The research of this group in the Department of Epidemiology is mainly based on the Netherlands Cohort Study on Diet and Cancer (NLCS). The NLCS started in 1986 and includes 120,852 women aged 55-69 years. At baseline, cohort members completed a mailed, self-administered questionnaire on dietary habits, and other risk factors for cancer (1). The NLCS is followed up regularly by record linkage to the Netherlands Cancer Registry, the national pathology registry PALGA, the municipal population registries and the causes of death registry (Statistics Netherlands).
Etiology and specific molecular endpoints
In close collaboration with the Department of Pathology (prof de Bruïne, dr van Engeland, dr de Goeij) tumor samples have been collected from 735 cases with colorectal cancer from the NLCS. Mutations in oncogenes and tumor suppressor genes have been determined in this population. Furthermore, it has been investigated whether promoter regions of tumor-suppressor genes have been inactivated by hypermethylation. In several PhD-projects, it was investigated whether dietary and environmental exposures at baseline are associated with specific mutations (see e.g. ref 2) or promoter methylation.
In 2007 three projects were ongoing in this area:
- The association between intake of methyl donors or degraders, several genetic polymorphisms and hypermethylation in colorectal cancer (funded by KWF Dutch Cancer Society)
- The association between alcohol intake, polymosphisms in the genes ADH1 and ADH3 and the risk of colorectal cancer (funded by ERAB)
- The association between indicators of weight balance, hypermethylation of tumor-suppressor genes and the risk of colorectal cancer (funded by WCRF)
In cooperation the Department of Urology of the Nijmegen University, also tumor samples have been collected of 235 cases with renal cell cancer from the NLCS. The association has been studied between several risk factors and the presence of mutation in the von Hippel-Lindau (VHL) gene in renal cell cancer. The sample collection has been moved to the Department of Pathology in Maastricht in 2007 and new projects are being prepared.
Survival of cancer
Since 2004 the NLCS has permission to collect information on the vital status from the automated municipal population registries GBA and information on the cause of death from Statistics Netherlands. The follow-up of cases with colorectal and renal cell cancer of whom tumor samples are available has been completed using these registries. In 2007, it was investigated whether mutation in the VHL gene was an independent prognostic factor in the survival or renal cell cancer. Projects investigating prognostic factors in colorectal cancer are being set up.
Nutrition and cancer
Several projects are currently conducted on the association between diet and cancer.
In collaboration with and funded by the Dutch Food Authority (VWA) the association is being investigated between dietary acrylamide and risk of cancer. In 2007, the NLCS was the first epidemiological study that found evidence that dietary acrylamide was also a human carcinogen. A high intake of dietary acrylamide was associated with an increased risk of both endometrial and ovarian cancer (3). The association of dietary acrylamide and other types of cancer will also be investigated and further results are expected in 2008.
The incidence of adenocarcinoma of the oesophagus and cardia cancer of the stomach is increasing rapidly. Whether risk factors for these cancers are different from the other cancer subtypes in these organs has not been investigated intensively. Funded by KWF, a study is being conducted in which the association of risk factors like BMI (4), smoking, alcohol consumption, vegetable and fruit consumption and selenium status (measured in toenails clippings) with these cancers is investigated. In this study, also the aetiology of the precursor of oesophageal adenocarcinoma, Barrett's oesophagus, will be investigated.
Gene-environment interactions
In collaboration with the Department of Health Risk Analysis and Toxicology (prof. van Schooten and dr. van Breda) it was investigated whether DNA could be isolated from toenail clippings. These toenail clippings were provided by approx. 90,000 of the 120,000 NLCS participants at baseline and have been kept in a cellar for 20 years. On average, 2 ?g DNA could be extracted from 10 mg toenail material. A complete genotype profile of 10 polymorphisms was successfully generated for 95% of the DNA samples (amplicon sizes ranging from 92 to 148 bp). This offers new and unique possibilities for genetic epidemiologic studies in a very large biobank in a large cohort with an extensive baseline dataset and follow-up (ref 5).
International collaboration
The NLCS collaborates with a.o. the Pooling Project of prospective studies of Diet and Cancer (coordinated by the Harvard School of Public Health) and the Collaborative Group on Epidemiological Studies of Breast and Ovarian Cancer (coordinated by Oxford University). Many high-impact publications are the result from this collaboration.
Selected publications
Van den Brandt PA, Goldbohm RA, van 't Veer P, Volovics A, Hermus RJJ, Sturmans F.
A large-scale prospective cohort study on diet and cancer in The Netherlands.
J Clin Epidemiol 1990; 43: 285-95.
Weijenberg MP, Lüchtenborg M, de Goeij AFPM, Brink M, van Muijen GNP, de Bruïne AP, Goldbohm RA, van den Brandt PA.
Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.
Cancer Causes Control 2007; 18: 865-879.
Hogervorst JG, Schouten LJ, Konings EJ, Goldbohm RA, van den Brandt PA.
A prospective study of dietary acrylamide intake and the risk of endometrial, ovarian, and breast cancer.
Cancer Epidem Biomar Prev 2007; 16: 2304-2313.
Merry AHH, Schouten LJ, Goldbohm RA, van den Brandt PA.
Body mass index, height and risk of adenocarcinomas of the esophagus and gastric cardia: a prospective cohort study.
Gut 2007; 56: 1503-11.
Van Breda SG, Hogervorst JG, Schouten LJ, Knaapen AM, van Delft JH, Goldbohm RA, van Schooten FJ, van den Brandt PA.
Toenails: an easily accessible and long-term stable source of DNA for genetic analyses in large-scale epidemiological studies.
Clin Chem 2007; 6: 1168-1170.
Scientific staff
Piet van den Brandt
Leo Schouten
Bas Verhage
Adri Voogd
Matty Weijenberg
Postdocs
Lina Leurs
Kim Smits
PhD students
Brenda Bongaerts
Janneke Hogervorst
Laura Hughes
Jessie Steevens
Stefan de Vogel
Technicians
Sacha van de Crommert
Jolanda Nelissen
Conny de Zwart