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Wingren, Sten
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Palmebäck Wegman, P., Marcus, N. J., Paul Malakkaran, B. & Wingren, S. (2009). Biological significance of allele specific loss of the p53 gene in breast carcinomas. BREAST CANCER RESEARCH AND TREATMENT, 118(1), 15-20
Open this publication in new window or tab >>Biological significance of allele specific loss of the p53 gene in breast carcinomas
2009 (English)In: BREAST CANCER RESEARCH AND TREATMENT, ISSN 0167-6806, Vol. 118, no 1, p. 15-20Article in journal (Refereed) Published
Abstract [en]

The p53 tumor suppressor gene has a central role in the defense against cancer, including breast cancer, and contains a polymorphic variant (Arg/Pro) at codon 72 that has been shown to have different biological properties regarding apoptosis and cell cycle arrest. Earlier studies have shown allele specific loss of heterozygosity (LOH) at this particular site and we aimed to investigate its biological relevance in codon 72 heterozygous breast cancer patients (i.e., survival and age of disease onset). 199 postmenopausal cases were analyzed for LOH using MegaBACE(1000) and statistics was performed using Statistical Package for Social Sciences. LOH was found in totally 124 (62.3%) patients and the Pro allele (n = 103) was significantly more often deleted compared to the Arg allele (n = 21) (P = 0.001). Patients with LOH of the Arg allele were diagnosed at an earlier age (mean age 62.5 years) than those with loss of the Pro allele (mean age 69.2 years) (P = 0.011). LOH of the Arg allele was also associated with worse survival (P = 0.05). LOH in comparison to ROH correlated significantly with increased S-phase fraction. Tumor size, stage or number of positive lymph nodes was not related to LOH. Our results and earlier findings suggest a selective loss of the Pro allele during carcinogenesis that might confer a growth advantage for cancer cells. On the other hand, it appears to be more harmful for patients to loose the Arg allele since we found that loss of this allele was associated with earlier onset and worse prognosis.

Keywords
Breast cancer, p53, Codon 72, Loss of heterozygosity, p53 Mutations
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51397 (URN)10.1007/s10549-008-0212-1 (DOI)
Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2009-10-30
Lang, A., Palmeback Wegman, P. & Wingren, S. (2009). The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer. ONCOLOGY REPORTS, 22(3), 575-579
Open this publication in new window or tab >>The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer
2009 (English)In: ONCOLOGY REPORTS, ISSN 1021-335X, Vol. 22, no 3, p. 575-579Article in journal (Refereed) Published
Abstract [en]

The p53 protein and its regulator MDM2 is central to tumorigenesis by directing cells to undergo cell cycle arrest and/or apoptosis in response to DNA damage or other stress signals. The genes encoding these proteins contain nucleotide variation (p53 codon 72, MDM2 SNP309) that influences cellular response. We examined the p53 codon 72 and MDM2 SNP309 to determine their implication with age of disease onset and risk of breast cancer in young women (andlt;= 36 years). No risk of breast cancer was observed for the genotypes of p53 and MDM2, however, a tendency (P=0.15) towards increased risk of early onset breast cancer was observed in carriers of two or more Pro and/or G alleles. We further calculated the influence on age at diagnosis. Cases were grouped according to the number of G and Pro alleles (0, 1, 2 or 3-4) and age at diagnosis. A significant trend towards decreased age at diagnosis with increased number of risk alleles was found (P=0.013). Our results suggest that p53 codon 72 and MDM2 SNP309 may be implicated in early onset breast cancer.

Keywords
breast cancer, early onset, age of onset, polymorphism, p53, MDM2, codon 72, SNP309
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19992 (URN)10.3892/or_00000474 (DOI)
Available from: 2009-08-24 Created: 2009-08-24 Last updated: 2009-08-24
Jerevall, P.-L., Brommesson, S., Strand, C., Gruvberger-Saal, S., Malmström, P., Nordenskjöld, B., . . . Stål, O. (2008). Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome. Breast Cancer Research and Treatment, 107(2), 225-234
Open this publication in new window or tab >>Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome
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2008 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 107, no 2, p. 225-234Article in journal (Refereed) Published
Abstract [en]

Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict the outcome of tamoxifen-treated breast cancer patients. We intended to examine whether this ratio can predict the benefit of 5 years vs. 2 years of tamoxifen treatment of postmenopausal patients. A further objective was to investigate any prognostic effects of the ratio in systemically untreated premenopausal patients. Based on the current knowledge of HOXB13 and IL17BR, we hypothesized that these genes may have individual prognostic or predictive power.

