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- Jansson, Agneta, 1973-, et al.
(författare)
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A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer
- 2007
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 106:1, s. 57-64
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Tidskriftsartikel (refereegranskat)abstract
- In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.
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| 2. |
- Margolin, Sara
(författare)
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Family history and breast cancer susceptibility : clinical and molecular studies
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apart from gender, family history is the most important risk factor for breast cancer. In 5-10 % of the cases there is a family history pattern of an autosomal dominant disease and there is also a familial clustering of breast cancer associated with a more modest increased risk of the disease. Mutations in the known high risk genes BRCA1, BRCA2 and p53 account for less than 25% of the familial risk for breast cancer, while the remainder remain genetically unexplained despite a large effort in research. A polygenic model has been proposed to best explain the residual familial breast cancer risk and also to contribute to sporadic breast cancer susceptibility in interaction with environmental factors. In order to further elucidate the impact of genetic susceptibility for familial and sporadic breast cancer, a population-basect-cohort of 489 breast cancer patients from southern Stockholm was collected. For all patients, information on family history, clinical data and 5 years follow-up was retrieved. In addition, a riskcohort of 350 non-BRCA1/2 familial patients from the Stockholm region were used for these studies. In total 32% of the patients in the population-based cohort reported a family history of breast cancer and 10% was defined a high-risk familial group. There was no relation between family history and age of onset, hormonal background, tumour characteristics, treatment or prognosis. The population-based cohort was screened for mutations in BRCA I (exon 11). Two mutations.(< 1 %) were detected, both in cases with a family history of both breast and ovarian cancer. Sporadic (n=313) and familial (n=387) breast cancer cases and controls (n=760) were screened for the rare truncating variant, CHEK2 1100delC, which has previously been shown to be associated with familial and unselected breast cancer. Of the familial patients 2.3% carried the variant compared to 0.7% of the controls. The prevalence was not increased in sporadic patients (0.3%), The variant seemed to influence age at onset, with a lower mean age in carriers than in non-carriers. Analysis of a common single single nucleotide polymorphism orphism, C975G, in the estrogen In receptor a (ESR1) gene in 288 sporadic, 197 low risk and 191 high risk non BRCA1/2 familial breast cancer suggested a protective effect of the variant allele in high-risk familial breast cancer compared to controls. No association was seen in low risk familial or sporadic cases. Three polymorphisms in the estrogen receptor â (ESR2) gene were analysed for association wi h familial and sporadic breast cancer. In total 723 breast cancer cases were genotyped, 323 sporadic cases and 400 non-BRCA1/2 familial cases. There was no overall significant difference in genotype distribution but one common haplotype .pc, G-A-G, was associated with an increased risk of sporadic breast cancer indicating a role for ER,â in breast cancer susceptibility.
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