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4. Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.

Author

Byun, Jinyoung, Han, Younghun, Li, Yafang, Xia, Jun, Long, Erping, Choi, Jiyeon, Xiao, Xiangjun, Zhu, Meng, Zhou, Wen, Sun, Ryan, Bossé, Yohan, Song, Zhuoyi, Schwartz, Ann, Lusk, Christine, Rafnar, Thorunn, Stefansson, Kari, Zhang, Tongwu, Zhao, Wei, Pettit, Rowland W, Liu, Yanhong, Li, Xihao, Zhou, Hufeng, Walsh, Kyle M, Gorlov, Ivan, Gorlova, Olga, Zhu, Dakai, Rosenberg, Susan M, Pinney, Susan, Bailey-Wilson, Joan E, Mandal, Diptasri, de Andrade, Mariza, Gaba, Colette, Willey, James C, You, Ming, Anderson, Marshall, Wiencke, John K, Albanes, Demetrius, Lam, Stephan, Tardon, Adonina, Chen, Chu, Goodman, Gary, Bojeson, Stig, Brenner, Hermann, Landi, Maria Teresa, Chanock, Stephen J, Johansson, Mattias, Muley, Thomas, Risch, Angela, Wichmann, H-Erich, Bickeböller, Heike, Christiani, David C, Rennert, Gad, Arnold, Susanne, Field, John K, Shete, Sanjay, Le Marchand, Loic, Melander, Olle, Brunnstrom, Hans, Liu, Geoffrey, Andrew, Angeline S, Kiemeney, Lambertus A, Shen, Hongbing, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil, Cox, Angela, Hong, Yun-Chul, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B, Aldrich, Melinda C, Patel, Alpa, Lan, Qing, Rothman, Nathaniel, Taylor, Fiona, Kachuri, Linda, Witte, John S, Sakoda, Lori C, Spitz, Margaret, Brennan, Paul, Lin, Xihong, McKay, James, Hung, Rayjean J, and Amos, Christopher I

Subjects
Humans, Lung Neoplasms, Genetic Predisposition to Disease, RNA-Binding Proteins, DNA-Binding Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Human Genome, Cancer, Genetics, Lung, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Published
2022

7. Preliminary results from the EMoLung clinical study showing early lung cancer detection by the LC score

Author

Rubio, Karla, Müller, Jason M., Mehta, Aditi, Watermann, Iris, Olchers, Till, Koch, Ina, Wessels, Sabine, Schneider, Marc A., Araujo-Ramos, Tania, Singh, Indrabahadur, Kugler, Christian, Stoleriu, Mircea Gabriel, Kriegsmann, Mark, Eichhorn, Martin, Muley, Thomas, Merkel, Olivia M., Braun, Thomas, Ammerpohl, Ole, Reck, Martin, Tresch, Achim, and Barreto, Guillermo

Published
2023
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8. PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms

Author

Grass, Albert, Kasajima, Atsuko, Foersch, Sebastian, Kriegsmann, Mark, Brobeil, Alexander, Schmitt, Maxime, Wagner, Daniel, Poppinga, Jelte, Wiese, Dominik, Maurer, Elisabeth, Kirschbaum, Andreas, Muley, Thomas, Winter, Hauke, Rinke, Anja, Gress, Thomas M., Kremer, Markus, Evert, Matthias, Märkl, Bruno, Quaas, Alexander, Eckstein, Markus, Tschurtschenthaler, Markus, Klöppel, Günter, Denkert, Carsten, Bartsch, Detlef K., and Jesinghaus, Moritz

Published
2024
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10. Early Detection of Lung Cancer Using Small RNAs

Author

Sikosek, Tobias, Horos, Rastislav, Trudzinski, Franziska, Jehn, Julia, Frank, Maurice, Rajakumar, Timothy, Klotz, Laura V., Mercaldo, Nathaniel, Kahraman, Mustafa, Heuvelman, Marco, Taha, Yasser, Gerwing, Jennifer, Skottke, Jasmin, Daniel-Moreno, Alberto, Sanchez-Delgado, Marta, Bender, Sophie, Rudolf, Christina, Hinkfoth, Franziska, Tikk, Kaja, Schenz, Judith, Weigand, Markus A., Feindt, Peter, Schumann, Christian, Christopoulos, Petros, Winter, Hauke, Kreuter, Michael, Schneider, Marc A., Muley, Thomas, Walterspacher, Stephan, Schuler, Martin, Darwiche, Kaid, Taube, Christian, Hegedus, Balazs, Rabe, Klaus F., Rieger-Christ, Kimberly, Jacobsen, Francine L., Aigner, Clemens, Reck, Martin, Bankier, Alexander A., Sharma, Amita, and Steinkraus, Bruno R.

