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2. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

Author

Egon Urgard, Tõnu Vooder, Urmo Võsa, Kristjan Välk, Mingming Liu, Cheng Luo, Fabian Hoti, Retlav Roosipuu, Tarmo Annilo, Jukka Laine, Christopher M. Frenz, Liqing Zhang, and Andres Metspalu

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2011

3. Gene Expression-Based Approaches in Differentiation of Metastases and Second Primary Tumour

Author

Tõnu Vooder, Kristjan Välk, Raivo Kolde, Retlav Roosipuu, Jaak Vilo, and Andres Metspalu

Subjects
Local recurrence, Non-small cell lung cancer, NSCLC, Metastasis, Gene expression profile, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

A 64-year-old male patient was diagnosed with 3 consecutive non-small cell lung carcinomas (NSCLC). In the current study, we applied whole-genome gene expression analysis to control, primary and locally recurrent cancer, and supposed metastasis samples of a single patient. According to our knowledge, there are no published papers describing the gene expression profiles of a single patient’s squamous cell lung cancers. As the histology and differentiation grade of the primary cancer and the supposed metastasis differed minimally, but local recurrence was poorly differentiated, molecular profiling of the samples was carried out in order to confirm or reject the hypothesis of second primary cancer. Principal component analysis of the gene expression data revealed distinction of the local recurrence. Gene ontology analysis showed no molecular characteristics of metastasis in the supposed metastasis. Gene expression analysis is valuable and can be supportive in decision-making of diagnostically complicated cancer cases.

Published
2010
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4. Methylation markers of early-stage non-small cell lung cancer.

Author

Kaie Lokk, Tõnu Vooder, Raivo Kolde, Kristjan Välk, Urmo Võsa, Retlav Roosipuu, Lili Milani, Krista Fischer, Marina Koltsina, Egon Urgard, Tarmo Annilo, Andres Metspalu, and Neeme Tõnisson

Subjects
Medicine, Science
Abstract

Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers.We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis.We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups.We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility.

Published
2012
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5. Correction: A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium.

Author

James D. McKay, Therese Truong, Valerie Gaborieau, Amelie Chabrier, Shu-Chun Chuang, Graham Byrnes, David Zaridze, Oxana Shangina, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Alexandru Bucur, Vladimir Bencko, Ivana Holcatova, Vladimir Janout, Lenka Foretova, Pagona Lagiou, Dimitrios Trichopoulos, Simone Benhamou, Christine Bouchardy, Wolfgang Ahrens, Franco Merletti, Lorenzo Richiardi, Renato Talamini, Luigi Barzan, Kristina Kjaerheim, Gary J. Macfarlane, Tatiana V. Macfarlane, Lorenzo Simonato, Cristina Canova, Antonio Agudo, Xavier Castellsagué, Ray Lowry, David I. Conway, Patricia A. McKinney, Claire M. Healy, Mary E. Toner, Ariana Znaor, Maria Paula Curado, Sergio Koifman, Ana Menezes, Victor Wünsch-Filho, José Eluf Neto, Leticia Fernández Garrote, Stefania Boccia, Gabriella Cadoni, Dario Arzani, Andrew F. Olshan, Mark C. Weissler, William K. Funkhouser, Jingchun Luo, Jan Lubiński, Joanna Trubicka, Marcin Lener, Dorota Oszutowska, Stephen M. Schwartz, Chu Chen, Sherianne Fish, David R. Doody, Joshua E. Muscat, Philip Lazarus, Carla J. Gallagher, Shen-Chih Chang, Zuo-Feng Zhang, Qingyi Wei, Erich M. Sturgis, Li-E Wang, Silvia Franceschi, Rolando Herrero, Karl T. Kelsey, Michael D. McClean, Carmen J. Marsit, Heather H. Nelson, Marjorie Romkes, Shama Buch, Tomoko Nukui, Shilong Zhong, Martin Lacko, Johannes J. Manni, Wilbert H. M. Peters, Rayjean J. Hung, John McLaughlin, Lars Vatten, Inger Njølstad, Gary E. Goodman, John K. Field, Triantafillos Liloglou, Paolo Vineis, Francoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Carlos A. González, J. Ramón Quirós, Carmen Martínez, Carmen Navarro, Eva Ardanaz, Nerea Larrañaga, Kay-Tee Khaw, Timothy Key, H. Bas Bueno-de-Mesquita, Petra H. M. Peeters, Antonia Trichopoulou, Jakob Linseisen, Heiner Boeing, Göran Hallmans, Kim Overvad, Anne Tjønneland, Merethe Kumle, Elio Riboli, Kristjan Välk, Tõnu Voodern, Andres Metspalu, Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Hélène Blanché, Ivo G. Gut, Pilar Galan, Simon Heath, Mia Hashibe, Richard B. Hayes, Paolo Boffetta, Mark Lathrop, and Paul Brennan

Subjects
Genetics, QH426-470
Published
2011
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6. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