Patients and methods: Expression of HOXB13 and IL17BR were quantified by real-time PCR in tumors from 264 randomized postmenopausal patients and 93 systemically untreated premenopausal patients.

Results: A high HOXB13:IL17BR ratio was associated with aggressive tumor characteristics, as were low levels of IL17BR alone. The ratio and HOXB13 alone predicted recurrence-free survival after endocrine treatment, with a benefit of prolonged treatment in estrogen receptor-positive patients correlated to a low ratio (recurrence rate ratio: RR=0.39; p=0.030), or low expression of HOXB13 (RR=0.37; p=0.015). No difference in recurrence-free survival was seen for the high ratio or high HOXB13 subgroups. The predictive value of HOXB13 and HOXB13:IL17BR was significant in multivariate analysis. In the systemically untreated cohort, only IL17BR showed independent prognostic significance.

Conclusion: We conclude that the ratio or HOXB13 alone can predict the benefit of endocrine therapy, with a high ratio or a high expression rendering patients less likely to respond. We have also shown that IL17BR might be an independent prognostic factor in breast cancer.

Place, publisher, year, edition, pages
Institutionen för klinisk och experimentell medicin, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-11861 (URN)10.1007/s10549-007-9541-8 (DOI)
Note
The original publication is available at www.springerlink.com: Piiha-Lotta Jerevall, Sara Brommesson, Carina Strand, Sofia Gruvberger-Saal, Per Malmström, Bo Nordenskjöld, Sten Wingren, Peter Söderkvist, Mårten Fernö and Olle Stål, Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome, 2008, Breast Cancer Research and Treatment, (107), 2, 225-234. http://dx.doi.org/10.1007/s10549-007-9541-8. Copyright: Springer, www.springerlink.comAvailable from: 2008-05-21 Created: 2008-05-21 Last updated: 2017-12-13Bibliographically approved
Licznerska, B. E., Wegman, P. P., Nordenskjöld, B. & Wingren, S. (2008). In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients. Breast Cancer Research and Treatment, 112(1), 15-23
Open this publication in new window or tab >>In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients
2008 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, no 1, p. 15-23Article in journal (Refereed) Published
Abstract [en]

Background: The risk of developing breast cancer is strongly correlated with the overall exposure to oestrogen and most tumours are more or less dependent on oestrogen for their growth. A great majority of breast cancers occur after menopause when the ovaries have ceased to be functional, yet breast tumours in postmenopausal women maintain high intratumoural oestrogen concentrations, primarily through enzymatic conversion of androgenic precursors. Patients with a hormone dependent tumour generally receive the anti-oestrogen tamoxifen that mediate its anti-tumour effect by competing with oestrogen for binding to the oestrogen-receptor (ER). We therefore propose that the levels of oestrogen producing enzymes may affect the prognosis in postmenopausal breast cancer patients treated with tamoxifen. Methods: We measured the mRNA and protein levels of aromatase and sulfatase by real-time PCR (n = 161) and immunohistochemistry (n = 131) in postmenopausal women with breast cancer. Results: A significant better recurrence-free survival was detected in patients with weak or high protein expression of stromal aromatase (P = 0.0008), as also demonstrated by a decreased relative risk (RR = 0.50, CI = 0.33-0.76, P = 0.003). When we combined patients with weak and high stromal aromatase and selected only ER-positive patients, the improved prognosis was even more evident (P = 0.0000) and was shown to be a significant prognostic factor in a multivariate Cox-model (HR = 0.15, CI = 0.06-0.39, P = 0.000). The mRNA expression of aromatase and sulfatase, as well as the protein expression of sulfatase revealed no prognostic significance. Conclusion: Protein expression of stromal aromatase may serve as a significant prognostic marker in ER-positive patients. © 2007 Springer Science+Business Media, LLC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43543 (URN)10.1007/s10549-007-9819-x (DOI)74144 (Local ID)74144 (Archive number)74144 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
Wegman Palmebäck, P., Elingarami, S., Carstensen, J., Stål, O., Nordenskjöld, B. & Wingren, S. (2007). Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients. Breast Cancer Research, 9(1), R7
Open this publication in new window or tab >>Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients
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2007 (English)In: Breast Cancer Research, ISSN 1465-5411, Vol. 9, no 1, p. R7-Article in journal (Refereed) Published
Abstract [en]