Published
2023
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11. High‐resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD

Author

Schwartz, Uwe, Llamazares Prada, Maria, Pohl, Stephanie T, Richter, Mandy, Tamas, Raluca, Schuler, Michael, Keller, Corinna, Mijosek, Vedrana, Muley, Thomas, Schneider, Marc A, Quast, Karsten, Hey, Joschka, Heußel, Claus P, Warth, Arne, Winter, Hauke, Serçin, Özdemirhan, Karmouty‐Quintana, Harry, Jyothula, Soma SK, Patel, Manish K, Herth, Felix, Koch, Ina, Petrosino, Giuseppe, Titimeaua, Alexandru, Mardin, Balca R, Weichenhan, Dieter, Jurkowski, Tomasz P, Imbusch, Charles D, Brors, Benedikt, Benes, Vladimir, Jung, Birgit, Wyatt, David, Stahl, Heiko F, Plass, Christoph, and Jurkowska, Renata Z

Published
2023
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12. Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

Author

Hung, Rayjean J, 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 PA, Liloglou, Triantafillos, Timofeeva, Maria, Muley, Thomas, Rennert, Hedy, Saliba, Walid, Ryan, Bríd M, Bowman, Elise, Barros-Dios, Juan-Miguel, Pérez-Ríos, Mónica, Morgenstern, Hal, Zienolddiny, Shanbeh, Skaug, Vidar, Ugolini, Donatella, Bonassi, Stefano, van der Heijden, Erik HFM, Tardon, Adonina, Bojesen, Stig E, Landi, Maria Teresa, Johansson, Mattias, Bickeböller, Heike, Arnold, Susanne, Le Marchand, Loic, Melander, Olle, Andrew, Angeline, Grankvist, Kjell, 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-Raviña, Alberto, Brenner, Hermann, Harris, Curtis C, Orlow, Irene, Rennert, Gadi, Risch, Angela, Brennan, Paul, Christiani, David C, Amos, Christopher I, Yang, Ping, and Gorlova, Olga Y

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Lung Cancer, Tobacco, Prevention, Cancer, Genetics, Clinical Research, Tobacco Smoke and Health, Lung, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Case-Control Studies, Chromosomes, Human, Pair 5, Europe, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Lung Neoplasms, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Telomerase, Lung cancer, Never smokers, Genome-wide association study, Genetic susceptibility, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

IntroductionInherited 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.MethodsWe 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.ResultsWe 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 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 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.ConclusionsWe 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.

Published
2019

14. Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Author

Rosenberger, Albert, Muttray, Nils, Hung, Rayjean J., Christiani, David C., Caporaso, Neil E., Liu, Geoffrey, Bojesen, Stig E., Le Marchand, Loic, Albanes, Demetrios, Aldrich, Melinda C., Tardon, Adonina, Fernández-Tardón, Guillermo, Rennert, Gad, Field, John K., Davies, Michael P. A., Liloglou, Triantafillos, Kiemeney, Lambertus A., Lazarus, Philip, Wendel, Bernadette, Haugen, Aage, Zienolddiny, Shanbeh, Lam, Stephen, Schabath, Matthew B., Andrew, Angeline S., Duell, Eric J., Arnold, Susanne M., Goodman, Gary E., Chen, Chu, Doherty, Jennifer A., Taylor, Fiona, Cox, Angela, Woll, Penella J., Risch, Angela, Muley, Thomas R., Johansson, Mikael, Brennan, Paul, Landi, Maria Teresa, Shete, Sanjay S., Amos, Christopher I., and Bickeböller, Heike

Published
2022
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15. A blood-based miRNA signature with prognostic value for overall survival in advanced stage non-small cell lung cancer treated with immunotherapy

Author

Rajakumar, Timothy, Horos, Rastislav, Jehn, Julia, Schenz, Judith, Muley, Thomas, Pelea, Oana, Hofmann, Sarah, Kittner, Paul, Kahraman, Mustafa, Heuvelman, Marco, Sikosek, Tobias, Feufel, Jennifer, Skottke, Jasmin, Nötzel, Dennis, Hinkfoth, Franziska, Tikk, Kaja, Daniel-Moreno, Alberto, Ceiler, Jessika, Mercaldo, Nathaniel, Uhle, Florian, Uhle, Sandra, Weigand, Markus A., Elshiaty, Mariam, Lusky, Fabienne, Schindler, Hannah, Ferry, Quentin, Sauka-Spengler, Tatjana, Wu, Qianxin, Rabe, Klaus F., Reck, Martin, Thomas, Michael, Christopoulos, Petros, and Steinkraus, Bruno R.

