Aage
    Zhang, Zuo-Feng
    Ruano-Ravina, Alberto
    Brenner, Hermann
    Harris, Curtis C.
    Orlow, Irene
    Rennert, Gadi
    Risch, Angela
    Brennan, Paul
    Christiani, David C.
    Amos, Christopher I.
    Yang, Ping
    Gorlova, Olga Y.
    Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region2019In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, no 8, p. 1360-1369Article in journal (Refereed)
    Abstract [en]

    Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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  • 5. Nyman, J.
    et al.
    Bergström, S.
    Björkestrand, H.
    Svärd, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ekman, S.
    Lundin, E.
    Holmberg, E.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Friesland, S.
    Hallqvist, A.
    Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S373-S373Article in journal (Other academic)
    Abstract [en]

    Background: Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

    Method: NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

    Result: A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

    Conclusion: Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

  • 6.
    Ramella, Sara
    et al.
    Operative Research Unit of Radiation Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Research Unit of Radiation Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy.
    Soda, Paolo
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Research Unit of Computer Systems and Bioinformatics, Department of Engineering, Università Campus Bio-Medico, Roma, Italy.
    Stage I stereotactic body radiation therapy outcome's prediction models: perfection is the enemy of utility2023In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 18, no 3, p. 262-264Article in journal (Other academic)
  • 7. Salomonsson, A.
    et al.
    Patthey, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Reuterswärd, C.
    Jönsson, M.
    Botling, J.
    Brunnström, H.
    Hussein, A.
    Monsef, N.
    Ortiz-Villalon, C.
    Bergman, B.
    De Petris, L.
    Lamberg, K.
    Vikström, A.
    Wagenius, G.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Brandén, E.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Koyi, H.
    Staaf, J.
    Planck, M.
    A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S431-S432Article in journal (Other academic)
    Abstract [en]

    Background: Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes.

    Method: Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients' medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4].

    Result: In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented.

    Conclusion: SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.

  • 8.
    Zhang, Ruyang
    et al.
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Massachusetts, Boston; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China.
    Shen, Sipeng
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Massachusetts, Boston; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
    Wei, Yongyue
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Massachusetts, Boston; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China.
    Zhu, Ying
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
    Li, Yi
    Department of Biostatistics, University of Michigan, MI, Ann Arbor, United States.
    Chen, Jiajin
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
    Guan, Jinxing
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
    Pan, Zoucheng
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
    Wang, Yuzhuo
    Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Zhu, Meng
    Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Xie, Junxing
    Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
    Xiao, Xiangjun
    The Institute for Clinical and Translational Research, Department of Medicine, Baylor College of Medicine, Texas, Houston.
    Zhu, Dakai
    The Institute for Clinical and Translational Research, Department of Medicine, Baylor College of Medicine, Texas, Houston.
    Li, Yafang
    The Institute for Clinical and Translational Research, Department of Medicine, Baylor College of Medicine, Texas, Houston.
    Albanes, Demetrios
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda.
    Landi, Maria Teresa
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda.
    Caporaso, Neil E.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda.
    Lam, Stephen
    Department of Medicine, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada.
    Tardon, Adonina
    Faculty of Medicine, University of Oviedo and CIBERESP, Oviedo, Spain.
    Chen, Chu
    Department of Epidemiology, University of Washington School of Public Health, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Risch, Angela
    Department of Biosciences and Cancer Cluster Salzburg, University of Salzburg, Salzburg, Austria.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Göttingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
    Rennert, Gadi
    Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Carmel, Israel.
    Arnold, Susanne
    Markey Cancer Center, University of Kentucky, Kentucky, Lexington.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    McKay, James D.
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Texas, Houston.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Liu, Geoffrey
    Princess Margaret Cancer Centre, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
    Andrew, Angeline S.
    Department of Epidemiology, Department of Community and Family Medicine, Dartmouth Geisel School of Medicine, New Hampshire, Hanover.
    Kiemeney, Lambertus A.
    Department for Health Evidence, Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands.
    Zienolddiny-Narui, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cox, Angela
    Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa.
    Aldrich, Melinda C.
    Department of Thoracic Surgery and Division of Epidemiology, Vanderbilt University Medical Center, TN, Nashville, United States.
    Dai, Juncheng
    Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Ma, Hongxia
    Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Zhao, Yang
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
    Hu, Zhibin
    China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Hung, Rayjean J.
    Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Dalla Lana School of Public Health, University of Toronto, ON, Toronto, Canada.
    Amos, Christopher I.
    The Institute for Clinical and Translational Research, Department of Medicine, Baylor College of Medicine, Texas, Houston.
    Shen, Hongbing
    China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Chen, Feng
    Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
    Christiani, David C.
    Department of Environmental Health, Harvard T. H. Chan School of Public Health, Massachusetts, Boston; Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Massachusetts, Boston.
    A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians2022In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 17, no 8, p. 974-990Article in journal (Refereed)
    Abstract [en]

    Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

    Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.

    Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10−13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10−13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10−13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10−13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10−4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification.

    Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

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