U555297.pdf (88.88 MB)
A study of allelic imbalance in human breast cancer.
thesisposted on 2015-11-19, 09:07 authored by Marie-Louise. Loupart
The analysis of loss of heterozygosity (LOH) in tumours can be used to map candidate sites of tumour-suppressor genes in the human genome. A panel of breast cancer patients was assembled as pairs of tumour and lymphocyte DNA samples and LOH studies carried out by Southern hybridization with polymorphic loci mapping to chromosomes 1 and X. Loci on other chromosomes were also studied as controls. Sequences on chromosome 1 were found to be subject to a variety of alterations creating very complex patterns of rearrangements, including LOH. Deletion mapping identified five independent regions of loss, three of which may correspond to regions identified in previous reports, although individually none occurred with high frequency to support the targeting of a specific locus. The short arm of chromosome 1 primarily underwent interstitial deletions whereas the long arm was subject to both whole arm events (gains and losses) and more localized events. Small deletions on chromosome 1 were found exclusively in patients with poorly-differentiated tumours (i.e. tumours of high grade, p<0.05). A similar study of the X chromosome revealed a high frequency of small regionalized deletions, primarily defining three small independent regions, one located in the distal portion of the pseudoautosomal region of Xp, another spanning the pseudoautosomal boundary into the sex-specific sequences of Xp and a possible third on distal Xq. No gains in copy number were identified at any locus on the X chromosome, in distinct contrast to chromosome 1. Small-scale deletions occurring on the X chromosome were found in patients with no spread of cancer to the lymph nodes, thus correlating with a favourable prognosis (p<0.005). Fluorescence in situ hybridization to formalin-fixed paraffin-embedded tumour sections defined the actual copy number of chromosome 1 for nine tumours. The results obtained confirmed the changes established by Southern hybridization.
Date of award1993-01-01
Awarding institutionUniversity of Leicester