| 1. |
- Middha, Pooja K., et al.
(author)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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In: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Journal article (peer-reviewed)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 2. |
- Mueller, Stefanie H., et al.
(author)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
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Journal article (peer-reviewed)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 3. |
- Mälarstig, Anders, et al.
(author)
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Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
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| 4. |
- Sartor, Hanna, et al.
(author)
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The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival : the Malmö Diet and Cancer Study
- 2020
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In: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 61:10, s. 1326-1334
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Journal article (peer-reviewed)abstract
- Background: Genetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear. Purpose: To investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS). Material and Methods: A total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991–2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1). Results: Minor homozygotes of SNPs rs9383589, CCDC170 and rs6557161, ESR1 were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35–59.57; AOR 2.08, 95% CI 1.19–3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HRadj] 6.46, 95% CI 1.95–21.39; HRadj 2.30, 95% CI 1.33–3.96, respectively) compared to major homozygotes. For SNP rs3757318, ESR1, minor homozygotes (HRadj 7.46, 95% CI 2.28–24.45) were associated with poorer survival. We confirmed that rs6557161, ESR1 was significantly associated with both density and survival in the LIBRO-1 study. Conclusion: These findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.
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| 5. |
- Ugalde-Morales, Emilio, et al.
(author)
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Association between breast cancer risk and disease aggressiveness : Characterizing underlying gene expression patterns
- 2021
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:4, s. 884-894
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Journal article (peer-reviewed)abstract
- The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P <.05) including Ki-67 proliferation status (P < 5 × 10−07). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10−13), HER2-enriched subtype (P < 5 × 10−07) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10−04). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.
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| 6. |
- Ugalde-Morales, Emilio, et al.
(author)
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Interval breast cancer is associated with interferon immune response
- 2022
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 162, s. 194-205
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Journal article (peer-reviewed)abstract
- Background: The aggressive nature of breast cancers detected between planned mammographic screens, so-called interval cancers, remains elusive. Here, we aim to characterise underlying molecular features of interval cancer. Methods: From 672 patients with invasive breast cancer, we analysed gene expression differences between 90 ‘true’ interval cancer cases (i.e. women with low-dense breasts defined as per cent mammographic density <25%) and 310 screen-detected tumours while accounting for PAM50 subtypes and thus overall tumour aggressiveness. We computed an interval cancer gene expression profile (IC-Gx) in a total of 2270 breast tumours (regardless of interval cancer status) and tested for association with expression-based immune subtypes in breast cancer. In addition, we investigated the contribution of inherited and somatic genetic variants in distinct features of interval cancer. Results: We identified 8331 genes nominally associated with interval cancer (P-value < 0.05, fold-change > 1.5). Gene set enrichment analysis showed immune-related pathways as key processes altered in interval cancer. Our IC-Gx, based on 47 genes with the strongest associations (false discovery rate < 0.05), was found to be associated mainly with immune subtypes involving interferon response. We isolated an interaction network of interval cancer and interferon genes for which a significant load of somatic and germline variants in class I interferon genes was observed. Conclusion: We identified novel molecular features of interval breast cancer highlighting interferon pathways as a potential target for prevention or treatment.
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| 7. |
- Yang, Haomin, et al.
(author)
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Risk of heart disease following treatment for breast cancer - results from a population-based cohort study
- 2022
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In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
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Journal article (peer-reviewed)abstract
- Background: There is a rising concern about treatment-associated cardiotoxicities in breast cancer patients. This study aimed to determine the time- and treatment-specific incidence of arrhythmia, heart failure, and ischemic heart disease in women diagnosed with breast cancer.Methods: A register-based matched cohort study was conducted including 8015 breast cancer patients diagnosed from 2001 to 2008 in the Stockholm-Gotland region and followed up until 2017. Time-dependent risks of arrhythmia, heart failure, and ischemic heart disease in breast cancer patients were assessed using flexible parametric models as compared to matched controls from general population. Treatment-specific effects were estimated in breast cancer patients using Cox model.Results: Time-dependent analyses revealed long-term increased risks of arrhythmia and heart failure following breast cancer diagnosis. Hazard ratios (HRs) within the first year of diagnosis were 2.14 (95% CI = 1.63-2.81) for arrhythmia and 2.71 (95% CI = 1.70-4.33) for heart failure. HR more than 10 years following diagnosis was 1.42 (95% CI = 1.21-1.67) for arrhythmia and 1.28 (95% CI = 1.03-1.59) for heart failure. The risk for ischemic heart disease was significantly increased only during the first year after diagnosis (HR = 1.45, 95% CI = 1.03-2.04). Trastuzumab and anthracyclines were associated with increased risk of heart failure. Aromatase inhibitors, but not tamoxifen, were associated with risk of ischemic heart disease. No increased risk of heart disease was identified following locoregional radiotherapy.Conclusions: Administration of systemic adjuvant therapies appears to be associated with increased risks of heart disease. The risk estimates observed in this study may aid adjuvant therapy decision-making and patient counseling in oncology practices.
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