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| 15. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 16. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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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.
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| 17. |
- Barnes, DR, et al.
(författare)
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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 114:1, s. 109-122
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
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| 20. |
- Dent, W. R. F., et al.
(författare)
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GASPS-A Herschel Survey of Gas and Dust in Protoplanetary Disks: Summary and Initial Statistics
- 2013
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 125:927, s. 477-505
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Tidskriftsartikel (refereegranskat)abstract
- We describe a large-scale far-infrared line and continuum survey of protoplanetary disk through to young debris disk systems carried out using the ACS instrument on the Herschel Space Observatory. This Open Time Key program, known as GASPS (Gas Survey of Protoplanetary Systems), targeted similar to 250 young stars in narrow wavelength regions covering the [OI] fine structure line at 63 mu m the brightest far-infrared line in such objects. A subset of the brightest targets were also surveyed in [OI]145 mu m, [CII] at 157 mu m, as well as several transitions of H2O and high-excitation CO lines at selected wavelengths between 78 and 180 mu m. Additionally, GASPS included continuum photometry at 70, 100 and 160 mu m, around the peak of the dust emission. The targets were SED Class II-III T Tauri stars and debris disks from seven nearby young associations, along with a comparable sample of isolated Herbig AeBe stars. The aim was to study the global gas and dust content in a wide sample of circumstellar disks, combining the results with models in a systematic way. In this overview paper we review the scientific aims, target selection and observing strategy of the program. We summarise some of the initial results, showing line identifications, listing the detections, and giving a first statistical study of line detectability. The [OI] line at 63 mu m was the brightest line seen in almost all objects, by a factor of similar to 10. Overall [OI]63 mu m detection rates were 49%, with 100% of HAeBe stars and 43% of T Tauri stars detected. A comparison with published disk dust masses (derived mainly from sub-mm continuum, assuming standard values of the mm mass opacity) shows a dust mass threshold for [OI] 63 mu m detection of similar to 10(-5) M-circle dot. Normalising to a distance of 140 pc, 84% of objects with dust masses >= 10(-5) M-circle dot can be detected in this line in the present survey; 32% of those of mass 10(-6)-10(-5) M-circle dot, and only a very small number of unusual objects with lower masses can be detected. This is consistent with models with a moderate UV excess and disk flaring. For a given disk mass, [OI] detectability is lower for M stars compared with earlier spectral types. Both the continuum and line emission was, in most systems, spatially and spectrally unresolved and centred on the star, suggesting that emission in most cases was from the disk. Approximately 10 objects showed resolved emission, most likely from outflows. In the GASPS sample, [OI] detection rates in T Tauri associations in the 0.3-4 Myr age range were similar to 50%. For each association in the 5-20 Myr age range, similar to 2 stars remain detectable in [OI]63 mu m, and no systems were detected in associations with age >20 Myr. Comparing with the total number of young stars in each association, and assuming a ISM-like gas/dust ratio, this indicates that similar to 18% of stars retain a gas-rich disk of total mass similar to 1 M-Jupiter for 1-4 Myr, 1-7% keep such disks for 5-10 Myr, but none are detected beyond 10-20 Myr. The brightest [OI] objects from GASPS were also observed in [OI]145 mu m, [CII]157 mu m and CO J = 18 - 17, with detection rates of 20-40%. Detection of the [CII] line was not correlated with disk mass, suggesting it arises more commonly from a compact remnant envelope.
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