Clinical Genetics 2

Hereditary Cancer Genetics

Principal investigators

dr. C.J. van Asperen, dr. F. Hes, dr. A. Vriends, dr. C. Tops, dr. J.T. Wijnen, dr. M.M. Weiss, dr. N. van der Stoep, prof. dr. E. Bakker, prof. dr. M.H. Breuning, prof. dr. A. Tibben

Aim and focus

In this project we study predisposition of inherited cancer from bench to bedside. The starting point of this translational research line is the family with a heavy cancer burden. We study clinical and psychological consequences of identifying predisposing genes with the aim of formulating evidence based guidelines and recommendations for clinical and laboratory practice. The focus is on familial breast cancer, familial colorectal cancer, polyposis, melanoma and paraganglioma.

Topics of particular interest are the low penetrance cancer predisposing genes, and the Variants of Unknown Clinical Significance (VUCS), genotype-phenotype correlations. Many sequence variants that may or may not be pathogenic are detected during sequencing of genes involved in predisposition to hereditary cancer. To improve genetic counselling clinical as well as experimental data are collected, and the psychological impact of genetic uncertainty on the counselee and the family is studied.

Position in international context

Researchers in clinical genetics continue to play coordinating roles or remain major contributors to national and international consortia. The aim of these consortia is to elucidate cancer risks that are conferred by genes that are already known or to find new cancer susceptibility genes. Examples are the Breast Cancer Linkage Consortium, INternational Society for GastroIntestinal Hereditary Tumors (INSIGHT) and the Melanoma Consortium Genomel. The extensive database of patients and families combined with the hospital based series of sporadic breast cancer patients provide an excellent opportunity to participate in genome wide association studies. These studies are aimed at searching for genes that increase the risk of breast- or colorectal cancer, or modify the cancer risk in carriers of a mutation predisposing to cancer, such as BRCA1,2, and the mismatch repair genes.  

Content / highlights / achievements

Five potential susceptibility genes have been identified by using genome wide association studies performed by the Breast Cancer Linkage Consortium. These gene variants were quickly tested in the Leiden cohort of consecutive breast cancer patients. Similarly, low risk variants that increase the risk of colorectal cancer have been identified by genome wide association studies in collaboration with Drs Tomlinson and Houlston. We have studied the influence of these variants on cancer risk in patients carrying a gene mutation inactivating the mismatch repair system leading to susceptibility to colorectal cancer. Somatic mosaïcism for a point mutation in the APC gene, as well as large deletions within the gene have been described as a cause of polyposis. Detailed analysis of clinical data from patients carrying two mutations in the MUTYH gene revealed genotype-phenotype associations between particular mutations and polyp count as well as the risk of colorectal cancer. Psychological impact of genetic counseling and DNA testing for hereditary cancer predisposition is being studied with a focus on uninformative and ambiguous results of DNA testing due to not finding a mutation, or finding an unclassified variant within a gene.

Future themes

The impact of identifying more predisposing genes for breast cancer, colorectal cancer, polyposis, paraganglioma and melanoma on patients and their family will be studied. Amongst others we are studying the effect of prophylactic surgery and/or regular surveillance on carriers of mutations predisposing to cancer, in terms of morbidity and mortality as well as psychological wellbeing. This growing group of healthy mutation carriers is an excellent source for testing new methods for early detection of tumors prior to trials in the general population.

Cohesion within LUMC and Leiden University

There is a strong flourishing multi-disciplinary collaboration with the Departments of Human Genetics, Pathology, Surgery, Gastroenterology, Gynaecology, Dermatology, and the Departments of Medical Statistics, and Medical Decision Making. 

Key publications

van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HFA, Ausems MGEM, Menko FH, Gomez Garcia EB, Klijn JGM, Hogervorst FBL, van Houwelingen JC, van’t Veer LJ, Rookus MA, van Leeuwen FE, on behalf of the Netherlands Collaborative Group on Hereditary Breast Cancer (HEBON) Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.  J Med Genet 2005; 42: 711-9.
IF 5.5

van Asperen CJ, van Dijk S, Zoeteweij MW, Timmermans DRM, de Bock GH, Meijers-Heijboer EJ, Niermeijer MF, Breuning MH, Kievit J, Otten W What do women really want to know? Motives for attending familial breast cancer clinics J Med Genet 2002; 39: 410-4.
IF 5.5  

Hendriks YM, Franken PF, Dierssen JWL, Leeuw W de, Wijnen JT, Dreef E, Tops CJM, Breuning MH, Brocker-Vriends A, Vasen HFA, Fodde R & Morreau H. Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol 2003; 162: 469-77.
IF 5.5

Hendriks YM, de Jong AE, Morreau H, Tops CM, Vasen HF, Wijnen JT, Breuning MH, Brocker-Vriends AH. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin 2006; 56: 213-25. Review.                                                                                                                                                                IF 63.3 

Hendriks YMC, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, Sandkuijl L, Moller P, Genuardi M, Van Houwelingen H, Tops C, Van Puijenbroek M, Verkuijlen P, Kenter G, Van Mil A, Meijers-Heijboer H, Tan GB, Breuning MH, Fodde R, Wijnen JT, Brocker-Vriends AHJT, Vasen H Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: Impact on counseling and surveillance Gastroenterology 2004; 127: 17-24.
IF 11.7 

Hes FJ, Nielsen M, Bik EC, Konvalinka D, Wijnen JT, Bakker E, Vasen HF, Breuning MH, Tops CM. Somatic APC mosaicism: an underestimated cause of polyposis coli. Gut 2008; 57: 71-6. IF 10.0        

Huijts PE, Vreeswijk MP, Kroeze-Jansema KH, Jacobi CE, Seynaeve C, Krol-Warmerdam EM, Wijers-Koster PM, Blom JC, Pooley KA, Klijn JG, Tollenaar RA,  Devilee P, van Asperen CJ. Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases. Breast Cancer Res 2007; 9: R78. IF 4.3

Nielsen M, Bik E, Hes FJ, Breuning MH, Vasen HF, Bakker E, Tops CM, Weiss MM (2007)Genotype-phenotype correlations in 19 Dutch cases with APC gene deletions and a literature review. Eur J Hum Genet 2007; 15: 1034-42. IF 4.0

Nielsen M, Franken PF, Reinards THCM, Weiss MM, Wagner A, van der Klift H, Kloosterman S, Houwing-Duistermaat JJ, Aalfs CM, Ausems MGEM, Bröcker-Vriends AHJT, Gomez Garcia EB, Hoogerbrugge N, Menko FH, Sijmons RH, Verhoef S, Kuipers EJ, Morreau H, Breuning MH, Tops CMJ, Wijnen JT, Vasen HFA, Fodde R and Hes FJ (2005) Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 2005; 42: e54. IF 5.5

Vos J, Otten W, Asperen CJ van, Jansen A, Menko F, Tibben A. The counsellees’view of an Unclassified Variant in BRCA1/2: interpretation, understanding and impact. PsychoOncology, 2008; 17: 822-30.
IF 2.6

Nielsen M, Joerink - van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, Sampson JR, Aretz S, Hes FJ. Analysis of MUTYH Genotypes and Colorectal Phenotypes in Patients with MUTYH Associated Polyposis. Accepted for publication in Gastroenterology - IF 11.7