Published
2022
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18. Impact of T Cell Ratios on Survival in Pleural Mesothelioma: Insights from Tumor Microenvironment Analysis.

Author

Klotz, Laura V., Weigert, Andreas, Eichhorn, Florian, Allgäuer, Michael, Muley, Thomas, Shah, Rajiv, Savai, Rajkumar, Eichhorn, Martin E., and Winter, Hauke

Subjects
T cells, CELL physiology, PLEURAL tumors, TUMOR markers, IMMUNE system, FLUORESCENT antibody technique, MULTIVARIATE analysis, MESOTHELIOMA, STAINS & staining (Microscopy), T helper cells, OVERALL survival
Abstract

Simple Summary: Although immunotherapy is well established for treating pleural mesothelioma, it has not shown a breakthrough in improving the overall survival of these patients. A detailed study of the tumor microenvironment could lead to a better understanding of the factors that influence tumor growth to optimize treatment. In our cohort, T cell infiltrate differences were strongly associated with overall survival. Background: Immunotherapy has significantly improved overall survival in patients with pleural mesothelioma, yet this benefit does not extend to those with the epithelioid subtype. Tumor growth is believed to be influenced by the immune response. This study aimed to analyze the tumor microenvironment to gain a better understanding of its influence on tumor growth. Methods: The tumor immune cell infiltration of 188 patients with pleural mesothelioma was characterized by multiplex immunofluorescence staining for CD3+ cells (CD3+), CD4+ cells (CD3+/CD4+), CD8+ cells (CD3+/CD8+), Treg (CD3+/CD4+/CD8-/CD163-/Foxp3+), PD1 cells (PD1+), and T helper cells (CD3+/CD4+/CD8-/CD163-/FoxP3-). The distribution of specific immune cells was correlated with clinical parameters. Results: A total of 188 patients with pleural mesothelioma (135 epithelioid, 9 sarcomatoid, 44 biphasic subtypes) were analyzed. The median age was 64.8 years. Overall survival was significantly longer in the epithelioid subtype than in the non-epithelioid subtype (p = 0.016). The presence of PD-L1 expression had a negative effect on overall survival (p = 0.041). A high ratio of CD4+ cells to regulatory T cells was associated with a significantly longer overall survival of more than 12 months (p = 0.015). The ratio of CD4+ cells to regulatory T cells retained its significant effect on overall survival in the multivariate analysis. Conclusions: Distinct differences in the T cell immune infiltrates in mesothelioma are strongly associated with overall survival. The tumor microenvironment could therefore serve as a source of prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Germline Polymorphisms Associated with Overall Survival in Lung Adenocarcinoma: Genome-Wide Analysis.

Author

Minnai, Francesca, Noci, Sara, Esposito, Martina, Schneider, Marc A., Kobinger, Sonja, Eichhorn, Martin, Winter, Hauke, Hoffmann, Hans, Kriegsmann, Mark, Incarbone, Matteo A., Mattioni, Giovanni, Tosi, Davide, Muley, Thomas, Dragani, Tommaso A., and Colombo, Francesca

Subjects
ADENOCARCINOMA, RESEARCH funding, GENOME-wide association studies, MULTIVARIATE analysis, GENETIC polymorphisms, KAPLAN-Meier estimator, GENE expression profiling, CHROMOSOMES, LUNG cancer, OVERALL survival, SINGLE nucleotide polymorphisms, ALLELES
Abstract

Simple Summary: Our study aimed to understand why some people with lung adenocarcinoma, a type of lung cancer, survive longer than others, even when their conditions seem similar. By studying the DNA of 1464 patients, we found six specific genetic differences that appear to affect survival. These differences are located in parts of the DNA that do not directly make proteins but might control how certain genes are turned on or off. The goal is to use this information to predict which patients might have better outcomes and to develop more personalized treatment options. Further research is needed to confirm these results and to understand the underlying biological mechanisms, but our findings could eventually improve how we treat lung cancer and understand its outcomes better. Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK, with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Peripheral Inflammation Featuring Eosinophilia or Neutrophilia Is Associated with the Survival and Infiltration of Eosinophils within the Tumor among Various Histological Subgroups of Patients with NSCLC.