Author

James D McKay, Therese Truong, Valerie Gaborieau, Amelie Chabrier, Shu-Chun Chuang, Graham Byrnes, David Zaridze, Oxana Shangina, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Alexandru Bucur, Vladimir Bencko, Ivana Holcatova, Vladimir Janout, Lenka Foretova, Pagona Lagiou, Dimitrios Trichopoulos, Simone Benhamou, Christine Bouchardy, Wolfgang Ahrens, Franco Merletti, Lorenzo Richiardi, Renato Talamini, Luigi Barzan, Kristina Kjaerheim, Gary J Macfarlane, Tatiana V Macfarlane, Lorenzo Simonato, Cristina Canova, Antonio Agudo, Xavier Castellsagué, Ray Lowry, David I Conway, Patricia A McKinney, Claire M Healy, Mary E Toner, Ariana Znaor, Maria Paula Curado, Sergio Koifman, Ana Menezes, Victor Wünsch-Filho, José Eluf Neto, Leticia Fernández Garrote, Stefania Boccia, Gabriella Cadoni, Dario Arzani, Andrew F Olshan, Mark C Weissler, William K Funkhouser, Jingchun Luo, Jan Lubiński, Joanna Trubicka, Marcin Lener, Dorota Oszutowska, Stephen M Schwartz, Chu Chen, Sherianne Fish, David R Doody, Joshua E Muscat, Philip Lazarus, Carla J Gallagher, Shen-Chih Chang, Zuo-Feng Zhang, Qingyi Wei, Erich M Sturgis, Li-E Wang, Silvia Franceschi, Rolando Herrero, Karl T Kelsey, Michael D McClean, Carmen J Marsit, Heather H Nelson, Marjorie Romkes, Shama Buch, Tomoko Nukui, Shilong Zhong, Martin Lacko, Johannes J Manni, Wilbert H M Peters, Rayjean J Hung, John McLaughlin, Lars Vatten, Inger Njølstad, Gary E Goodman, John K Field, Triantafillos Liloglou, Paolo Vineis, Francoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Carlos A González, J Ramón Quirós, Carmen Martínez, Carmen Navarro, Eva Ardanaz, Nerea Larrañaga, Kay-Tee Khaw, Timothy Key, H Bas Bueno-de-Mesquita, Petra H M Peeters, Antonia Trichopoulou, Jakob Linseisen, Heiner Boeing, Göran Hallmans, Kim Overvad, Anne Tjønneland, Merethe Kumle, Elio Riboli, Kristjan Välk, Tõnu Vooder, Andres Metspalu, Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Hélène Blanché, Ivo G Gut, Pilar Galan, Simon Heath, Mia Hashibe, Richard B Hayes, Paolo Boffetta, Mark Lathrop, and Paul Brennan

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Published
2011
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7. Lentiviral HSV-Tk. 007- mediated suicide gene therapy is not toxic for normal brain cells

Author

Kristjan Välk, Lars A. Rømo Ystaas, Boris Fehse, Hrvoje Miletic, Kristoffer Riecken, Jubayer A Hossain, Janne Grønli, Rolf Bjerkvig, and Jelena Mrdalj

Subjects
0301 basic medicine, Ganciclovir, business.industry, viruses, Mutant, Brain tumor, Prodrug, Pharmacology, Suicide gene, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Apoptosis, 030220 oncology & carcinogenesis, Glioma, Drug Discovery, Genetics, medicine, Molecular Medicine, business, Molecular Biology, Gene, Genetics (clinical), medicine.drug
Abstract

Introduction Gene therapeutic strategies with suicide genes are currently investigated in clinical trials for brain tumors. Previously we have shown that lentiviral vectors delivering the suicide gene HSV-Tk to experimental brain tumors promote a highly significant treatment effect and are thus promising vectors for clinical translation. Aims Here, we tested lentiviral vectors delivering the suicide gene HSV-Tk.007, a highly active mutant of HSV-Tk, to rat brains as a preclinical toxicity study. We injected 106 VSV-G pseudotyped functional lentiviral particles harboring the suicide gene HSV-Tk.007 into the brain of healthy, immunocompetent rats. During prodrug treatment with Ganciclovir (GCV), we measured weight and assessed the behavior of the rats in an open field test. After 14 days of GCV treatment, we analyzed HSV-Tk.007 expression in different brain cell populations as well as inflammatory responses and apoptosis. Results During prodrug treatment with Ganciclovir, behavior experiments did not reveal differences between treated rats and the control groups. Analysis of HSV-Tk expression in different brain cell populations showed that transduced normal brain cells survived Ganciclovir treatment. There were no statistically significant differences in the number of transduced cells between treatment and control groups. Furthermore, inflammatory responses and apoptosis of brain cells were not observed. Conclusion Here we show that HSV-Tk.007 mediated suicide gene therapy is not toxic to normal brain cells. This observation is of high relevance for translation of lentivirus-mediated suicide gene therapies into the clinic to treat brain tumor patients.

Published
2016

8. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

Author

Neonilia Szeszenia-Dabrowska, Olaide Y. Raji, John R. Gosney, Margaret R. Spitz, Darren R. Brenner, James McKay, Inger Njølstad, Kari Stefansson, Rayjean J. Hung, Chu Chen, H.-Erich Wichmann, Juncheng Dai, Christopher I. Amos, Dakai Zhu, John K. Field, Yufei Wang, Thomas Muley, Hans E. Krokan, Gary E. Goodman, Vladimir Bencko, Mari Nelis, Vladimir Janout, Mala Pande, Valerie Gaborieau, Tõnu Vooder, Frank Skorpen, Hongbing Shen, Michael J. Thun, Kristjan Välk, Peter Rudnai, Albert Rosenberger, Heike Bickeböller, T. Eisen, Jolanta Lissowska, John R. McLaughlin, Steven A. Narod, Thorunn Rafnar, David C. Christiani, Maiken Elvestad Gabrielsen, Demetrius Albanes, Maria Teresa Landi, Lenka Foretova, Ying Chen, Triantafillos Liloglou, Hendrik Dienemann, Paul Brennan, Richard S. Houlston, Angela Risch, Yang Zhao, Wei Chen, Andres Metspalu, David Zaridze, Maria Timofeeva, Xifeng Wu, Younghun Han, Gudmar Thorleifsson, Simone Benhamou, Eleonora Fabianova, Neil E. Caporaso, Lars J. Vatten, Mark Lathrop, and Dana Mates

Subjects
Asian Continental Ancestry Group, Risk, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Lung Neoplasms, European Continental Ancestry Group, Genome-wide association study, Single-nucleotide polymorphism, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Asian People, CDKN2A, Genetic variation, Genetics, medicine, Genetic predisposition, Humans, Lung cancer, Molecular Biology, CHEK2, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Association Studies Articles, Genetic Variation, General Medicine, medicine.disease, 3. Good health, genetic variation, lung cancer risk, 030220 oncology & carcinogenesis, Case-Control Studies, Genome-Wide Association Study
Abstract

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer. peerReviewed

Published
2017

9. Lentiviral HSV-Tk.007-mediated suicide gene therapy is not toxic for normal brain cells

Author

Jubayer A, Hossain, Lars Rømo, Ystaas, Jelena, Mrdalj, Kristjan, Välk, Kristoffer, Riecken, Boris, Fehse, Rolf, Bjerkvig, Janne, Grønli, and Hrvoje, Miletic

Subjects
Microscopy, Confocal, Lentivirus, Genes, Transgenic, Suicide, Brain, Apoptosis, Genetic Therapy, Motor Activity, Antiviral Agents, Thymidine Kinase, Rats, Cell Line, Tumor, Mutation, Animals, Humans, Simplexvirus, Ganciclovir
Abstract

