Hereditary cancer genetics

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 low penetrance cancer predisposing genes and variants, 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.

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. We are national recognized expertise centra for familial and heritable forms of breast cancer, colon cancer and melanoma. We are furthermore member of the European Reference Network on GENetic TUmour Risk Syndromes. Other participations for breast cancer include 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), the The Prospective Lynch Syndrome Database (PLDS) and the International Mismatch Repair Consortium (IMRC), for melanoma there is the Genomel Consortium.

The extensive database of patients and, families combined with the hospital based series of sporadic 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 melanoma, or modify the cancer risk in carriers of a mutation predisposing to cancer, such as BRCA1/2, CDKN2A, and the mismatch repair genes.

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.

Lynch syndrome caused by mismatch repair (MMR) gene explains about 2 to 5% of these cancers. Polyposis syndromes (mainly germline APC or MUTYH mutations) are present in 1-2 % of colon cancer patients. By assembling the world largest PMS2 cohort we have analyzed 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. Also we have the molecular background of tumors and the geno-phenotype correlation in PMS2 for the first time. Currently the same endeavor is being doing for MSH6 and results are expected in 2022.

Our research has furthermore focused on unsolved cases with mismatch repair deficiency- or polyposis without detectable APC or MUTYH mutations. We perform tumor molecular analysis and literature meta-analysis to understand the background of unsolved MMR deficiency in tumors. Molecular tumour analysis -also showed that 20% of unsolved polyposis cases  are in fact APC mosaic. In 2021 we have furthermore shown the presence of certain bacteria in the gut can also predispose to polyposis, leaving a specific molecular signature in the polyps. These outcomes have a great impact on the advice given to family members and aids in preventing unnecessary colonoscopies for first degree relatives.

The major high-risk gene for hereditary melanoma is CDKN2A. Our research has mainly been centered around patients with a specific Dutch founder mutation (CDKN2A-p16-Leiden) which is rather frequent in the geographical area around Leiden. With a focus on cancer risks and surveillance strategies, there is a strong clinical and scientific collaboration between the departments of Clinical Genetics, Dermatology and Gastroenterology. More recently, we have extended our genetic studies to melanoma families without a known underlying mutation and found that a specific gain-of-function mutation in the moderate penetrance MITF gene is the second most frequently involved gene in these families. Nevertheless, no monogenetic cause can be found in at least 60% of melanoma families, and thus our studies continue to focus on polygenic risk score (PRS) for melanoma which might (partly) explain this missing heritability. In a first study including 418 patient with familial melanoma, PRS was significantly associated with melanoma risk (OR 5.7 for patients with a PRS in the top 90th percentile), which underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families.

In 2019 we started a multidisciplinary clinic and research line for BAP1 associated tumor syndrome.  Studies on cancer risk and tumor profile for this rare tumor syndrome have been started in 2021.

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.

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 importance of breast cancer associated single nucleotide polymorphisms (SNPS) in Dutch breast cancer families. A polygenic risk score to individual women can be calculated when these SNPS have been analyzed. Our research focuses on the implications and usability of this test in the clinic. Based on these data advice for clinical management can be given and clinical guidelines can be developed.

For Lynch syndrome, we have assembled a larges cohort of MSH6 Lynch families and will analyze cancer risk amongst others. Currently, data on 300 families and approximately 5000 relatives are available from almost al Dutch cancer genetic centers. Together with the university of Melbourne we aim to perform cancer risk analysis in this group and correct for ascertainment bias. Secondly, we will try to unravel risk modifiers by analyzing genotype-phenotype and parent-of-origin correlation.
In cooperation with the department of Pathology we are analyzing the prevalence of APC mosaicism in multiple cohorts of polyposis and CRC patients, for example we are studying how and when certain E. colibacteria can lead to the formation of polyps.

We are analyzing a large cohort of MSH6, as well as other Lynch related colon cancers to understand the molecular background of these tumors and differences in cancer risk development with possible consequence for preventing and treating cancer in this patient group to define the molecular, immunological and histological profile which will aid in detection and possibly provide therapeutic handles.

In cooperation with the Dutch cancer institute and also other Dutch genetic centres variant of unknown significance in MMR genes (Lynch syndrome) are being collected in a consortium (INVUSE) and functional analysis in our institute as wel as the NKI are aimed add solving many of these cases.
The melanoma-specific PRS is promising for future risk stratification in melanoma families and we will therefore continue to study this PRS, not only in genetically unexplained families but also in families with a known underlying gene mutation like CDKN2A and MITF, because in these families, the PRS could also be a risk modifier which might explain the sometimes large variability in disease penetrance between family members with the same mutation. With a clinically useful PRS, patients can be better informed about their (age-specific) cancer risk and it can help patients and clinicians taking decisions regarding the starting age and frequency of cancer surveillance or other (preventive) measures to decrease cancer risks.

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.