Author

Alashkar Alhamwe, Bilal, Yuskaeva, Kadriya, Wulf, Friederike, Trinkmann, Frederik, Kriegsmann, Mark, Thomas, Michael, Keber, Corinna Ulrike, Strandmann, Elke Pogge von, Herth, Felix J., Kolahian, Saeed, Renz, Harald, and Muley, Thomas

Subjects
NON-small-cell lung carcinoma, EOSINOPHILIA, OVERALL survival, SURVIVAL rate, MAST cells, C-reactive protein
Abstract

Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

Author

Budczies, Jan, Kirchner, Martina, Kluck, Klaus, Kazdal, Daniel, Glade, Julia, Allgäuer, Michael, Kriegsmann, Mark, Heußel, Claus-Peter, Herth, Felix J., Winter, Hauke, Meister, Michael, Muley, Thomas, Goldmann, Torsten, Fröhling, Stefan, Wermke, Martin, Waller, Cornelius F., Tufman, Amanda, Reck, Martin, Peters, Solange, Schirmacher, Peter, Thomas, Michael, Christopoulos, Petros, and Stenzinger, Albrecht

Published
2022
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23. SIAH3 is frequently epigenetically silenced in cancer and regulates mitochondrial metabolism.

Author

Deutschmeyer, Verena E., Schlaudraff, Nico A., Walesch, Sara K., Moyer, Janine, Sokol, Anna M., Graumann, Johannes, Meissner, Wolfgang, Schneider, Marc, Muley, Thomas, Helmbold, Peter, Schwinn, Markus, Richter, Antje M., Schmitz, M. Lienhard, and Dammann, Reinhard H.

Abstract

Of the seven in absentia homologue (SIAH) family, three members have been identified in the human genome. In contrast to the E3 ubiquitin ligase encoding SIAH1 and SIAH2, little is known on the regulation and function of SIAH3 in tumorigenesis. In this study, we reveal that SIAH3 is frequently epigenetically silenced in different cancer entities, including cutaneous melanoma, lung adenocarcinoma and head and neck cancer. Low SIAH3 levels correlate with an impaired survival of cancer patients. Additionally, induced expression of SIAH3 reduces cell proliferation and induces cell death. Functionally, SIAH3 negatively affects cellular metabolism by shifting cells form aerobic oxidative phosphorylation to glycolysis. SIAH3 is localized in the mitochondrion and interacts with proteins involved in mitochondrial ribosome biogenesis and translation. We also report that SIAH3 interacts with ubiquitin ligases, including SIAH1 or SIAH2, and is degraded by them. These results suggest that SIAH3 acts as an epigenetically controlled tumor suppressor by regulating cellular metabolism through the inhibition of oxidative phosphorylation. [ABSTRACT FROM AUTHOR]

Published
2025
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24. FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC

Author

Richtmann, Sarah, Wilkens, Dennis, Warth, Arne, Lasitschka, Felix, Winter, Hauke, Christopoulos, Petros, Herth, Felix J. F., Muley, Thomas, Meister, Michael, Schneider, Marc A., Richtmann, Sarah, Wilkens, Dennis, Warth, Arne, Lasitschka, Felix, Winter, Hauke, Christopoulos, Petros, Herth, Felix J. F., Muley, Thomas, Meister, Michael, and Schneider, Marc A.

Abstract

Although targeted therapy has improved the survival rates in the last decade, non-small-cell lung cancer (NSCLC) is still the most common cause of cancer-related death. The challenge of identifying new targets for further effective therapies still remains. The FAMily with sequence similarity 83 (FAM83) members have recently been described as novel oncogenes in numerous human cancer specimens and shown to be involved in epidermal growth factor receptor (EGFR) signaling. Here, gene expression of FAM83A and B was analyzed in a cohort of 362 NSCLC patients using qPCR. We further investigated relations in expression and their prognostic value. Functional assays in NSCLC cell lines were performed to evaluate FAM83A and B involvement in proliferation, anchorage-independent growth, migration, and the EGFR pathway. We observed a highly increased gene expression level of FAM83A (ø = 68-fold) and FAM83B (ø = 20-fold) which resulted in poor survival prognosis (p < 0.0001 and p = 0.002). Their expression was influenced by EGFR levels, pathway signaling, and mutation status. Both genes affected cell proliferation, and FAM83A depletion resulted in reduced migration and anchorage-independent growth. The results support the hypothesis that FAM83A and B have different functions in different histological subtypes of NSCLC and might be new therapeutic targets.

