Worldwide Study of Cancer Risks for Lynch Syndrome

Principal Investigator: Mark A. Jenkins, The University of Melbourne

Accurate risk estimates are needed to inform genetic counselling guidelines and the clinical management of high-risk families. The only way to address these problems is to conduct comprehensive penetrance analyses on large, ethnically heterogeneous samples of persons/families segregating mutations in MMR genes. To address these critical research needs, we will: (i) establish a combined data set of pedigree data from around the world for approximately 8,800 Lynch syndrome families; (ii) estimate the age-specific cumulative risk (penetrance) of cancers at each anatomical site by sex, mismatch repair gene, type of mutation, and nationality/geographic region; and (iii) develop a personal risk tool for clinical use that provides 10-year risks of cancer based on the age, sex, mismatch repair gene, type of mutation, and nationality/geographic region.

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  • Mark Jenkins (co-founder)
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  • Aung Ko Win
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  • Jeanette Reece (coordinator)
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Mismatch Repair Variant Classification

Principal Investigators: Marcus Greenblatt, University of Vermont; Sean Tavtigian, University of Utah

In clinical cancer genetics, molecular diagnostic testing is now commonly performed looking for pathogenic mutations in cancer susceptibility genes. A critical challenge in the field is interpreting whether a genetic variant causes disease or not. About 20-30% of the variants identified in MMR and other cancer susceptibility genes are missense or non-coding changes that may or may not be pathogenic, but whose effects on function and disease cannot be interpreted easily. They are designated “Variants of Unknown Significance”. Classifying variants as pathogenic and neutral significantly improves the management of LS and other hereditary cancer syndromes by identifying which individuals carry a harmful genetic variant and thus benefit from screening and therapeutic measures.  To address these needs we will: (i) generate a list of MMR missense variants and how they are classified using available data and criteria; (ii) validate and quantify the classifying ability of in vitro, in silico, and clinic-pathologic data; and (iii) create qualitative and quantitative models to classify variants.

  • Marcus Greenblatt
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  • Sean Tavtigian
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Worldwide Study of Genetic Testing and Cancer Screening in Lynch Syndrome

Principal Investigator: Robert Haile, Cedars-Sinai Medical Center, California, USA

Development of successful programs to increase the use of colonoscopy screening within Lynch syndrome family members depends on the availability and uptake of genetic testing of relatives in families with documented Lynch syndrome mutations.  Therefore an understanding of the variables underlying the choice of individual family members to be tested is important for reducing the burden of colorectal cancer screening in Lynch syndrome families. Colonoscopy screening has been demonstrated to significantly decrease both colorectal cancer incidence and mortality in Lynch syndrome. Additional studies in more racial/ethnic groups and in more countries and with longer follow-up are needed to better understand current compliance with screening guidelines and the reasons for lack of screening among those who harbor a deleterious mutation in a mismatch repair gene. Such information is as prerequisite to design methods to increase compliance with screening guidelines in this very high-risk population.  To address these needs we will: (i) clarify the country-specific guidelines for genetic counselling and testing for Lynch syndrome families and then collect data on the uptake of genetic counselling/testing by members of Lynch syndrome families; (ii) clarify country-specific guidelines for cancer screening in Lynch syndrome and then collect data on compliance with screening guidelines by members of Lynch syndrome families; and (iii) conduct focus groups to better understand “local”, country-specific barriers to compliance.

  • Robert Haile (co-founder)
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Collaborative Study on the Role of Lifestyle Factors/Diet/Body Fatness in the Development of Tumours in Lynch Syndrome

Principal Investigator: Franzel van Duijnhoven, Wageningen University

Lifestyle factors have a pronounced effect in those at a very high lifetime risk of cancer due to an inherited mutation: being overweight and smoking strongly increases the risk of colorectal tumours in persons with Lynch syndrome. Other lifestyle factors such as diet as well as other outcomes such as endometrial cancer in Lynch syndrome have not or only scarcely been studied. To further elucidate the role of lifestyle factors in the development of tumours in persons with Lynch syndrome, large populations with a variety in lifestyle habits are needed. Therefore, we propose to cooperate internationally and set-up a worldwide collaborative study on the role of lifestyle factors/diet/body fatness in the development of tumours in Lynch syndrome. To do this, we will: (i) perform a pilot study on smoking and overweight in relation to cancer risk in those cohorts that already have this information available; and (ii) write a large grant application (which includes the results from the pilot study) to collect and analyse data on lifestyle/diet/body fatness for all cohorts in our worldwide collaborative study. Our ultimate goal is to develop evidence-based lifestyle recommendations to decrease the risk of cancer in persons with Lynch syndrome.

  • Franzel van Duijnhoven
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  • Ellen Kampman
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MLH1 Epimutations in Predisposing to the Development of Lynch-type Tumors

Principal Investigator: Megan Hitchins, Cedars-Sinai Medical Center, California, USA

MLH1 epimutations manifests high levels of MLH1 methylation throughout normal tissues, and though comparatively rare, may account for a significant fraction of Lynch-type cases whose tumors demonstrate MLH1 absence but who have no germline sequence mutation of MLH1. Given its rarity, meaningful comprehensive studies will benefit from collaboration on an international scale. To address these needs we will: (i) establish the frequency of MLH1 epimutations in cases with a clinical suspicion of Lynch syndrome by testing the colorectal cancer cases clinically suspected of Lynch syndrome, but for whom no pathogenic mutation can be identified; (ii) measuring the clinical phenotype of epimutation carriers to gain a more detailed clinical profile; (iii) measuring the molecular profiling of tumors in epimutation-positive cases to determine the "second hit" plus more detailed TGCA-type analysis to elucidate the tumor molecular phenotype; and (iv) determining the inheritance patterns associated with MLH1 epimutations and the mechanisms underlying them by studying family members of epimutation carriers.

  • Megan Hitchins
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Cancer Risk in Family Members of CMMR-D Patients

Principal Investigator: Maartje Nielsen, Leiden University Medical Center

Risk of cancer is high for people who have inherited a mutation in a mismatch repair gene from both parents and therefore have constitutional mismatch repair-deficiency (CMMRD). However very little is known about the risks of cancer for their relatives on both sides of their family who carry a mutation (most often in the PMS2-gene). Understanding these risks is important for the clinical care of family members of CMMRD patients. Studying such relatives provides an unbiased estimate of cancer risk for heterozygous MMR mutation carriers in general. This is because in principal CMMRD families are ascertained because of the distinct phenotype of the index case, not because of family history of cancer. Due to the increased use of detection methods for Lynch syndrome, such as standardized IHC/MSI analysis in all CRC cases, and next generation sequencing, there will be an increase in the detection of apparently sporadic Lynch syndrome cases. For these patients knowledge on unbiased cancer risk is important to provide justified screening protocols. To address this gap, we will: (i) determine retrospectively the cancer risk in family members (up to third degree) of patients with CMMR-D; and (ii) conduct a follow-up study of family members with an identified heterozygous MMR mutation to prospectively estimate risk of cancer.

  • Maartje Nielsen
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