Gene therapeutic strategies with suicide genes are currently investigated in clinical trials for brain tumors. Previously, we have shown that lentiviral vectors delivering the suicide gene HSV-Tk to experimental brain tumors promote a highly significant treatment effect and thus are promising vectors for clinical translation.In the present study, we tested lentiviral vectors delivering the suicide gene HSV-Tk.007, a highly active mutant of HSV-Tk, to rat brains as a preclinical toxicity study. We injected 10(6) vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped functional lentiviral particles harboring the suicide gene HSV-Tk.007 into the brain of healthy, immunocompetent rats. During prodrug treatment with ganciclovir (GCV), we measured weight and assessed the behavior of the rats in an open field test. After 14 days of GCV treatment, we analyzed HSV-Tk.007 expression in different brain cell populations, as well as inflammatory responses and apoptosis.During prodrug treatment with GCV, behavior experiments did not reveal differences between the treated rats and the control groups. Analysis of HSV-Tk expression in different brain cell populations showed that transduced normal brain cells survived GCV treatment. There were no statistically significant differences in the number of transduced cells between treatment and control groups. Furthermore, inflammatory responses and apoptosis of brain cells were not observed.We show that HSV-Tk.007-mediated suicide gene therapy is not toxic to normal brain cells. This observation is of high relevance for the translation of lentivirus-mediated suicide gene therapies into the clinic for the treatment of brain tumor patients. Copyright © 2016 John WileySons, Ltd.

Published
2016

10. Lung cancer and DNA repair genes: multilevel association analysis from the International Lung Cancer Consortium

Author

Alain Sarasin, Endre Anderssen, Valerie Gaborieau, Simone Benhamou, Andres Metspalu, Maiken Bratt Elvestad, John R. McLaughlin, Mark Lathrop, Hans E. Krokan, Marie-Claude Babron, Kristjan Välk, Tõnu Vooder, Rayjean J. Hung, Rémi Kazma, Emmanuelle Génin, John K. Field, Frank Skorpen, and Paul Brennan

Subjects
Adult, Male, Cancer Research, Lung Neoplasms, DNA Repair, DNA polymerase, DNA repair, Adenocarcinoma of Lung, Cell Cycle Proteins, Single-nucleotide polymorphism, Genome-wide association study, Adenocarcinoma, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Cancer Biomarkers and Molecular Epidemiology, 030304 developmental biology, Genetics, 0303 health sciences, biology, Smoking, Cancer, General Medicine, Middle Aged, medicine.disease, 3. Good health, Chromatin, Case-Control Studies, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, biology.protein, Female, Homologous recombination, Genome-Wide Association Study, Signal Transduction
Abstract

Lung cancer (LC) is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity and polymorphisms in DNA repair genes may contribute to susceptibility to LC. To explore the role of DNA repair genes in LC, we conducted a multilevel association study with 1655 single nucleotide polymorphisms (SNPs) in 211 DNA repair genes using 6911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5) and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 (0.84-1.30) for adenocarcinomas, 1.52 (1.28-1.80) for squamous cell carcinomas and 1.31 (1.09-1.57) for other histologies (heterogeneity test: P = 9.1 × 10(-)(3)). Gene-based association analysis identifies three repair genes associated with LC (P < 0.01): UBE2N, structural maintenance of chromosomes 1L2 and POLB. Two additional genes (RAD52 and POLN) are borderline significant. Pathway-based association analysis identifies five repair pathways associated with LC (P < 0.01): chromatin structure, DNA polymerases, homologous recombination, genes involved in human diseases with sensitivity to DNA-damaging agents and Rad6 pathway and ubiquitination. This first international pooled analysis of a large dataset unravels the role of specific DNA repair pathways in LC and highlights the importance of accounting for gene and pathway effects when studying LC.

Published
2012

11. Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

Author

Keitaro Matsuo, Neil E. Caporaso, John R. Gosney, Juncheng Dai, Maiken Elvestad Gabrielsen, Margaret R. Spitz, Frank Skorpen, Tõnu Vooder, Neonila Szeszenia-Dabrowska, Paul Brennan, Brian E. Henderson, Shelley S. Tworoger, Vladimir Bencko, Xuchen Zong, Younghun Han, Olaide Y. Raji, Yufei Wang, Andres Metspalu, Hidemi Ito, Irene Orlow, Michael W. Marcus, Eleonora Fabianova, Chu Chen, James McKay, Ping Yang, Gary E. Goodman, Hans E. Krokan, Demetrius Albanes, Timothy Eisen, Geoffrey Liu, Ying Chen, Triantafillos Liloglou, Jolanta Lissowska, Lynne R. Wilkens, Mari Nelis, Mark Lathrop, John K. Field, Fumihiko Matsuda, Di Zhang, Yongyue Wei, Dana Mates, Peter Rudnai, Yonathan Brhane, Jun She, Victoria L. Stevens, Inger Njølstad, Hongbing Shen, Darren R. Brenner, Maria Teresa Landi, Susan M. Gapstur, Li Su, Michael P.A. Davies, David Zaridze, Loic Le Marchand, John R. McLaughlin, Dong Xie, Paolo Boffetta, Rayjean J. Hung, Peter Broderick, Albert Rosenberger, Hendrik Dienemann, Lenka Foretova, Thomas Muley, Christopher I. Amos, Vladimi Janout, David C. Christiani, Joachim Heinrich, Yafang Li, Lars J. Vatten, Mattias Johansson, Richard S. Houlston, Xifeng Wu, Kristjan Välk, Wei V. Chen, Heike Bickeböller, Angela Risch, Maria Timofeeva, Brenner, D.R., Amos, C.I., Brhane, Y., Timofeeva, M.N., Caporaso, N., Wang, Y., Christiani, D.C., Bickeböller, H., Yang, P., Albanes, D., Stevens, V.L., Gapstur, S., McKay, J., Boffetta, P., Zaridze, D., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Krokan, H.E., Skorpen, F., Gabrielsen, M.E., Vatten, L., Njølstad, I., Chen, C., Goodman, G., Lathrop, M., Vooder, T., Välk, K., Nelis, M., Metspalu, A., Broderick, P., Eisen, T., Wu, X., Zhang, D., Chen, W., Spitz, M.R., Wei, Y., Su, L., Xie, D., She, J., Matsuo, K., Matsuda, F., Ito, H., Risch, A., Heinrich, J., Rosenberger, A., Muley, T., Dienemann, H., Field, J.K., Raji, O., Chen, Y., Gosney, J., Liloglou, T., Davies, M.P.A., Marcus, M., McLaughlin, J., Orlow, I., Han, Y., Li, Y., Zong, X., Johansson, M., Liu, G., Tworoger, S.S., Le Marchand, L., Henderson, B.E., Wilkens, L.R., Dai, J., Shen, H., Houlston, R.S., Landi, M.T., Brennan, P., and Hung, R.J.

