| 1. |
- Ahearn, Thomas U., et al.
(författare)
-
Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
-
Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
-
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.
|
|
| 2. |
- Barnekow, Elin, et al.
(författare)
-
A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31
- 2023
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:5
-
Tidskriftsartikel (refereegranskat)abstract
- Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.
|
|
| 3. |
- Barnekow, Elin, et al.
(författare)
-
A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16
- 2022
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:5
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility.Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls.Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68.Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.
|
|
| 4. |
- Couch, Fergus J., et al.
(författare)
-
Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
-
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.
|
|
| 5. |
- Dixon-Suen, Suzanne C, et al.
(författare)
-
Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
-
Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
|
|
| 6. |
- Eriksson, Mikael, et al.
(författare)
-
Low-Dose Tamoxifen for Mammographic Density Reduction : A Randomized Controlled Trial
- 2021
-
Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 39:17, s. 1899-
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
|
|
| 7. |
- Escala-Garcia, Maria, et al.
(författare)
-
A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
-
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.
|
|
| 8. |
- Hollestelle, Antoinette, et al.
(författare)
-
No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
|
|
| 9. |
- Jiao, Xiang, et al.
(författare)
-
PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
-
Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
-
Tidskriftsartikel (refereegranskat)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
|
|
| 10. |
- Lawrenson, Kate, et al.
(författare)
-
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
|
|
