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Association between CYP17 gene polymorphism and risk of breast cancer in young women
Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
1999 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, s. 350-353Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
1999. Vol. 84, s. 350-353
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-24933DOI: 10.1002/(SICI)1097-0215(19990820)84:4<350::AID-IJC3>3.0.CO;2-LLokalt ID: 9339OAI: oai:DiVA.org:liu-24933DiVA, id: diva2:245257
Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Genetic polymorphism and breast cancer risk in young women
Öppna denna publikation i ny flik eller fönster >>Genetic polymorphism and breast cancer risk in young women
2004 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköpings universitet, 2004. s. 80
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 837
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-24060 (URN)3619 (Lokalt ID)91-7373-811-5 (ISBN)3619 (Arkivnummer)3619 (OAI)
Disputation
2004-03-05, Administrationshusets aula, Hälsouniversitetet, Linköping, 09:00 (Svenska)
Opponent
Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2012-10-22

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