Published
2024

25. Genome-Wide DNA Methylation Profiling in Early Stage I Lung Adenocarcinoma Reveals Predictive Aberrant Methylation in the Promoter Region of the Long Noncoding RNA PLUT: An Exploratory Study

Author

Kim-Wanner, Soo-Zin, Assenov, Yassen, Nair, Mridul B., Weichenhan, Dieter, Benner, Axel, Becker, Natalia, Landwehr, Katharina, Kuner, Ruprecht, Sültmann, Holger, Esteller, Manel, Koch, Ina, Lindner, Michael, Meister, Michael, Thomas, Michael, Bieg, Matthias, Klingmüller, Ursula, Schlesner, Matthias, Warth, Arne, Brors, Benedikt, Seifried, Erhard, Bönig, Halvard, Plass, Christoph, Risch, Angela, and Muley, Thomas

Published
2020
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26. Programmed death-ligand 1 expression influenced by tissue sample size. Scoring based on tissue microarrays' and cross-validation with resections, in patients with, stage I–III, non-small cell lung carcinoma of the European Thoracic Oncology Platform Lungscape cohort

Author

Thunnissen, Erik, Kerr, Keith M., Dafni, Urania, Bubendorf, Lukas, Finn, Stephen P., Soltermann, Alex, Biernat, Wojciech, Cheney, Richard, Verbeken, Erik, Warth, Arne, Marchetti, Antonio, Speel, Ernst-Jan M., Pokharel, Saraswati, Quinn, Anne Marie, Monkhorst, Kim, Navarro, Atilio, Madsen, Line Bille, Tsourti, Zoi, Geiger, Thomas, Kammler, Roswitha, Peters, Solange, Stahel, Rolf A., Rosell, Rafael, Blackhall, Fiona, Molina, Miguel Angel, Weder, Walter, Finn, Stephen, Hiltbrunner, Anita, Marti, Nesa, Polydoropoulou, Varvara, Zygoura, Panagiota, Nicolson, Marianne, Stevenson, David A.J, Mathieson, William, Smit, Egbert, Radonic, Teodora, Rulle, Undine, Curioni, Alessandra, Gray, Steven G., Gately, Kathy, Barr, Martin, Meldgaard, Peter, Madsen, Line B., Savic, Spasenija, Lardinois, Didier, Nackaerts, Kristiaan, Dooms, Christophe, Wauters, Els, Van Der Borght, Sara, Wrona, Ania, Rzyman, Witold, Jassem, Jacek, Dienemann, Hendrik, Muley, Thomas, De Luca, Graziano, di Lorito, Alessia, Dingemans, Anne-Marie, Ruland, Andrea, Ferenczy, Philip, Franklin, Lynsey, Baas, Paul, van de Wiel, Bart, Camps, Carlos, and Martorell, Miguel

Published
2020
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28. Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples

Author

Kriegsmann, Katharina, Zgorzelski, Christiane, Muley, Thomas, Christopoulos, Petros, Thomas, Michael, Winter, Hauke, Eichhorn, Martin, Eichhorn, Florian, von Winterfeld, Moritz, Herpel, Esther, Goeppert, Benjamin, Stenzinger, Albrecht, Herth, Felix J. F., Warth, Arne, and Kriegsmann, Mark

Published
2021
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29. Comprehensive genomic profiles of small cell lung cancer

Author

George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretić, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernández-Cuesta, Lynnette, Bosco, Graziella, Müller, Christian, Dahmen, Ilona, Jahchan, Nadine S, Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N, Vaka, Dedeepya, Torres, Angela, Wang, Maia Segura, Korbel, Jan O, Menon, Roopika, Chun, Sung-Min, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Pützer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmüller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A, Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P, Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M, Russell, Prudence A, Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A, la Torre, Annamaria, Field, John K, Jakopovic, Marko, Knezevic, Jelena, Castaños-Vélez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Köhler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B, Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M, Zander, Thomas, Ansén, Sascha, Hallek, Michael, Wolf, Jürgen, Vingron, Martin, Yatabe, Yasushi, Travis, William D, Nürnberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Büttner, Reinhard, Haas, Stefan A, Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, and Thomas, Roman K

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Rare Diseases, Lung, Lung Cancer, Aetiology, 2.1 Biological and endogenous factors, Alleles, Animals, Cell Line, Tumor, Chromosome Breakpoints, Cyclin D1, DNA-Binding Proteins, Disease Models, Animal, Female, Gene Expression Profiling, Genome, Human, Genomics, Humans, Lung Neoplasms, Male, Mice, Mutation, Neurosecretory Systems, Nuclear Proteins, Receptors, Notch, Retinoblastoma Protein, Signal Transduction, Small Cell Lung Carcinoma, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, General Science & Technology
Abstract

