Investigation of the genetic basis of familial non-BRCA1/2 breast cancer

Sammanfattning: Breast cancer is the most common female malignancy in the Western world and approximately 510% of all breast cancer cases present with some degree of family history. In the mid-nineties genetic linkage analyses successfully identified two breast cancer predisposing genes, BRCA1 and BRCA2. Mutations in these genes are responsible for the majority of large early onset breast and breast-ovarian cancer families. However, a large proportion of breast cancer families do not have mutations in BRCA1 or BRCA2 and therefore the genetic component in these nonBRCA1/2 families remains to be elucidated. HIN-1 is a putative tumour suppressor gene on chromosome 5q, which is silenced by methylation in the majority of sporadic breast cancers. Ten families exhibiting suggestive linkage to the region on 5q were investigated for germline mutations in the HIN-1 gene. No sequence alterations were identified in the ten families, or in DNA from 15 BRCA1 tumours and 35 sporadic tumours. In contrast to sporadic tumours, the HIN-1 promoter was completely unmethylated in BRCA1 tumours. HIN-1 is therefore unlikely to play a major role in breast cancer predisposition, however its altered expression may have consequences for breast cancer pathogenesis. (Paper I) Comparative genomic hybridization of non-BRCA1/2 breast carcinomas revealed that loss of chromosome 17 and chromosome 6q were frequent events in high-risk families while gain of 8q was a frequent event in low-risk families. Loss of genetic material from chromosome 17 suggested the presence of a tumour suppressor gene. Investigation of ten genes within a candidate locus on chromosome 17q1 1.2-12 revealed no obvious pathogenic sequence alterations. However, the frequent observation of genetic alterations involving chromosome 17 in breast tumours suggests the presence of novel genes, which may be involved in breast carcinogenesis. (Paper II) Re-evaluation of genetic linkage data based on global gene expression profliling of nonBRCA1/2 breast tumours identified chromosome 6 as a candidate locus for two non-BRCA1/2 families. Breast cancer in families 6006 and 6043 was linked to a 43.8 Mb region on chromosome 6, with suggestive LOD scores of 1.48 and 0.78 in the region for families 6006 and 6043 respectively. Detailed fine mapping revealed that these families shared a common four-marker haplotype 2-7-5-2 over a 2.8 Mb region on chromosome 6q14.1. The six genes within this region were investigated for the presence of a possible founder mutation in these two families. A number of shared sequence variants were identified in the two families, none of them were obviously pathogenic. (Paper III) Three polymorphisms in the estrogen receptor beta (ESR2) were investigated for their association to breast cancer. A total of 723 breast cancer cases were genotyped, 323 sporadic cases and 400 familial cases. No statistically significant differences in genotype distributions were observed for any of the three polymorphisms individually. However haplotype analysis revealed an association between one common haplotype G-A-G and increased risk of sporadic breast cancer (OR=3.0 p=0.03). This result suggests a role for ESR2 in breast cancer. (Paper IV)