Hereditary cancer genetics

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Clinical Genetics.

Aim and focus

In this project we study predisposition of inherited cancer from bench to bedside. The starting point of this translational research line are patients with young age of onset of cancer, with multiple tumors, or counselees that seek advice because of a family history 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 and ovarian cancer, familial colorectal cancer, polyposis, melanoma and paraganglioma.

Topics of particular interest are the low penetrance cancer predisposing genes, modifier genes, somatic mosaicism, and the variants of unknown significance (VUS), genotype-phenotype correlations and unbiased cancer risks. Many sequence variants that may or may not be pathogenic, are more and more detected since the implementation of next generation sequencing (NGS) of genes involved in the predisposition to hereditary cancer. Next to VUS in recognized and well-studied cancer predisposition genes, also variants in new or relatively unknown genes are identified. 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 for breast cancer are the HEBON (Netherlands collaborative group of hereditary breast cancer), BCAC (Breast Cancer Association Consortium) , ENIGMA (evidence based network for the interpretation of germ line mutant alleles) and BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing). For colorectal cancers there is the INternational Society for GastroIntestinal Hereditary Tumors (INSIGHT) and the International Mismatch Repair Consortium (IMRC), for melanoma there is the 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 next generation sequence 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

  • Detailed analysis of clinical data from patients  with a genetic predisposition for breast cancer, colorectal cancer, polyposis, melanoma and paraganglioma revealed genotype-phenotype associations and have been instrumental for calculating the risks of various types of associated cancers.
  • The BRCA1 and BRCA2 genes together make the largest contribution to the predisposition to hereditary breast and ovarian cancer. However, in about 10% of the DNA tests gene variants of uncertain significance (VUS) are identified. In close collaboration with the department of Human Genetics and the ENIGMA consortium, existing methods (multifactorial likelihood classification and functional analysis) were improved and novel approaches were developed to determine the clinical significance of VUS. New clinical guidelines were developed and published for clinical practice.
  • The most common genetic predisposition to colon cancer is Lynch syndrome caused by mismatch repair gene mutations, explaining about 2 to 5% of these cancers. Polyposis syndromes (mainly germline APC or MUTYH mutations) are present in 1-2 % of colon cancer patients. A clinical problem is that most studies assessing cancer risk in Lynch patients have focused on two genes, MLH1 and MSH2, and have included only highly affected clinic based families. Studies on PMS2 and MSH6 are lacking behind. By assembling the world largest PMS2 cohort we have recently analysed the cancer risk for this group, taking into account selection and testing bias and found significantly lower cancer risk than previous studies. The outcomes of this study have led to changes in advices to patients and changes in screening policy are currently being discussed. To elucidate what is causing the differences between patients in cancer risk and age of cancer diagnosis we have analysed GWAS CRC snps in more than 400 PMS2 patients and MUTYH patients. Also we have analysed geno-phenotype correlation in PMS2 for the first time. No clear effect of these factors could be found and thus we will continue looking for other modifying factors in these patients groups, such as lifestyle
  • Our research has furthermore focused on unsolved cases with Lynch like phenotype or polyposis without detectable APC or MUTYH mutations. We have shown in cooperation with the department of pathology that about 50% of Lynch like cases are in fact caused by somatic mutations in the tumor and not germline mutations. Molecular tumour analysis  also showed that 20% of unsolved polyposis cases  are in fact APC mosaic. These outcomes have a great impact on the advice given to family members and aids in preventing unnecessary colonoscopies for first degree relatives.
  • 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

  • Next generation sequencing techniques will be applied in the search for cancer predisposing genes. The impact of identifying more predisposing genes for breast cancer, colorectal cancer, polyposis, paraganglioma and melanoma on patients and their family will be studied.
  • In close collaboration with BRIDGES and Hebon we want to explore the additional fraction of Dutch breast cancer families that will have an advantage of gene panel sequencing. Which non BRCA1/2 breast cancer genes are important to add to the diagnostic tests in the clinic? Based on these data advice for clinical management  can be given and clinical guidelines can be developed.
  • For Lynch syndrome, next to PMS2, we will also start in 2017 to assemble the largest cohort of MSH6 families worldwide. Currently, data on 100 families and approximately 2500 relatives are available from the LUMC and the Erasmus MC. With the cooperation of other centres data on over 200 families will become available for penetrance analysis, for which we will use a modified segregation analysis to correct for ascertainment bias. Secondly, we will try to unravel risk modifiers by analyzing genotype-phenotype and parent-of-origin correlation. to be able to perform also cancer risk studies for this gene. We expect that this project will establish unbiased cancer risks and increase our understanding of risk modifiers in MHS6. This will have implications for screening and treatment advice.
  • Furthermore, cancer risk studies in worldwide assembled biallelic LYNCH (CMMRD) families, including about 90 families,  will also be done to look at cancer risk in these families, which not has been done before.
  • Also tumours of Lynch patients, mainly PMS2 and MSH2 and MUTYH associated patients will be analysed to define the molecular, immunological and histological profile which will aid in detection and possibly provide therapeutic handles.
  • Psychological issues concern risk perception and subsequent management of risks, and the challenges for sound genetic counseling in the era of next generation sequencing. Based on our research we can give recommendations for clinical management.

Cohesion within LUMC

There is a strong flourishing multi-disciplinary collaboration within the medical profile Cancer Pathogenesis and Treatment (CPT) with the Departments of Human Genetics, Pathology, Surgery, Gastroenterology, Gynaecology, Dermatology, and the Departments of Medical Statistics, Epidemiology and Medical Decision Making.