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

Published
2015

30. Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts

Author

Kazdal, Daniel, Endris, Volker, Allgäuer, Michael, Kriegsmann, Mark, Leichsenring, Jonas, Volckmar, Anna-Lena, Harms, Alexander, Kirchner, Martina, Kriegsmann, Katharina, Neumann, Olaf, Brandt, Regine, Talla, Suranand B., Rempel, Eugen, Ploeger, Carolin, von Winterfeld, Moritz, Christopoulos, Petros, Merino, Diana M., Stewart, Mark, Allen, Jeff, Bischoff, Helge, Meister, Michael, Muley, Thomas, Herth, Felix, Penzel, Roland, Warth, Arne, Winter, Hauke, Fröhling, Stefan, Peters, Solange, Swanton, Charles, Thomas, Michael, Schirmacher, Peter, Budczies, Jan, and Stenzinger, Albrecht

Published
2019
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32. Procedure-Specific Risk Prediction for Recurrence in Patients Undergoing Lobectomy or Sublobar Resection for Small (≤2 cm) Lung Adenocarcinoma: An International Cohort Analysis

Author

Bains, Sarina, Eguchi, Takashi, Warth, Arne, Yeh, Yi-Chen, Nitadori, Jun-ichi, Woo, Kaitlin M., Chou, Teh-Ying, Dienemann, Hendrik, Muley, Thomas, Nakajima, Jun, Shinozaki-Ushiku, Aya, Wu, Yu-Chung, Lu, Shaohua, Kadota, Kyuichi, Jones, David R., Travis, William D., Tan, Kay See, and Adusumilli, Prasad S.

Published
2019
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35. CYFRA 21-1, CA 125 and CEA provide additional prognostic value in NSCLC patients with stable disease at first CT scan

Author

Muley, Thomas, primary, Schneider, Mark A., additional, Meister, Michael, additional, Thomas, Michael, additional, Heußel, Claus Peter, additional, Kriegsmann, Mark, additional, Holdenrieder, Stefan, additional, Wehnl, Birgit, additional, Rolny, Vinzent, additional, Mang, Anika, additional, Gerber, Rebecca, additional, and Herth, Felix, additional

Published
2023
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37. Evaluation of NGS and RT-PCR Methods for ALK Rearrangement in European NSCLC Patients: Results from the European Thoracic Oncology Platform Lungscape Project

Author

Stahel, Rolf A., Rosell, Rafael, Blackhall, Fiona, Dafni, Urania, Kerr, Keith M., Molina, Miguel Ángel, Bubendorf, Lukas, Weder, Walter, Thunnissen, Erik, Peters, Solange, Finn, Stephen, Hiltbrunner, Anita, Kammler, Roswitha, Geiger, Thomas, Marti, Nesa, Tsourti, Zoi, Polydoropoulou, Varvara, Zygoura, Panagiota, Smyth, Paul, O’Brien, Cathal, Gray, Steven, Soltermann, Alex, Opitz, Isabelle, Curioni, Alessandra, Savic, Spasenija, Lardinois, Didier, Dingemans, Anne-Marie, Speel, Ernst-Jan M., Ruland, Andrea, Marchetti, Antonio, Di Lorito, Alessia, De Luca, Graziano, Malatesta, Sara, Nonaka, Daisuke, Quinn, Anne Marie, Franklin, Lynsey, Biernat, Wojciech, Wrona, Ania, Rzyman, Witold, Jassem, Jacek, Meldgaard, Peter, Hager, Henrik, Madsen, Line B., Camps, Carlos, Martorell, Miguel, Jantus-Lewintre, Eloisa, Guijarro, Ricardo, Nicolson, Marianne, Stevenson, David A.J., Mathieson, William, Baas, Paul, de Jong, Jeroen, Monkhorst, Kim, Smit, Egbert, van Setten, Coralien, de Langen, Joop, Felip, Enriqueta, Hernandez-Losa, Javier, Sansano, Irene, Cheney, Richard, Pine, Mary Beth, Reid, Mary, Taylor, Elizabeth, Nackaerts, Kristiaan, Dooms, Christophe, Wauters, Els, Van Der Borght, Sara, Dienemann, Hendrik, Muley, Thomas, Warth, Arne, Letovanec, Igor, Speel, Ernst-Jan, Sejda, Aleksandra, Verbeken, Eric, Navarro, Atilio, Dziadziuszko, Rafal, Vansteenkiste, Johan, O'Brien, Cathal, Sherlock, Jon, Schageman, Jeoffrey, Kerr, Keith, and Stahel, Rolf

Published
2018
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38. Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Author