Subjects
Cancer Research, Lung Neoplasms, Bayesian probability, Genome-wide association study, Original Manuscript, Computational biology, Adenocarcinoma, Bioinformatics, 03 medical and health sciences, Bayes' theorem, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Lung cancer, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, Case-control study, Bayes Theorem, General Medicine, medicine.disease, 3. Good health, ComputingMethodologies_PATTERNRECOGNITION, 030220 oncology & carcinogenesis, Meta-analysis, Case-Control Studies, Carcinoma, Squamous Cell, business, Genome-Wide Association Study
Abstract

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

Published
2015

12. Erratum: Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Author

Mari Nelis, Neil E. Caporaso, Tõnu Vooder, H. Bas Bueno-de-Mesquita, Ben Kinnersley, Frank Skorpen, Stephen J. Chanock, Mattias Johansson, Gary E. Goodman, Athena Matakidou, Kay-Tee Khaw, Amy Lloyd, Dana Mates, Neonilia Szeszenia-Dabrowska, Elisabete Weiderpass, Maiken Elvestad Gabrielsen, Paul Brennan, David C. Christiani, Maria Teresa Landi, Susan M. Gapstur, Yuanqing Ye, Andres Metspalu, Hendrik Dienemann, Nilanjan Chatterjee, Margaret R. Spitz, Younghun Han, Christopher I. Amos, James McKay, Manon Delahaye-Sourdeix, Lars J. Vatten, William Wheeler, Eleonora Fabianova, Daniel Chubb, Simone Benhamou, T. Eisen, Peter Rudnai, Chu Chen, Ghislaine Scelo, Antonio Agudo, Paolo Vineis, Marcin Lener, Mikael Johansson, Angela Risch, Maria Timofeeva, Mark Lathrop, Li Su, Yongyue Wei, Victoria L. Stevens, Peter Broderick, Maxime Vallée, Inger Njølstad, Rayjean J. Hung, David Zaridze, Thorunn Rafnar, Vladimir Janout, Yufei Wang, Jian Gu, Hans E. Krokan, Marc Henrion, Lenka Foretova, Kari Stefansson, Gudmar Thorleifsson, Demetrius Albanes, Patrick Sulem, Geoffrey Liu, Rudolf Kaaks, Marina Laplana, Jan Lubinski, Xuchen Zong, Vladimir Bencko, Elio Riboli, Zhaoming Wang, Françoise Clavel-Chapelon, Albert Rosenberger, Dimitrios Trichopoulos, Valerie Gaborieau, Florence Le Calvez-Kelm, Anne Tjønneland, Wei V. Chen, Jolanta Lissowska, Kristjan Välk, Richard S. Houlston, and Xifeng Wu

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Biology, Affect (psychology), medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Internal medicine, Genetics, medicine, Lung cancer, CHEK2
Abstract

Nat. Genet. 46, 736–741 (2014); published online 1 June 2014; corrected after print 23 January 2017 In the version of this article initially published, the name of author Florence Le Calvez-Kelm appeared incorrectly as Florence LeCalvez-Kelm. The error has been corrected in the HTML and PDF versionsof the article.

Published
2017

13. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Author

Paul Brennan, Younghun Han, Vladimir Janout, Eleonora Fabianova, Mark Lathrop, Zhaoming Wang, Inger Njølstad, James McKay, Dana Mates, Jolanta Lissowska, Frank Skorpen, Chu Chen, Neonilia Szeszenia-Dabrowska, Françoise Clavel-Chapelon, Antonio Agudo, Mattias Johansson, David C. Christiani, Kay-Tee Khaw, Yongyue Wei, Thorunn Rafnar, Gary E. Goodman, Mikael Johansson, Daniel Chubb, Xuchen Zong, Simone Benhamou, Vladimir Bencko, Manon Delahaye-Sourdeix, Lars J. Vatten, Elio Riboli, Peter Rudnai, Maria Teresa Landi, Susan M. Gapstur, Yuanqing Ye, Nilanjan Chatterjee, Amy Lloyd, Margaret R. Spitz, Paolo Vineis, H. Bas Bueno-de-Mesquita, William Wheeler, Ghislaine Scelo, Jan Lubinski, Stephen J. Chanock, Valerie Gaborieau, Victoria L. Stevens, Marc Henrion, Kari Stefansson, David Zaridze, Peter Broderick, Jian Gu, Mari Nelis, Elisabete Weiderpass, Albert Rosenberger, Maiken Elvestad Gabrielsen, Dimitrios Trichopoulos, Kristjan Välk, Florence LeCalvez-Kelm, Tõnu Vooder, Ben Kinnersley, Richard S. Houlston, Xifeng Wu, Anne Tjønneland, Yufei Wang, Hans E. Krokan, Demetrius Albanes, Patrick Sulem, Neil E. Caporaso, Geoffrey Liu, Marina Laplana, Christopher I. Amos, T. Eisen, Li Su, Lenka Foretova, Gudmar Thorleifsson, Rayjean J. Hung, Andres Metspalu, Maxime Vallée, Athena Matakidou, Hendrik Dienemann, Rudolf Kaaks, Marcin Lener, Angela Risch, Maria Timofeeva, and Wei V. Chen

Subjects
Lung Neoplasms, Genome-wide association study, Biology, Adenocarcinoma, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Lung cancer, CHEK2, 030304 developmental biology, BRCA2 Protein, 0303 health sciences, 9. Industry and infrastructure, Case-control study, Odds ratio, medicine.disease, Prognosis, 3. Good health, Checkpoint Kinase 2, 030220 oncology & carcinogenesis, Case-Control Studies, Carcinoma, Squamous Cell, Imputation (genetics), Genome-Wide Association Study
Abstract

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.

