Chapter One: Literature Review 1.1 Background The inception of a cancer occurs in cell division with a chance mutation. Thus cancer incidence depends on the number of cells at risk, their rate of division, the frequency of cancerous mutations and the viability of mutated cells. Figure 1: The Risk Paradigm Number of cells Genetic susceptibility Viable divisions time Cancerous transformation of a cell is therefore a rare event, occurring for breast cancer somewhere in the order of once in every ten to a hundred million cell divisions. This rate may be increased by events that increase the frequency of gene mutations (e.g.: irradiation), or by prior “pre – cancerous” mutation – a germline mutation that increases the number of cells at high risk of cancer formation. After the initial mutation a cancer cell may undergo many subsequent genetic alterations. Hence in sporadic breast cancer, mutations are commonly found in tumour cells. These somatic mutations may determine the phenotype of a particular breast cancer and their recognition may be of clinical value in determining prognosis. However, only germline (inherited) mutations can be found in normal cells and are therefore the only ones available to predetermine an individual’s risk of developing breast cancer. The significance of a germline mutation depends upon its prevalence and its penetrance (i.e.: the level of risk it imparts). If either of these factors is high then the mutation is likely to be clinically important. Highly penetrant mutations that are also prevalent are, of course, likely to be relatively easy to identify because of the clustering of cases in families. Mutations of low penetrance may be more prevalent and thus account for a higher percentage of all breast cancers but identifying carriers may be difficult. It is likely that there are few highly penetrant mutations that cause breast cancer (BR Cancer genes, BRCA1 and BRCA2). There may be more low penetrance mutations (Ataxia telangiectasia (mutated), ATM) and others yet to be identified). There are also a few rare mutations, which produce recognisable multicancer syndromes (Li Fraumeni and Bloom Syndromes). While landmark discoveries in the genetic mechanisms of breast cancer susceptibility have been made recently, the task of translating this new knowledge to clinical benefit remains daunting. This introduction aims to review all present knowledge of breast cancer susceptibility genes and those that are most likely to have successful application in the clinical arena. 1.2 BRCA Genes 1.2.1 Discovery of BRCA1 and BRCA2 breast cancer susceptibility genes Population-based studies have attempted to define the cancer risk associated with a positive family history of breast cancer. One of the largest studies was conducted in Sweden using mailed questionnaires, which were supported by pathology and hospital reports1. This involved 1330 women with histologically confirmed newly diagnosed breast cancer within a defined geographical region and included age-matched controls without breast cancer. Breast cancer in a first-degree relative was found in 11.2% of breast cancer patients as opposed to 6.7% of controls (p[...]... of BRCA1 and BRCA2 BRCA1 is a large gene consisting of 5592 nucleotides spread over 100 000 bases of genomic DNA The gene is composed of 24 exons that encode a protein containing 1863 amino acids14 Much of BRCA1 shows no homology to other known genes with the exception of a 126 nucleotide sequence at the amino terminus that encodes a RING finger motif This motif is found in other proteins that interact... arising in Israel, where genotyping for ancient mutations found that only three 18 BRCA1 mutations account for nearly all BRCA1 Jewish families45 In contrast, nearly all mutations of BRCA1 families in Italy are unique46,47 All germline BRCA mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect in which a certain mutation is common to a well-defined... respectively, another developed breast cancer at age 78, and two other carriers remained cancer-free at age 73 and 81 These variations in cancer phenotype and the degree of familial clustering in carriers of the same mutation suggest the presence of presently unknown modifying factors, either environmental or (more likely) genetic, that alters the clinical expression of these mutations The penetrance... and can theoretically be traced back to a common ancestor Given the complexity of mutation screening for BRCA1 and BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations Analysis of mutations that occur with high frequency also permits the study of a larger proportion of the general population, and this in turn to the study of their clinical expression... cancer, Struewing et al50 detected the BRCA1 185delAG mutation in 0.9% of subjects This is 2 logarithms higher than the expected frequency of all BRCA1 mutations combined in the general population No BRCA1 mutations were found in controls, which consisted of 815 individuals not selected for ethnic origin In a similar study carried out by Oddoux et al on 1255 Ashkenazi Jewish individuals, again unselected... outside of the OCCR Of the 82 families with mutations within the OCCR, the breast:ovarian cancer ratio was 160:48, while the 28 families with mutations outside the OCCR had a ratio of 103:14 This was not found to be statistically significant (p=0.12) and more studies are required to establish whether a clinically useful clustering of ovarian cancer predisposing mutations does exist In summary, the initial... quantifiable inherited cancer risk An intriguing approach to interpreting these early findings has been to look for a 29 phenotype – genotype correlation, where mutations at certain points in the gene may give rise to definite levels of risk of breast or ovarian cancer Given the large size of the gene and its wide mutation spectrum, such a correlation will be difficult to prove considering the relative... Ashkenazi Jews, where four mutations in BRCA1 and BRCA2 have been reported to account for the majority of Ashkenazi Jewish patients with inherited breast and/or ovarian cancer: 185delAG, 188del11 and 5382insC in the BRCA1 gene30,37,50-53 , and 6174delT in BRCA254 The 185delAG mutation in exon 2 was the commonest mutation reported in a collaborative review of the mutation spectrum of the BRCA1 gene by Shattuck-Eidens... Only 1 of the 6 was later found to have a significant family history of cancer Of the remaining 5 mutation carriers, 188del11 was found in 3 cases of late onset cancer, all of whom had breast cancer diagnosed in their 80s and had unremarkable family histories The 6174delT mutation in BRCA2 was first detected in a breast-ovarian cancer family of Ashkenazi Jewish descent In order to determine the frequency... the majority of women were therefore considered to be at low or moderate risk for breast cancer based on their family history For the BRCA1 185delAG and BRCA2 6174delT mutations, the lifetime risk for breast cancer was calculated to be 36%, similar to the Baltimore data Similar results were obtained by Dorum et al28, who examined the penetrance of the Norwegian BRCA1 1675delA and 1135insA founder mutations, . linked to the BRCA1 locus. Of these, 7 were later found to show positive linkage to BRCA2 and the remaining 3 families were in fact found to carry BRCA1 mutations when mutation analysis of the. obtained by Dorum et al 28 , who examined the penetrance of the Norwegian BRCA1 1675delA and 1135insA founder mutations, and Hopper et al 29 in a study of protein truncating mutations in Australia mutations are commonly found in tumour cells. These somatic mutations may determine the phenotype of a particular breast cancer and their recognition may be of clinical value 1 in determining