Brenner, Darren R, Brennan, Paul, Boffetta, Paolo, Amos, Christopher I, Spitz, Margaret R, Chen, Chu, Goodman, Gary, Heinrich, Joachim, Bickeböller, Heike, Rosenberger, Albert, Risch, Angela, Muley, Thomas, McLaughlin, John R, Benhamou, Simone, Bouchardy, Christine, Lewinger, Juan Pablo, Witte, John S, Chen, Gary, Bull, Shelley, and Hung, Rayjean J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Prevention, Lung Cancer, Human Genome, Lung, Cancer, Aetiology, 2.1 Biological and endogenous factors, Alleles, Canada, Case-Control Studies, Europe, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Inflammation, Likelihood Functions, Lung Neoplasms, Male, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide, Risk, United States, White People, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8p21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.

Published
2013

41. MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically

Author

Munkhbaatar, Enkhtsetseg, Dietzen, Michelle, Agrawal, Deepti, Anton, Martina, Jesinghaus, Moritz, Boxberg, Melanie, Pfarr, Nicole, Bidola, Pidassa, Uhrig, Sebastian, Höckendorf, Ulrike, Meinhardt, Anna-Lena, Wahida, Adam, Heid, Irina, Braren, Rickmer, Mishra, Ritu, Warth, Arne, Muley, Thomas, Poh, Patrina S. P., Wang, Xin, Fröhling, Stefan, Steiger, Katja, Slotta-Huspenina, Julia, van Griensven, Martijn, Pfeiffer, Franz, Lange, Sebastian, Rad, Roland, Spella, Magda, Stathopoulos, Georgios T., Ruland, Jürgen, Bassermann, Florian, Weichert, Wilko, Strasser, Andreas, Branca, Caterina, Heikenwalder, Mathias, Swanton, Charles, McGranahan, Nicholas, and Jost, Philipp J.

Published
2020
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44. Protein-altering germline mutations implicate novel genes related to lung cancer development

Author

Ji, Xuemei, Mukherjee, Semanti, Landi, Maria Teresa, Bosse, Yohan, Joubert, Philippe, Zhu, Dakai, Gorlov, Ivan, Xiao, Xiangjun, Han, Younghun, Gorlova, Olga, Hung, Rayjean J., Brhane, Yonathan, Carreras-Torres, Robert, Christiani, David C., Caporaso, Neil, Johansson, Mattias, Liu, Geoffrey, Bojesen, Stig E., Le Marchand, Loic, Albanes, Demetrios, Bickeböller, Heike, Aldrich, Melinda C., Bush, William S., Tardon, Adonina, Rennert, Gad, Chen, Chu, Byun, Jinyoung, Dragnev, Konstantin H., Field, John K., Kiemeney, Lambertus FA., Lazarus, Philip, Zienolddiny, Shan, Lam, Stephen, Schabath, Matthew B., Andrew, Angeline S., Bertazzi, Pier A., Pesatori, Angela C., Diao, Nancy, Su, Li, Song, Lei, Zhang, Ruyang, Leighl, Natasha, Johansen, Jakob S., Mellemgaard, Anders, Saliba, Walid, Haiman, Christopher, Wilkens, Lynne, Fernandez-Somoano, Ana, Fernandez-Tardon, Guillermo, Heijden, Erik H. F. M. van der, Kim, Jin Hee, Davies, Michael P. A., Marcus, Michael W., Brunnström, Hans, Manjer, Jonas, Melander, Olle, Muller, David C., Overvad, Kim, Trichopoulou, Antonia, Tumino, Rosario, Goodman, Gary E., Cox, Angela, Taylor, Fiona, Woll, Penella, Wichmann, Erich, Muley, Thomas, Risch, Angela, Rosenberger, Albert, Grankvist, Kjell, Johansson, Mikael, Shepherd, Frances, Tsao, Ming-Sound, Arnold, Susanne M., Haura, Eric B., Bolca, Ciprian, Holcatova, Ivana, Janout, Vladimir, Kontic, Milica, Lissowska, Jolanta, Mukeria, Anush, Ognjanovic, Simona, Orlowski, Tadeusz M., Scelo, Ghislaine, Swiatkowska, Beata, Zaridze, David, Bakke, Per, Skaug, Vidar, Butler, Lesley M., Offit, Kenneth, Srinivasan, Preethi, Bandlamudi, Chaitanya, Hellmann, Matthew D., Solit, David B., Robson, Mark E., Rudin, Charles M., Stadler, Zsofia K., Taylor, Barry S., Berger, Michael F., Houlston, Richard, McLaughlin, John, Stevens, Victoria, Nickle, David C., Obeidat, Ma’en, Timens, Wim, Artigas, María Soler, Shete, Sanjay, Brenner, Hermann, Chanock, Stephen, Brennan, Paul, McKay, James D., and Amos, Christopher I.