Published
2013

14. Methylation Markers of Early-Stage Non-Small Cell Lung Cancer

Author

Lili Milani, Urmo Võsa, Raivo Kolde, Tõnu Vooder, Marina Koltšina, Krista Fischer, Kristjan Välk, Andres Metspalu, Neeme Tõnisson, Retlav Roosipuu, Tarmo Annilo, Kaie Lokk, and Egon Urgard

Subjects
Male, Oncology, Lung Neoplasms, Time Factors, lcsh:Medicine, Transcriptomes, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Pathology, Gene Regulatory Networks, Stage (cooking), lcsh:Science, Lung, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, 0303 health sciences, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Smoking, Methylation, Genomics, Middle Aged, 3. Good health, Functional Genomics, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, DNA methylation, Medicine, Female, Epigenetics, DNA modification, Research Article, Adult, medicine.medical_specialty, Histology, Biology, 03 medical and health sciences, Breast cancer, Genome Analysis Tools, Diagnostic Medicine, Internal medicine, Biomarkers, Tumor, medicine, Adenocarcinoma of the lung, Genetics, Cancer Genetics, Cancer Detection and Diagnosis, Humans, Gene Networks, Lung cancer, Survival analysis, Aged, Neoplasm Staging, 030304 developmental biology, Clinical Genetics, Behavior, lcsh:R, Personalized Medicine, Reproducibility of Results, Correction, Cancer, DNA Methylation, medicine.disease, Survival Analysis, CpG Islands, lcsh:Q, Gene expression, Gene Function, Biomarkers, General Pathology
Abstract

Background Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers. Methods We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis. Results We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups. Conclusions We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility.

