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Title: Genetic and epigenetic studies of autosomal recessive predisposition to neoplasia
Author: De Vos, Michel
ISNI:       0000 0001 3397 3624
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2006
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The availability of comprehensive genetic and structural data on the human genome, far from signalling the end of the era of human genetics, has greatly increased the power of genetic approaches to biological and pathological questions. For autosomal recessive . disorders, homozygosity mapping has proved to be a powerful method for gene mapping and identification. In this thesis, linkage and molecular studies are described of two distinct disorders offamilial cancer predisposition. .' Through homo,zygosity mapping of rare cases ofAsian origin, an attempt has been made to refine the localisation, on chromosome 19q13.4, of a gene causing biparental complete hydatidiform mole (BiCHM), a condition that predisposes to gestational trophoblastic disease and to choriocarcinoma. In one other family, that did not show linkage to the 19q13.4 locus, high-resolution mapping of an autozygous segment on chromosome 10 was p~rformed. Although BiCHM is geneti~ally heterogeneous, methylation studies of imprinted genes demonstrated an identical global lack of maternal imprints in the abnormal conceptions of all cases tested, which points towards a common oocyte-specific defect of epigenetic control underlying most if not all BiCHM cases. Using a similar approach, homozygosity ~apping ~as performed in an Asian family with an unusual combination of early-onset haematological and brain tumours, along with features suggestive of neurofibromatosis type I (NFl). Biallelic mutations in PMS2, a mismatch repair gene rarely implicated in HNPCC and Turcot syndrome, were eventually identified in seven unrelated families with this cancer syndrome. Evidence was obtained that the R802X nonsense mutation, which was subsequently found in 5 unrelated Pakistani Muslim fCl:milies, may represent a common allele in this population. This could have important implications for future carrier screening programs. Finally, a start was made in establishing the nature and the clinical significance ofgene conversion between PMS2 proper and PMS2CL, a novel inverted pseudogene, located less than I Mb centromeric ofPMS2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available