| 1. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 2. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 3. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 4. |
- Escala-Garcia, Maria, et al.
(författare)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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| 5. |
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| 6. |
- Gaudet, Mia M, et al.
(författare)
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Blood Levels of Cadmium and Lead in Relation to Breast Cancer Risk in Three Prospective Cohorts.
- 2019
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Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 144:5, s. 1010-1016
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Tidskriftsartikel (refereegranskat)abstract
- Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy), and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR=1.01, 95% CI 0.76 - 1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR=0.80, 95% CI 0.61 - 1.03) and NSHDS cohorts (continuous RR=0.73, 95% CI 0.54 - 0.97). The inverse association was also evident in the meta-analysis (continuous RR=0.84, 95% CI 0.69 - 1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis.
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| 7. |
- Barrdahl, Myrto, et al.
(författare)
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A comprehensive analysis of polymorphic variants in steroid hormone and insulin-like growth factor-1 metabolism and risk of in situ breast cancer : Results from the Breast and Prostate Cancer Cohort Consortium
- 2018
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 142:6, s. 1182-1188
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom=3.05, 95%CI=1.72-5.44, Phom=1.47 × 10-4), MAST2-rs12124649 (ORhom=1.73, 95% CI =1.18-2.54, Phom=5.24 × 10-3), and INSR-rs10500204 (ORhom=1.96, 95% CI=1.44-2.67, Phom=1.68 × 10-5) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom=1.78, 95% CI=1.30-2.44, Phom=3.23 × 10-4). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further.
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| 8. |
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| 9. |
- Cook, Michael B, et al.
(författare)
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Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium.
- 2015
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 24:3, s. 520-531
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Tidskriftsartikel (refereegranskat)abstract
- Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) odds ratios (OR) and 95% confidence intervals (CI), which were then combined using fixed effects meta-analysis. Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one sub-analysis of very high recent alcohol consumption (>60 grams/day) was tentatively associated with male breast cancer (ORunexposed referent=1.29, 95%CI:0.97-1.71; OR>0-<7 g/day referent=1.36, 95%CI:1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. Conclusions: In this analysis of the Male Breast Cancer Pooling Project we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer.
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