Published
2012

15. A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Author

J. Ramón Quirós, Eva Ardanaz, Stefania Boccia, Wilbert H.M. Peters, Dimitrios Trichopoulos, Mario Foglio, Luigi Barzan, Lenka Foretova, Joshua E. Muscat, Françoise Clavel-Chapelon, Elio Riboli, Diana Zelenika, Paul Brennan, Salvatore Panico, Eleonora Fabianova, Lars J. Vatten, Kay-Tee Khaw, David I. Conway, Pilar Galan, Doris Lechner, Erich M. Sturgis, Shilong Zhong, Shama Buch, Jolanta Lissowska, Franco Merletti, Carmen Enid Martínez, Li E. Wang, H. Bas Bueno-de-Mesquita, Vittorio Krogh, Andres Metspalu, Anne Tjønneland, Shen Chih Chang, Rayjean J. Hung, Silvia Franceschi, Amelie Chabrier, Kristina Kjærheim, Gabriella Cadoni, Sergio Koifman, Ariana Znaor, Chu Chen, Pagona Lagiou, Ivana Holcatova, Richard B. Hayes, James McKay, Graham Byrnes, Philip Lazarus, Christine Bouchardy, Ray Lowry, Vladimir Bencko, Merethe Kumle, Jingchun Luo, Antonio Agudo, Mark Lathrop, David R. Doody, Victor Wünsch-Filho, Joanna Trubicka, Lorenzo Simonato, Martin Lacko, Cristina Canova, John K. Field, Sherianne Fish, Valerie Gaborieau, Xavier Castellsagué, Mary Toner, Thérèse Truong, Tomoko Nukui, Carla J. Gallagher, Wolfgang Ahrens, Triantafillos Liloglou, Kim Overvad, Vladimir Janout, Ivo Gut, Paolo Boffetta, Shu Chun Chuang, Göran Hallmans, Jakob Linseisen, Marjorie Romkes, David Zaridze, Mark C. Weissler, Simone Benhamou, Antonia Trichopoulou, Nerea Larrañaga, José Eluf Neto, Neonila Szeszenia-Dabrowska, Jan Lubinski, Stephen M. Schwartz, Peter Rudnai, Hélène Blanché, Mia Hashibe, William K. Funkhouser, Paolo Vineis, Maria Paula Curado, Gary J. Macfarlane, Marcin Lener, Claire M. Healy, Michael D. McClean, Domenico Palli, Marc Delepine, Tõnu Voodern, Carmen J. Marsit, Zuo-Feng Zhang, Kristjan Välk, Dorota Oszutowska, Heiner Boeing, Ana M. B. Menezes, Rolando Herrero, Leticia Fernández Garrote, Heather H. Nelson, Renato Talamini, Anne Boland, Alexandru Bucur, Qingyi Wei, Gary E. Goodman, Lorenzo Richiardi, Carmen Navarro, Karl T. Kelsey, Rosario Tumino, Inger Njølstad, Johannes J. Manni, Carlos A. González, Oxana Shangina, John R. McLaughlin, Patricia A. McKinney, Timothy J. Key, Andrew F. Olshan, Dario Arzani, Tatiana V. Macfarlane, Simon Heath, Petra H.M. Peeters, International Agency for Research on Cancer (IARC), Russian Academy of Medical Sciences, Department of Epidemiology, Institute of Occupational Medicine, Maria Skłodowska Curie Memorial Cancer Center, National Institute for Environment, Partenaires INRAE, Regional Authority of Public Health, Institute of Public Health, Charles University [Prague] (CU), Palacky University Olomouc, Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute (RECAMO), National and Kapodistrian University of Athens (NKUA), The Netherlands Cancer Institute, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université de Genève (UNIGE), Bremen Institute for Prevention Research and Social Medicine (BIPS), University of Bremen, Universita di Torino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), General Hospital, Cancer Registry of Norway, School of Medicine and Dentistry, Universita di Padova, Imperial College London, Catalan Institute of Oncology, CIBER de Epidemiología y Salud Pública (CIBERESP), Newcastle University [Newcastle], Dental School, Centre for Epidemiology and Biostatistics, University of Leeds, NHS NSS ISD, School of Dental Science, University of Liverpool, National Institute of Public Health, National School of Public Health, Universidade Federal de Pelotas = Federal University of Pelotas (UFPel), Universidade de São Paulo (USP), Institute of Oncology and Radiobiology, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Institute of Hygiene, Università cattolica del Sacro Cuore [Milano] (Unicatt), University of North Carolina, Pomeranian Medical University, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Penn State College of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, University of California [Los Angeles] (UCLA), University of California, Anderson Cancer Center, The University of Texas Health Science Center at Houston (UTHealth), Instituto de Investigación Epidemiológica, Brown University, School of public health, The University of Hong Kong (HKU), Masonic Cancer Center, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, University of Pittsburgh (DEPARTMENT OF MATHEMATICS), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Maastricht University [Maastricht], Radboud University Medical Center [Nijmegen], Mount Sinai Hospital [Toronto, Canada] (MSH), Cancer Care Ontario, Norwegian University of Science and Technology (NTNU), University of Tromsø (UiT), Piedmont Reference Center for Epidemiology and Cancer Prevention, Department of Epidemiology and Public Health, Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto per lo Studio e la Prevezione Oncologica, Civile - M.P.Arezzo Hospital, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa, France, US NCI [R01 CA092039 05/05S1], Benhamou, Simone, Bouchardy Magnin, Christine, Charles University in Prague, Università cattolica del Sacro Cuore [Roma] (Unicatt), Penn State System-Pennsylvania Commonwealth System of Higher Education (PCSHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), [McKay, JD, Truong, T, Gaborieau, V, Chabrier, A, Chuang, SC, Byrnes, G, Curado, MP, Franceschi, S, Hashibe, M, Boffetta, P, Brennan, P] IARC, Lyon, France. [Zaridze, D, Shangina, O] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, N] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, J] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, J] Inst Oncol, Warsaw, Poland. [Rudnai, P] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, E] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Bucur, A] Inst Publ Hlth, Bucharest, Romania. [Bencko, V, Holcatova, I] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Janout, V] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Foretova, L] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Trichopoulos, D] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benhamou, S] INSERM U946, Paris, France. [Benhamou, S] Inst Gustave Roussy, CNRS UMR8200, Villejuif, France. [Bouchardy, C] Univ Geneva, Geneva Canc Registry, Inst Social & Prevent Med, Geneva, Switzerland. [Ahrens, W] Univ Bremen, Bremen Inst Prevent Res & Social Med BIPS, Bremen, Germany. [Merletti, F, Richiardi, L] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Talamini, R] IRCCS, Natl Canc Inst, Aviano, Italy. [Barzan, L] Gen Hosp Pordenone, Pordenone, Italy. [Kjaerheim, K] Canc Registry Norway, Oslo, Norway. [Macfarlane, GJ, Macfarlane, TV] Univ Aberdeen, Sch Med & Dent, Aberdeen, Scotland. [Simonato, L, Canova, C] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Canova, C] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Agudo, A, Castellsague, X] ICO, Barcelona, Spain. [Castellsague, X, Navarro, C, Ardanaz, E] CIBERESP, Madrid, Spain. [Lowry, R] Univ Newcastle Dent Sch, Newcastle Upon Tyne, Tyne & Wear, England. [Conway, DI] Univ Glasgow Dent Sch, Glasgow, Lanark, Scotland. [McKinney, PA] Univ Leeds Ctr Epidemiol & Biostat, Leeds, W Yorkshire, England. [McKinney, PA] NHS NSS ISD, Edinburgh, Midlothian, Scotland. [Healy, CM, Toner, ME] Trinity Coll Sch Dent Sci, Dublin, Ireland. [Znaor, A] Croatian Natl Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia. [Koifman, S] Natl Sch Publ Hlth FIOCRUZ, Rio De Janeiro, Brazil. [Menezes, A] Univ Fed Pelotas, Pelotas, Brazil. [Wuensch, V, Neto, JE] Univ Sao Paulo, Sao Paulo, Brazil. [Garrote, LF] Inst Oncol & Radiobiol, Havana, Cuba. [Boccia, S, Cadoni, G, Arzani, D] Univ Cattolica Sacro Cuore, Inst Hyg, Rome, Italy. [Boccia, S] IRCCS San Raffaele Pisana, Rome, Italy. [Olshan, AF] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Weissler, MC, Funkhouser, WK, Luo, JC] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Lubinski, J, Trubicka, J, Lener, M, Oszutowska, D] Pomeranian Med Univ, Dept Genet & Pathomorphol, Int Hereditary Canc Ctr, Szczecin, Poland. [Oszutowska, D] Pomeranian Med Univ, Dept Hyg Epidemiol & Publ Hlth, Szczecin, Poland. [Schwartz, SM, Chen, C, Fish, S, Doody, DR, Goodman, GE] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Muscat, JE, Lazarus, P, Gallagher, CJ] Penn State Coll Med, Hershey, PA USA. [Chang, SC, Zhang, ZF] Univ Calif Los Angeles Sch Publ Hlth, Los Angeles, CA USA. [Wei, QY, Sturgis, EM, Wang, LE] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Herrero, R] Inst Invest Epidemiol, San Jose, Costa Rica. [Kelsey, KT, Marsit, CJ] Brown Univ, Providence, RI 02912 USA. [McClean, MD] Boston Univ Sch Publ Hlth, Boston, MA USA. [Nelson, HH] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Romkes, M, Buch, S, Nukui, T, Zhong, SL] Univ Pittsburgh, Pittsburgh, PA USA. [Lacko, M, Manni, JJ] Maastricht Univ Med Ctr, Dept Otorhinolaryngol & Head & Neck Surg, Maastricht, Netherlands. [Peters, WHM] St Radboud Univ Nijmegen Med Ctr, Dept Gastroenterol, Nijmegen, Netherlands. [Hung, RJ] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [McLaughlin, J] Canc Care Ontario, Toronto, ON, Canada. [Vatten, L] Norwegian Univ Sci & Technol, N-7034 Trondheim, Norway. [Njolstad, I] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Field, JK, Liloglou, T] Univ Liverpool Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside, England. [Vineis, P] Univ Turin, Serv Epidemiol Tumori, Turin, Italy. [Vineis, P] CPO Piemonte, Turin, Italy. [Vineis, P, Riboli, E] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Clavel-Chapelon, F] E3N EPIC Grp Inst Gustave Roussy, INSERM, Villejuif, France. [Palli, D] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Canc Registry, Ragusa, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Histopathol Unit, Ragusa, Italy. [Krogh, V] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. [Panico, S] Univ Naples Federico 2, Dipartimento Med Clin & Sperimentale, Naples, Italy. [Gonzalez, CA] ICO, RETICC DR06 0020, IDIBELL, Unit Nutr Environm & Canc, Barcelona, Spain. [Quiros, JR] Principado Asturias, Consejeria Serv Sociales, Jefe Secc Informac Sanitaria, Oviedo, Spain. [Martinez, C] Escuela Andaluza Salud Publ, Granada, Spain. [Navarro, C] Murcia Hlth Council, Dept Epidemiol, Murcia, Spain. [Ardanaz, E] Navarra Publ Hlth Inst, Pamplona, Spain. [Larranaga, N] Gobierno Vasco, Subdirecc Salud Publ Gipuzkoa, San Sebastian, Spain. [Khaw, KT] Univ Cambridge, Sch Clin Med, Cambridge, England. [Key, T] Univ Oxford, Canc Res UK, Oxford, England. [Bueno-de-Mesquita, HB] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Peeters, PHM] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Trichopoulou, A] Univ Athens Sch Med, WHO Collaborating Ctr Nutr, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Linseisen, J] Helmholtz Ctr Munich, Inst Epidemiol, Neuherberg, Germany. [Linseisen, J] German Canc Res Ctr, Div Clin Epidemiol, D-6900 Heidelberg, Germany. [Boeing, H] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Hallmans, G] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Overvad, K] Aarhus Univ, Dept Epidemiol & Social Med, Aarhus, Denmark. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Kumle, M] Univ Hosp No Norway, Tromso, Norway. [Valk, K, Voodern, T, Metspalu, A] Univ Tartu, EE-50090 Tartu, Estonia. [Zelenika, D, Boland, A, Delepine, M, Foglio, M, Lechner, D, Gut, IG, Heath, S, Lathrop, M] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Blanche, H, Lathrop, M] Fdn Jean Dausset CEPH, Paris, France. [Galan, P] Univ Paris 13, INSERM INRA CNAM U557 U1125, Bobigny, France. [Hayes, RB] New York Univ Langone Med Ctr, New York, NY USA, Support for the central Europe and ARCAGE genome-wide studies and follow-up genotyping was provided by INCa, France. Additional funding for study coordination, genotyping of replication studies, and statistical analysis was provided by the US NCI (R01 CA092039 05/05S1)., Norges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for samfunnsmedisin, McKay, J.D., Truong, T., Gaborieau, V., Chabrier, A., Chuang, S.-C., Byrnes, G., Zaridze, D., Shangina, O., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Holcatova, I., Janout, V., Foretova, L., Lagiou, P., Trichopoulos, D., Benhamou, S., Bouchardy, C., Ahrens, W., Merletti, F., Richiardi, L., Talamini, R., Barzan, L., Kjaerheim, K., Macfarlane, G.J., Macfarlane, T.V., Simonato, L., Canova, C., Agudo, A., Castellsagué, X., Lowry, R., Conway, D.I., McKinney, P.A., Healy, C.M., Toner, M.E., Znaor, A., Curado, M.P., Koifman, S., Menezes, A., Wünsch-Filho, V., Neto, J.E., Garrote, L.F., Boccia, S., Cadoni, G., Arzani, D., Olshan, A.F., Weissler, M.C., Funkhouser, W.K., Luo, J., Lubinski, J., Trubicka, J., Lener, M., Oszutowska, D., Schwartz, S.M., Chen, C., Fish, S., Doody, D.R., Muscat, J.E., Lazarus, P., Gallagher, C.J., Chang, S.-C., Zhang, Z.-F., Wei, Q., Sturgis, E.M., Wang, L.-E., Franceschi, S., Herrero, R., Kelsey, K.T., McClean, M.D., Marsit, C.J., Nelson, H.H., Romkes, M., Buch, S., Nukui, T., Zhong, S., Lacko, M., Manni, J.J., Peters, W.H.M., Hung, R.J., McLaughlin, J., Vatten, L., Njølstad, I., Goodman, G.E., Field, J.K., Liloglou, T., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., González, C.A., Quirós, J.R., Martínez, C., Navarro, C., Ardanaz, E., Larrañaga, N., Khaw, K.-T., Key, T., Bueno-de-Mesquita, H.B., Peeters, P.H.M., Trichopoulou, A., Linseisen, J., Boeing, H., Hallmans, G., Overvad, K., Tjønneland, A., Kumle, M., Riboli, E., Välk, K., Voodern, T., Metspalu, A., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Blanché, H., Gut, I.G., Galan, P., Heath, S., Hashibe, M., Hayes, R.B., Boffetta, P., Lathrop, M., Brennan, P., Promovendi PHPC, Metamedica, KNO, RS: MHeNs School for Mental Health and Neuroscience, and RS: GROW - School for Oncology and Reproduction

