Carcinogenesis Advance Access published online on September 6, 2006
Carcinogenesis, doi:10.1093/carcin/bgl159
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1 ISI Foundation, Torino, Italy
* To whom correspondence should be addressed. It is becoming increasingly evident that single-locus effects cannot explain complex multifactorial human diseases like cancer. We applied the Multi-factor Dimensionality Reduction (MDR) method to a large cohort study on gene-environment and gene-gene interactions. The study (case-control nested in the EPIC cohort) was established to investigate molecular changes and genetic susceptibility in relation to air pollution and environmental tobacco smoke in non-smokers. We have analyzed 757 controls and 409 cases with bladder cancer (n=124), lung cancer (n=116), and mycloid leukemia (n=169). Thirty-six gene variants (DNA repair and metabolic genes) and three environmental exposure variables (measures of air pollution and environmental tobacco smoke at home and at work) were analyzed. Interactions were assessed by prediction error percentage and cross-validation consistency (CVC) frequency. For lung cancer, the best model was given by a significant gene-environment association between the base excision repair (BER) XRCC1-Arg399Gln polymorphism, the double strand break repair (DSBR) BRCA2-Asn372His polymorphism and the exposure variable "distance from heavy traffic road", an indirect and robust indicator of air pollution (mean prediction error of 26%, p<0.001, mean CVC of 6.60, p=0.02). For bladder cancer, we found a significant 4-loci association between the BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3'UTR polymorphism and the metabolic gene polymorphisms COMT-Val158Met and MTHFR-677C>T (mean prediction error of 22%, p<0.001, mean CVC consistency of 7.40, p<0.037). For leukemia, a 3-loci model including RAD52-2259C>T, MnSOD-Ala9Val and CYP1A1-Ile462Val had a minimum prediction error of 31% (p<0.001) and a maximum CVC of 4.40 (p=0.086). The MDR method seems promising, because it provides a limited number of statistically stable interactions; however the biological intrerpretation remains to be understood.
Received May 9, 2006
Revised August 25, 2006
Accepted August 25, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions
M. Manuguerra 1, G. Matullo 2 *, F. Veglia 1, H. Autrup 3, A. M. Dunning 4, S. Garte 5, E. Gormally 6, C. Malaveille 6, S. Guarrera 1, S. Polidoro 1, F. Saletta 1, M. Peluso 7, L. Airoldi 8, K. Overvad 9, O. Raaschou-Nielsen 10, F. Clavel-Chapelon 11, J. Linseisen 12, H. Boeing 13, D. Trichopoulos 14, A. Kalandidi 14, D. Palli 15, V. Krogh 16, R. Tumino 17, S. Panico 18, H. B. Bueno-De-Mesquita 19, P. H. Peeters 20, E. Lund 21, G. Pera 22, C. Martinez 23, P. Amiano 24, A. Barricarte 25, M. J. Tormo 26, J. R. Quiros 27, G. Berglund 28, L. Janzon 28, B. Jarvholm 29, N. E. Day 30, N. E. Allen 31, R. Saracci 6, R. Kaaks 6, P. Ferrari 6, E. Riboli 32, and P. Vineis 33
2 ISI Foundation, Torino, Italy; Dept. of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy
3 Department of Environmental and Occupational Medicine, Aarhus Universitet, Aarhus, Denmark
4 Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom
5 Genetics Research Institute, Milan, Italy
6 International Agency for Research on Cancer, Lyon, France
7 Tuscany Cancer Institute, Cancer Risk Factor Branch, CSPO-Scientific Institute of Tuscany; Florence, Italy
8 Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
9 Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
10 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
11 INSERM U521, Institut Gustave Roussy, Villejuif, France
12 Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
13 German Institute of Human Nutrition, Potsdam-Rehbücke, Germany
14 Department of Hygiene and Epidemiology, Medical School, University of Athens, Greece
15 Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Florence, Italy
16 Department of Epidemiology, National Cancer Istitute, Milan, Italy
17 Cancer Registry, Azienda Ospedaliera "Civile MP Arezzo", Ragusa, Italy
18 Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, Naples, Italy
19 Centre for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, Netherlands
20 Department of Cancer Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Netherlands
21 Institute of Community Medicine, University of Tromso, Norway.
22 Department of Epidemiology, Catalan Institute of Oncology, Consejería de Sanidad y Servicios Sociales, Barcelona, Spain
23 Andalusian School of Public Health, Granada, Spain
24 Department of Public Health of Guipuzkoa, San Sebastian, Spain
25 Public Health Institute, Navarra, Spain
26 Consejería de Sanidad y Consumo, Murcia, Spain
27 Public Health and Health Planning Directorate, Asturias, Spain
28 Malmö Diet and Cancer Study, Lund University, Malmö, Sweden
29 Department of Public Health and Clinical Medicine, University of Umeå, Sweden
30 MRC Dunn Human Nutrition Unit, Cambridge, UK
31 Cancer Research UK Epidemiology Unit, University of Oxford, UK
32 Imperial College London, London UK; University of Torino, Italy
33 ISI Foundation, Torino, Italy; Imperial College London, London UK; University of Torino, Italy
G. Matullo, E-mail: matullo{at}isiosf.isi.it
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