Mutagenesis in a family with Constitutional Mismatch Repair Deficiency Syndrome+ L. Lamola1,2, A. Vorster1, E. Chimusa1, U. Algar3, P. Goldberg3, R. Ramesar1 1Division of Human Genetics, Department of Pathology, Institute of infectious Disease and Molecular Medicine (IDM) University of Cape Town (UCT), 2Division of Human Genetics, National Health Laboratory Service, School of Pathology, University of the Witwatersrand; 3Surgical Gastroenterology Unit, Department of Surgery, Groote Schuur Hospital, (UCT) Introduction: The mismatch repair (MMR) system plays an important role in maintaining genome integrity. A heterozygous mutation in one of the MMR genes i.e. MLH1, MSH2, MSH6 and PMS2 cause dominant adult cancer syndrome, Lynch syndrome. In a large South African family of mixed ancestry, a c.1528C>T mutation in exon 13 of the MLH1 gene is the most common Lynch syndrome-causing variant in our cohort of patients in the Western Cape Province. A paediatric patient homozygous for this mutation diagnosed with Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome was described within this extended family. CMMR-D syndrome results in an increased predisposition to a range of cancers, most commonly brain and haematological tumours in early childhood. The aims of this study were to focus on the CMMR-D syndrome as a branch of Lynch syndrome and to potentially use the hyper-mutability-status to develop a working hypothesis for carcinogenesis in CMMR-D and Lynch syndromes. Methods: Whole exome sequencing (WES) was performed in the blood of the mother and father and the saliva of the CMMR-D proband and her sibling. A cancer panel (designed in house) was used for targeted NGS on seven tissues (including adrenal gland, bowel, cerebellum, cerebrum, kidney, liver, and spleen) and saliva, from the proband who had developed brain cancer and had demised by five (5) years of age. In order to investigate the extent of hyper-mutability in CMMR-D, sequence comparisons were performed to identify new mutations in the proband not present in her parents and to compare mutations across her different tissues. The list of new variants was used to identify genes that were involved and to assess protein-protein interactions and pathway-based analysis to identify the most enriched pathways in hyper-mutability. Results: No specific regions of the genome were identified as prone to acquiring more variants due to MMR deficiency in CMMR-D. However, a range of pathways that were enriched among genes in which variants were identified, including the extracellular matrix, WNT signalling, TGFβ and p53 and that could be linked to MMR deficiency. Discussion and Conclusion: This study points to the potential involvement of a range of pathways associated with cancer development in CMMR-D which may be indirectly involved in tumorigenesis as a result of MMR deficiency. The study suggests that it is likely that some of these biological processes or pathways are also involved in the emergence of extra-colonic cancers in individuals affected with Lynch syndrome.
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