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Genetic polymorphism and breast cancer risk in young women
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Breast cancer is the most common malignancy among women in the western world. Although the disease is rare in young women, it is one of the main causes of death at young age. The early onset breast cancer has demonstrated more aggressive pathological features than the late onset disease. These observations have raised the hypothesis that the biological background may differ between age categories.

Breast carcinogenesis is a micro-evolutionary process that requires accumulation of DNA-damage and other epigenetic changes that promote cell survival and proliferation. The complexity of the disease makes it difficult to identify specific risk factors. Nevertheless, a large and compelling body of epidemiological and experimental data suggests that the cumulative dose of oestrogen is one key factor in the aetiology. Also, substantial data indicates that oxidative stress, from phosphorylation or other metabolic processes, is involved in the development of breast cancer. In young women, there is a strong genetic influence of breast cancer risk and beside mutations in highly penetrant genes, polymorphisms in a number of crucial genes may modify an individual's risk. Such modifier genes, associated with a more modest risk and high prevalence in the population, may contribute to a large proportion of the disease in the population. Identification of such predisposing polymorphisms may be an important step forward in identifiying individuals at risk. In the present thesis genetic polymorphisms in four different genes and their relation to early onset breast cancer, were analysed.

In the first study, a polymorphism with a TaqI restriction site in the vitamin D3 receptor (VDR) gene was studied. VDR and its ligand, 1,25(OH)2D3, have been suggested to be important factors for differentiation of the breast epithelium and may suppress mammary tumorigenesis. The presence of a TaqI restriction site has been shown to correlate with increased transcriptional activity and mRNA stability of VDR, as well as high serum levels of 1,25(OH)2D3 and this high receptor activity may be protective against breast cancer. In the present study VDR TaqI polymorphism did not predict risk of early onset breast cancer. However, the results indicate an association between lymph node metastasis and genotype. In the second study, a promoter polymorphism in the CYP17 gene, which may influence the oestrogen synthesis, has been analysed. The polymorphism was correlated to the risk of early onset breast cancer, and the risk increased in a dose dependent manner. The fmdings indicated also a trend for risk allele carriers to have ER-negative and large tumours. Oestrogens are metabolized to potentially carcinogenic catecholoestrogens, which could be inactivated by and O-methylation, catalysed by Catechol-O-methyltransferase (COMT). This gene contains a variant which encode for a protein with decreased activity and is therefore predicted to be a risk allele. In the third study, the investigation of allele frequencies of the polymorphic COMT gene did not show any epidemiological evidences of implication in breast cancer. Finally; increasing numbers of studies indicate an important role for MnSOD in a number of cancer cell types. A genetic variant of MnSOD results in a less efficient transport into the mitochondria which may lead to an insufficient scavenging of free radicals. In this study, the mitochondrial targeting polymorphism was associated with risk of breast cancer in young women.

In conclusion, genetic polymorphism in crucial genes may have impact on the risk of early onset breast cancer. Furthermore, some genotypes seems to influences the progression and outcome of the disease.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2004. , 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 837
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24060Local ID: 3619ISBN: 91-7373-811-5 (print)OAI: oai:DiVA.org:liu-24060DiVA: diva2:244376
Public defence
2004-03-05, Administrationshusets aula, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22
List of papers
1. Association of breast cancer progression with a vitamin D receptor gene polymorphism
Open this publication in new window or tab >>Association of breast cancer progression with a vitamin D receptor gene polymorphism
Show others...
1999 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 10, 2332-2334 p.Article in journal (Refereed) Published
Abstract [en]

The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1α,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age, <37 years) and a control population (n = 130), revealed no overall association to risk for breast cancer. However, patients without TaqI site (TT genotype) showed a significantly increased risk for lymph node metastasis (relative risk, 1.8, 95% confidence interval, 1.3- 2.6). Furthermore, a tendency toward an increased survival was found among estrogen receptor-positive, tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early- onset breast carcinomas.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24934 (URN)10344739 (PubMedID)9340 (Local ID)9340 (Archive number)9340 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved
2. Association between CYP17 gene polymorphism and risk of breast cancer in young women
Open this publication in new window or tab >>Association between CYP17 gene polymorphism and risk of breast cancer in young women
1999 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, 350-353 p.Article in journal (Refereed) Published
Abstract [en]