Published
2020
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46. Prognostic value of tumor markers ProGRP, NSE and CYFRA 21-1 in patients with small cell lung cancer and chemotherapy-induced remission.

Author

Muley, Thomas, Herth, Felix J., Heussel, Claus Peter, Kriegsmann, Mark, Thomas, Michael, Meister, Michael, Schneider, Marc A., Wehnl, Birgit, Mang, Anika, and Holdenrieder, Stefan

Subjects
SMALL cell lung cancer, PROGNOSIS, TUMOR markers, CANCER remission, OVERALL survival
Abstract

BACKGROUND: Despite successful response to first line therapy, patients with small-cell lung cancer (SCLC) often suffer from early relapses and disease progression. OBJECTIVE: To investigate the relevance of serum tumor markers for estimation of prognosis at several time points during the course of disease. METHODS: In a prospective, single-center study, serial assessments of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1) and carcino-embryogenic antigen (CEA) were performed during and after chemotherapy in 232 SCLC patients, and correlated with therapy response and overall survival (OS). RESULTS: ProGRP, NSE and CYFRA 21-1 levels decreased quickly after the first chemotherapy cycle and correlated well with the radiological response. Either as single markers or in combination they provided valuable prognostic information regarding OS at all timepoints investigated: prior to first-line therapy, after two treatment cycles in patients with successful response to first-line therapy, and prior to the start of second-line therapy. Furthermore, they were useful for continuous monitoring during and after therapy and often indicated progressive disease several months ahead of radiological changes. CONCLUSIONS: The results indicate the great potential of ProGRP, NSE and CYFRA 21-1 for estimating prognosis and monitoring of SCLC patients throughout the course of the disease. [ABSTRACT FROM AUTHOR]

Published
2024
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47. CYFRA 21-1, CA 125 and CEA provide additional prognostic value in NSCLC patients with stable disease at first CT scan.

Author

Muley, Thomas, Schneider, Mark A., Meister, Michael, Thomas, Michael, Heußel, Claus Peter, Kriegsmann, Mark, Holdenrieder, Stefan, Wehnl, Birgit, Rolny, Vinzent, Mang, Anika, Gerber, Rebecca, and Herth, Felix

Subjects
COMPUTED tomography, PROGNOSIS, NON-small-cell lung carcinoma, IMMUNE checkpoint inhibitors, PROTEIN-tyrosine kinase inhibitors
Abstract

BACKGROUND: Serum tumor markers (STM) may complement imaging and provide additional clinical information for patients with non-small cell lung cancer (NSCLC). OBJECTIVE: To determine whether STMs can predict outcomes in patients with stable disease (SD) after initial treatment. METHODS: This single-center, prospective, observational trial enrolled 395 patients with stage III/IV treatment-naïve NSCLC; of which 263 patients were included in this analysis. Computed Tomography (CT) scans were performed and STMs measured before and after initial treatment (two cycles of chemotherapy and/or an immune checkpoint inhibitor or tyrosine kinase inhibitor); analyses were based on CT and STM measurements obtained at first CT performed after cycle 2 only PFS and OS were analyzed by Kaplan-Meier curves and Cox-proportional hazard models. RESULTS: When patients with SD (n = 100) were split into high- and low-risk groups based on CYFRA 21-1, CEA and CA 125 measurements using an optimized cut-off, a 4-fold increase risk of progression or death was estimated for high- vs low-risk SD patients (PFS, HR 4.17; OS, 3.99; both p < 0.0001). Outcomes were similar between patients with high-risk SD or progressive disease (n = 35) (OS, HR 1.17) and between patients with low-risk SD or partial response (n = 128) (PFS, HR 0.98; OS, 1.14). CONCLUSIONS: STMs can provide further guidance in patients with indeterminate CT responses by separating them into high- and low-risk groups for future PFS and OS events. [ABSTRACT FROM AUTHOR]

Published
2024
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50. Preanalytics in Lung Cancer

Author

Warth, Arne, Muley, Thomas, Meister, Michael, Weichert, Wilko, Schlag, Peter M., Series editor, Senn, Hans-Jörg, Series editor, Dietel, Manfred, editor, Wittekind, Christian, editor, Bussolati, Gianni, editor, and von Winterfeld, Moritz, editor

Published
2015
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