Subjects
Male, Cancer Research, Candidate gene, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Genome-wide association study, FAMILY-HISTORY, genome-wide, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings], 0302 clinical medicine, Gene Frequency, NECK-CANCER, Risk Factors, Càncer, SUSCEPTIBILITY LOCUS, SENSITIVITY PROTEIN MUS308, Genetics (clinical), Cancer, Genetics & Heredity, Genetics, Publication Characteristics::Study Characteristics::Multicenter Study [Medical Subject Headings], 0303 health sciences, TOBACCO-RELATED CANCERS, Tumor, Continental Population Groups, Middle Aged, 3. Good health, LUNG-CANCER, POOLED ANALYSIS, EPIDEMIOLOGY CONSORTIUM, INTERNATIONAL HEAD, ALCOHOL-DRINKING, Head and Neck Neoplasms, Drinking of alcoholic beverages, 030220 oncology & carcinogenesis, NEOPLASIAS, Consum d'alcohol, Head and Neck Neoplasms/enzymology/epidemiology/genetics, Genetics and Genomics/Gene Discovery, Female, Settore MED/31 - OTORINOLARINGOIATRIA, Life Sciences & Biomedicine, Medical Genetics, Research Article, Adult, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Diseases::Neoplasms::Neoplasms by Site::Head and Neck Neoplasms [Medical Subject Headings], lcsh:QH426-470, Neoplasias de Cabeza y Cuello, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Genetics and Genomics/Complex Traits, Biology, association study, Estudio de Asociación del Genoma Completo, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, upper aerodigestive tract, Genetic variation, Biomarkers, Tumor, medicine, cancers, cancer, Humans, Genetic Predisposition to Disease, ddc:610, Tumor Markers, Biological/genetics, Genetics and Genomics/Cancer Genetics, Molecular Biology, Genotyping, Allele frequency, Settore MED/42 - IGIENE GENERALE E APPLICATA, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, ddc:613, Aged, Medicinsk genetik, Estudio Multicéntrico, Science & Technology, Racial Groups, Genetic Variation, Aldehyde Dehydrogenase, medicine.disease, lcsh:Genetics, Aldehyde Dehydrogenase/genetics, Genome-Wide Association Study, Persons::Persons::Population Groups::Continental Population Groups [Medical Subject Headings], INHANCE consortium, sensitivity protein mus308, tobacco-related cancers, lung-cancer, pooled analysis, susceptibility locus, neck-cancer, epidemiology consortium, international head, alcohol-drinking, family-history, INHANCE Consortium, Biomarkers, Genètica
Abstract

