The Identification of Genetic Alterations in Pre-Invasive Breast Cancer

Medicine, Oncology

Wilson, Christopher Reid

University:University of Glasgow

关键词: Medicine, Oncology;   

Others  :  http://theses.gla.ac.uk/75922/1/13818660.pdf

来源: University of Glasgow

【 摘 要 】

In recent years much interest has focused on the early detection of breast carcinoma and the potential for prevention strategies for women at high risk, and this has been fuelled by the implementation of breast screening programmes which have increased the diagnosis of all forms of pre-invasive disease. The management of women found to have proliferative breast disease is unsatisfactory with mammographic surveillance being the only realistic option for these patients. It is therefore particularly important that the genetic profile of these lesions is comprehensively studied in order to detect potential biomarkers for progression and hence future avenues for therapeutic intervention and prevention. The aim of the study is to reconstruct the molecular evolution of breast cancer progression with particular emphasis on the critical pre-invasive steps. It is hypothesised that a normal breast epithelium can evolve to breast cancer through the intermediary stages of proliferative disease without atypia [PDWA], atypical ductal hyperplasia [ADH] and ductal carcinoma in situ [DCIS]. The characterisation of genetic alterations shared by DCIS and invasive breast cancer has reinforced evidence that DCIS is a true non-obligate precursor of breast cancer, however there is little genetic evidence to substantiate the hypothesis that PDWA is a precursor of invasive breast cancer. Our group had previously shown DCIS to have chromosomal imbalances involving chromosomes 1, 3, 10, 17 & 18, therefore 31 cases of PDWA were analysed by fluorescence in-situ hybridisation [FISH] using chromosome specific centromeric probes for chromosomes 1, 3, 10, 17 &18. Chromosomal imbalances affecting those chromosomes were detected in PDWA which mirror those found in DCIS but at a reduced frequency suggesting that a subpopulation of PDWA resembles DCIS at a molecular level and are at a greater risk of progression. A huge increase in the frequency of chromosomal imbalances affecting chromosomes 3 & 17 occurs between PDWA and DCIS thus key genetic events involved in the progression of PDWA to DCIS may be present on those chromosomes. In contrast chromosome imbalances affecting chromosome 18 were present at a high frequency in both PDWA and DCIS suggesting that this chromosome harbours genes responsible for the earliest stages of breast cancer progression. There is therefore a requirement to define the regions of change in chromosome 18 in more detail to identify candidate genes. Multiple foci of DCIS from sections known to have a loss of chromosome 18 sequences were therefore microdissected and three polymorphic microsatellite markers for chromosome 18 were PCR amplified in order to detect regional alterations to chromosome 18 and to investigate the phenomenon of intratumour genetic heterogeneity. A high frequency of allelic imbalance was found for all the markers with the highest frequency incorporating the region of 18q23, suggesting that this region harbours genes crucial to the early progression of breast cancer. Individual foci of DCIS exhibited a high degree of genetic heterogeneity for chromosome 18 which suggests that several subclones of DCIS may coexist within an individual. These results set the agenda for the future investigation of genetic alterations in pre-invasive breast disease.