| 1. |
- Arason, Adalgeir, et al.
(författare)
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Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
- 2010
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:4, s. R50-
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
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| 2. |
- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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| 3. |
- Hagman, Anna, et al.
(författare)
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Obstetric and neonatal outcome after oocyte donation in 106 women with Turner syndrome: a Nordic cohort study.
- 2013
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Ingår i: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 28:6, s. 1598-609
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Tidskriftsartikel (refereegranskat)abstract
- What are the obstetric and neonatal outcomes of deliveries after oocyte donation (OD) in women with Turner syndrome (TS)? SUMMARY ANSWER: Pregnancies among women with TS carry a substantial risk, particularly for hypertensive disorders. Potentially life-threatening complications occurred in 3.3% of pregnancies. The neonatal outcomes were generally reassuring, with similar rates of preterm birth and low birthweight (LBW) as after conventional IVF and better than previously reported in deliveries after OD in women with TS. WHAT IS KNOWN ALREADY: OD pregnancies in women with TS are known to be high-risk pregnancies. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 106 women with TS who delivered after OD (n = 122 deliveries, n = 131 newborns) in three Nordic countries (Finland, Denmark, Sweden) between 1992 and 2011. PARTICIPANTS, SETTING AND METHODS: Women with TS who delivered after OD in three Nordic countries were identified (n = 110). Four women declined to participate or were lost to follow-up, thus 106 women were included in the study. The medical data from fertility clinics, antenatal clinics and the hospitals where the women had been treated and/or delivered were scrutinized. MAIN RESULTS AND THE ROLE OF CHANCE: In this cohort, the karyotype was 45,X in 44% of the women with TS. Ten women (9.4%) had a known cardiac defect before pregnancy. Single embryo transfer was performed in 70.3% of the cases and the multiple birth rate was 7.4%. In total, 35.0% of the pregnancies were associated with a hypertensive disorder including pre-eclampsia in 20.5%. Potentially life-threatening complications occurred in four pregnancies (3.3%), including one woman with aortic dissection, one with mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and one who underwent a post-partum hysterectomy due to severe haemorrhaging. Neonatal outcomes were reassuring, with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. Major birth defects were found in 3.8% of the children. The perinatal mortality was 2.3% (3/131), including a set of extremely preterm twins. LIMITATIONS, REASONS FOR CAUTION: Although this study was performed over a period of almost 20 years in three different countries, with a low drop-out rate and little missing data, much larger series are needed to assess rare events. This study also lacks an appropriate control group. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that cardiovascular evaluation before and during pregnancy may contribute to favourable obstetric outcomes in many cases. Maternal outcomes were in agreement with the literature while neonatal outcomes were generally better than previously reported. The outcomes were consistent across the three countries, supporting generalizability to similar populations. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest was reported. The study was supported by grants from the Gothenburg Medical Society, the Medical Care Executive Board of the Region Västra Götaland, grants from the ALF agreement at the Sahlgrenska University Hospital, the Hjalmar Svensson foundation, NFOG Nordic Fund, the Finnish Society of Paediatric and Adolescent Gynecology and Liv och hälsa Foundation in Finland. The Nordic Expert group's research work was unconditionally supported by MSD Finland, Norway and Denmark.
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| 4. |
- Heikkinen, Tuomas, et al.
(författare)
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Variants on the promoter region of PTEN affect breast cancer progression and patient survival
- 2011
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:6, s. R130-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUTION:The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.METHODS:We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.RESULTS: All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.CONCLUSIONS:Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.
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| 5. |
- Low, Yen Ling, et al.
(författare)
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Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:7, s. e1001012-
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Tidskriftsartikel (refereegranskat)abstract
- Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (rho(global) = 0.034) and endometrial (rho(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (rho(global) = 0.008) and endometrial cancer (rho(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (rho(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (rho(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
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| 6. |
- Osorio, Ana, et al.
(författare)
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DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
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| 7. |
- Peurala, Hanna, et al.
(författare)
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MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11, s. e26122-
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Tidskriftsartikel (refereegranskat)abstract
- MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41-0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
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| 8. |
- Stevens, Kristen N, et al.
(författare)
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19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
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Tidskriftsartikel (refereegranskat)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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