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A molecular genetic analysis of the chromosome 17q21 region containing the familial breast/ovarian cancer susceptibility gene, BRCA1

Jones, Karen Anne; (1995) A molecular genetic analysis of the chromosome 17q21 region containing the familial breast/ovarian cancer susceptibility gene, BRCA1. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Breast cancer is the most common malignancy in women, affecting about one in ten in the Western world. Although most cases are sporadic, around 5% are due to inherited susceptibility genes. One such gene, termed BRCA1 may account for up to 1/3 of all cases diagnosed before 30 years and in addition appears to be important in the onset of some cases of ovarian cancer. In families in which both breast and ovarian cancer cases are inherited, BRCA1 appears to be almost always responsible. With the lack of positional, biochemical and functional clues to the identity of BRCA1, its isolation required a positional cloning strategy. The work described here commenced with the physical characterisation of the chromosome 17q21 region containing BRCA1 and progressed through the various stages of the positional cloning strategy with the aim of isolating the responsible gene. The initial part of this work was concerned with the construction of a detailed long-range restriction map spanning over 3.5 megabase pairs of the BRCA1 region. This map detailed the precise location of previously isolated genes and markers in addition to the identification of the putative locations of other genes in the region. This information proved crucial to the construction of genomic clone contigs by orientating genomic clone walks and estimating the distances between them. As part of the next stage in the positional cloning process, this project concentrated on a 1.0-1.5 megabase pair stretch of the region which appeared to be the most likely location of the BRCA1 gene, as suggested by parallel genetic studies. This work involved the construction of a complete genomic clone contig spanning the distal half of this region to complement other work in the laboratory concerned with cloning the remaining half of the region. A thorough transcriptional analysis of this contig was carried out as part of this project and a number of new genes in the region were isolated with the aid of a variety of gene isolation techniques including direct selection, exon-trapping, surveying for evolutionary conservation and the identification of CpG islands. The work culminated in the mutational analysis of a strong candidate in the region. With the recent identification of a novel gene bearing all the requirements for BRCA1, the detailed physical characterisation described here of the region surrounding this gene will be useful in future efforts to reveal the normal functions of this gene and how it causes oncogenesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A molecular genetic analysis of the chromosome 17q21 region containing the familial breast/ovarian cancer susceptibility gene, BRCA1
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10103774
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