Introduction

Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

Methods

In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

Results

The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

Conclusion

The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14535 (URN)10.1186/bcr1640 (DOI)
Note

Original Publication: Pia Wegman, Sauli Elingarami, John Carstensen, Olle Stål, Bo Nordenskjöld and Sten Wingren, Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients, 2007, Breast Cancer Research, (9), R7. http://dx.doi.org/10.1186/bcr1640 Licensed by: CURRENT SCIENCE LTD

Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2018-02-12Bibliographically approved
Wegman (Palmebäck), P., Stål, O., Stenmark Askmalm, M., Nordenskjöld, B., Rutqvist, L.-E. & Wingren, S. (2006). p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients. Pharmacogenetics and Genomics, 16(5), 347-351
Open this publication in new window or tab >>p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
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2006 (English)In: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, no 5, p. 347-351Article in journal (Refereed) Published
Abstract [en]

Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.

 

Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.

 

Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).

 

Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14537 (URN)10.1097/01.fpc.0000204997.84182.69 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-03-28
Palmebäck Wegman, P. & Wingren, S. (2005). CYP2D6 variants and the prediction of tamoxifen response in randomized patients: authors' response. Breast Cancer Research, 7(6), 234-234
Open this publication in new window or tab >>CYP2D6 variants and the prediction of tamoxifen response in randomized patients: authors' response
2005 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 6, p. 234-234Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33339 (URN)10.1186/bcr1326 (DOI)19350 (Local ID)19350 (Archive number)19350 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13
Wegman (Palmebäck), P., Vainikka, L., Stål, O., Nordenskjöld, B., Skoog, L., Rutqvist, L.-E. & Wingren, S. (2005). Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Research, 7(3), R284-R290
Open this publication in new window or tab >>Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
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2005 (English)In: Breast Cancer Research, ISSN 1465-5411, Vol. 7, no 3, p. R284-R290Article in journal (Refereed) Published
Abstract [en]

Background

Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

Methods

The patients were genotyped using PCR followed by cleavage with restriction enzymes.

Results

Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

Conclusion

The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

Keywords
breast cancer, CYP2D6, polymorphism, SULT1A1, tamoxifen
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14534 (URN)10.1186/bcr993 (DOI)
Note

Original Publication: Pia Wegman, Linda Vainikka, Olle Stål, Bo Nordenskjöld, Lambert Skoog, Lars-Erik Rutqvist and Sten Wingren, Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients, 2005, Breast Cancer Research, (7), R284-290. http://dx.doi.org/10.1186/bcr993 Licensed by: CURRENT SCIENCE LTD

Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2018-02-06Bibliographically approved
Bergman, M., Ahnström, M., Palmebäck Wegman, P. & Wingren, S. (2005). Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women. Journal of Cancer Research and Clinical Oncology, 131(7), 439-444
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, p. 439-444Article 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: 2017-12-13Bibliographically approved
Jerevall, P.-L., Ahmadi, A., Bergman, M., Stål, O. & Wingren, S. (2005). Sulfotransferase1A1 and risk of postmenopausal breast cancer. Anticancer Research, 25(3 C), 2515-2517
Open this publication in new window or tab >>Sulfotransferase1A1 and risk of postmenopausal breast cancer
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2005 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 3 C, p. 2515-2517Article in journal (Refereed) Published
Abstract [en]

The detoxification enzyme sulfotransferase1A1 (SULT1A1) is implicated in the inactivation of estrogens and the activation of promutagens andprocarcinogens. SULT1A1 activity varies among individuals, and this difference in phenotype is, in part, controlled by genetic polymorphism (Arg→His in codon 213). It is hypothesized that the His allele contributes to the risk of postmenopausal breast cancer. Frequencies of the Arg/His alleles were estimated in 229 postmenopausal breast cancer patients and 227 age-matched controls using a PCR-RFLP assay. Allele frequencies and genotype distributions were not statistically different between postmenopausal breast cancer patients and the population-based controls, i.e. neither of the alleles is associated with an increased risk of breast cancer in the present study.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31348 (URN)17114 (Local ID)17114 (Archive number)17114 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
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