Molecular mechanisms of tissue-specific MMRD-driven cancer development
Mentor Name: Uri Tabori
Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) is the most aggressive human cancer predisposition syndrome known to date. CMMRD patients will typically develop hematological, gastrointestinal, and brain malignancies at young age, and most will not survive into adulthood. At the root of CMMRD lies functional impairment of DNA replication repair triggered by germline biallelic mutations in one of the four mismatch repair (MMR) genes (MSH2, MSH6, MLH1, and PMS2). This functional impairment, mismatch repair deficiency (MMRD), leads to rapid accumulation of somatic mutations and the development of tumours with the highest somatic mutation burden of any human cancer. Through the International Replication Repair Deficiency Consortium (IRRDC), the Tabori laboratory aims to comprehensively dissect the genetic mechanisms underlying these tumors and improve diagnostics and treatment for CMMRD patients. As founder of the IRRDC, Dr. Tabori is uniquely skilled to serve as a mentor in developing the student’s knowledge base on genetic cancer predisposition syndromes. The province of Newfoundland and Labrador (NL) has the world’s highest recorded prevalence of colorectal cancer and, over the last 20 years, unusual familial clusters of brain tumours have also been detected. These observations suggest a yet unidentified, genetic, and possibly hereditary etiology for these cancers. Furthermore, the increased NL prevalence of particular cancer types suggests a yet undiscovered biological mechanism of tissue-specific cancer development. At present, most known CMMRD driver mutations have been identified within the coding sequences of MMR genes. Interestingly, by analyzing NL brain tumor samples covering the last 20 years, we have recently identified a novel germline mutation, located in the MSH2 gene promoter (-82G>C) and present in all -82G>C homozygous NL early-onset brain cancer patients (Homozygous=5%, n=117, age range:0-40). Importantly, all brain tumours from homozygous -82G>C patients display concomitant MSH2 promoter DNA hypermethylation and complete loss of MSH2 by immunohistochemistry analysis (IHC). Using reporter gene assays, we have previously shown that, in vitro, -82G>C mutation significantly decreases MSH2 promoter function (>60%) and that MSH2 promoter DNA hypermethylation completely ablates promoter activity (unpublished data). Based on these observations, we hypothesize that -82G>C MSH2 promoter mutation leads to tissue-specific promoter DNA hypermethylation, followed by MSH2 downregulation and corresponding MMRD, resulting in MMRD-driven tumorigenesis.
