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- Maguire, Paula
(författare)
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Investigation of the genetic basis of familial non-BRCA1/2 breast cancer
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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)
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- Schoumans, Jacqueline, et al.
(författare)
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Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients
- 2007
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 15:2, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5' untranslated region (5' UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.
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