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Author Summary We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.

Published
2011

16. Identification of miR-374a as a prognostic marker for survival in patients with early-stage nonsmall cell lung cancer

Author

Raivo Kolde, Krista Fischer, Neeme Tõnisson, Jaak Vilo, Urmo Võsa, Tarmo Annilo, Tõnu Vooder, Andres Metspalu, Kristjan Välk, and Retlav Roosipuu

Subjects
Adult, Estonia, Male, Cancer Research, Lung Neoplasms, Down-Regulation, Treatment of lung cancer, Biology, medicine.disease_cause, Bioinformatics, Real-Time Polymerase Chain Reaction, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, microRNA, Genetics, medicine, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Lung cancer, Lung, Survival analysis, 030304 developmental biology, Aged, Neoplasm Staging, Regulation of gene expression, 0303 health sciences, Gene Expression Profiling, Cancer, Middle Aged, medicine.disease, Prognosis, Survival Analysis, 3. Good health, Up-Regulation, Gene expression profiling, Gene Expression Regulation, Neoplastic, MicroRNAs, Early Diagnosis, 030220 oncology & carcinogenesis, Cancer research, Female, Carcinogenesis
Abstract

Lung cancer is one of the deadliest types of cancer proven by the poor survival and high relapse rates after surgery. Recently discovered microRNAs (miRNAs), small noncoding RNA molecules, play a crucial role in modulating gene expression networks and are directly involved in the progression of a number of human cancers. In this study, we analyzed the expression profile of 858 miRNAs in 38 Estonian nonsmall cell lung cancer (NSCLC) samples (Stage I and II) and 27 adjacent nontumorous tissue samples using Illumina miRNA arrays. We found that 39 miRNAs were up-regulated and 33 down-regulated significantly in tumors compared with normal lung tissue. We observed aberrant expression of several well-characterized tumorigenesis-related miRNAs, as well as a number of miRNAs whose function is currently unknown. We show that low expression of miR-374a in early-stage NSCLC is associated with poor patient survival. The combinatorial effect of the upand down-regulated miRNAs is predicted to most significantly affect pathways associated with cell migration, differentiation and growth, and several signaling pathways that contribute to tumorigenesis. In conclusion, our results demonstrate that expression of miR-374a at early stages of NSCLC progression can serve as a prognostic marker for patient risk stratification and may be a promising therapeutic target for the treatment of lung cancer. V C 2011 Wiley-Liss, Inc.

Published
2010

17. Gene expression profiles of non-small cell lung cancer: survival prediction and new biomarkers

Author

Tõnu Vooder, Mari-Ann Reintam, Jaak Vilo, Raivo Kolde, Cathleen Petzold, Kristjan Välk, and Andres Metspalu

Subjects
Oncology, Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Lung Neoplasms, Biology, Adenocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, Gene expression, medicine, Biomarkers, Tumor, Humans, RNA, Messenger, Stage (cooking), Lung cancer, 030304 developmental biology, Aged, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Respiratory disease, Cancer, General Medicine, Rna degradation, Adenocarcinoma, Bronchiolo-Alveolar, Middle Aged, medicine.disease, Prognosis, respiratory tract diseases, 3. Good health, Predictive factor, Survival Rate, 030220 oncology & carcinogenesis, Case-Control Studies, Lymphatic Metastasis, Carcinoma, Squamous Cell, Female, Non small cell
Abstract

Objectives: Despite the well-defined histological types of non-small cell lung cancer (NSCLC), a given stage is often associated with wide-ranging survival rates and treatment outcomes. This disparity has led to an increased demand for the discovery and identification of new informative biomarkers. Methods: In the current study, we screened 81 NSCLC samples using Illumina® whole-genome gene expression microarrays in an effort to identify differentially expressed genes and new NSCLC biomarkers. Results: We identified novel genes whose expression was upregulated in NSCLC, including SPAG5, POLH, KIF23, and RAD54L, which are associated with mitotic spindle formation, DNA repair, chromosome segregation, and dsDNA break repair, respectively. We also identified several novel genes whose expression was downregulated in NSCLC, including SGCG, NLRC4, MMRN1, and SFTPD, which are involved in extracellular matrix formation, apoptosis, blood vessel leakage, and inflammation, respectively. We found a significant correlation between RNA degradation and survival in adenocarcinoma cases. Conclusions: Even though the follow-up time was too limited to draw final conclusions, we were able to show better prediction p values in a group selection based on molecular profiles compared to histology. The current study also uncovered new candidate biomarker genes that are likely to be involved in diverse processes associated with NSCLC development.

Published
2010

18. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

Author

Tarmo Annilo, Cheng Luo, Urmo Võsa, Jukka Laine, Kristjan Välk, Egon Urgard, Retlav Roosipuu, Mingming Liu, Liqing Zhang, Fabian Hoti, Christopher M. Frenz, Tõnu Vooder, and Andres Metspalu

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Microarray, Disease, Bioinformatics, Proteomics, lcsh:RC254-282, metagenes, Internal medicine, Gene expression, medicine, Lung cancer, Gene, non-small cell lung cancer, Survival analysis, Original Research, TNM stage, business.industry, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, gene expression pattern, Kaplan-Meier curve, business, microarray
Abstract

NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies. A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR. Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified. Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients.

Published
2011

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