Long-term exposure to oestrogens is a well-recognised risk factor for breast cancer, whereas little is known about the influence of polymorphisms of genes involved in oestrogen biosynthesis and metabolism. A candidate, containing a single bp polymorphism, T→C, (designated, A2 allele), might be the CYP17 gene, which codes for an enzyme involved in oestrogen synthesis. This polymorphism creates an additional Sp1-type promoter site (CCACC box), which has been shown to be associated with increased serum oestrogen levels. We performed a case-control study, to evaluate association of the CYP17 gene polymorphism with risk of breast cancer in young women (younger than 37 years). We found a statistically significant increased risk in carriers of at least 1 A2 allele [odds ratio (OR), 2.0; 95% confidence interval (CI), 1.1–3.5, p = 0.027], and a trend toward a gene-dose effect illustrated by a slightly higher risk for A2-homozygous subjects (OR, 2.8) than for heterozygous women (OR, 1.9). Furthermore, when we investigated the CYP17 genotype in relation to tumour characteristics, breast cancer patients with 1 or 2 A2 alleles tended to have lower oestrogen receptor levels (risk ratio, 0.70; CI, 0.41–1.2, p = 0.44). Our findings suggest that CYP17 gene polymorphism influences breast carcinogenesis in young women.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24933 (URN)10.1002/(SICI)1097-0215(19990820)84:4<350::AID-IJC3>3.0.CO;2-L (DOI)9339 (Local ID)9339 (Archive number)9339 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved
3. Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women
Open this publication in new window or tab >>Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women
2001 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 6, 859-862 p.Article in journal (Refereed) Published
Abstract [en]

Oestrogen exposure has long been considered to be a main risk factor of breast cancer. More recently, interest has also focused on the possible carcinogenic influence from oestrogen metabolites, such as catechol oestrogens. O-methylation, catalysed by Catechol-O-Methyltransferase (COMT), is one pathway by which the potentially carcinogenic catechol oestrogens can be inactivated. The gene coding for COMT protein contains a single-nucleotide polymorphism (SNP), resulting in an amino acid shift Val Met, which has been shown to determine high- and low-activity configuration of the enzyme. We hypothesized that the low-activity allele, COMTMet, may be implicated in early onset breast cancer. In the present case–control study, including 126 young breast cancer patients ( 36 years) and 117 healthy female blood donors, we analysed the association between COMTMet genotype and risk of breast cancer. No significant difference in the frequency of low-/high-activity alleles was found between cases and controls, indicating that the polymorphism, as a single factor, may not contribute to breast carcinogenesis in young women.

Keyword
Catechol-O-Methyltransferase, COMT, genetic polymorphism, breast cancer, early onset, catechol oestrogens
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24935 (URN)10.1054/bjoc.2001.2009 (DOI)9341 (Local ID)9341 (Archive number)9341 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved
4. Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women
Open this publication in new window or tab >>Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women
2005 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 131, no 7, 439-444 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Manganese superoxide dismutase (MnSOD) is one of the major enzymes implicated in the cellular defence against reactive oxygen species. Low expression of MnSOD has been observed in different cancer tissues and several reports have shown that overexpression of MnSOD inhibits growth in various human cancer cells. These observations suggest that MnSOD is involved in carcinogenesis. A polymorphism (Ala-9Val) in the mitochondrial targeting sequence (MTS) of the MnSOD gene has been proposed to affect protein localization and thereby influence cellular defence against superoxide radicals.

Methods: In the present case-control study, including 118 early onset breast cancer patients (≤36 years) and 174 age-matched controls, the MTS polymorphism and loss of heterozygosity (LOH) in the locus of MnSOD were analysed.

Results: We found that individuals with MnSODVal/Val and MnSODVal/Ala genotypes showed an increased risk of breast cancer (OR, 2.7; 95% CI, 2.2–5.5, p=0.01, OR, 3.0; 95%CI, 1.4–6.5, p=0.002). Moreover, 45% of the informative cases expressed allelic loss at the chromosomal locus of the MnSOD gene. No correlation was found between LOH and the genotype.

Conclusion: The present study suggests that MnSOD may be implicated in breast carcinogenesis in young women.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31124 (URN)10.1007/s00432-004-0663-7 (DOI)16858 (Local ID)16858 (Archive number)16858 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-22Bibliographically approved

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