1. |
- Figlioli, G, et al.
(author)
-
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
-
In: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
-
Journal article (peer-reviewed)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
|
|
2. |
- Lawrenson, Kate, et al.
(author)
-
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)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.
|
|
3. |
- Backlund, Y., et al.
(author)
-
Micromachining of Silicon for Thermal and Position-Sensitive Nuclear-Detector Applications
- 1989
-
In: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002. ; 279:3, s. 555-559
-
Journal article (peer-reviewed)abstract
- As part of a programme aiming at the development of small nuclear radiation detectors, for example thermal detectors and position sensitive mosaic structures of surface barrier type, a technique for micromachining the detector bodies in silicon has been developed. The technique is based on an anisotropic etching property of a solution, mainly consisting of KOH. The etch rate is strongly orientation dependent with a speed in the 〈100〉 direction about 400 times faster than in the 〈111〉 direction. The major steps in the etching procedure are described and some examples of deep etching in Si are shown.
|
|
4. |
- Coron, N., et al.
(author)
-
A Composite Bolometer as a Charged-Particle Spectrometer
- 1985
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 314:6006, s. 75-76
-
Journal article (peer-reviewed)abstract
- The measurement of radioactivity by direct conversion of nuclear radiation into a temperature rise of a calorimeter is as old as nuclear physics itself. As part of a general programme aiming at a determination of the mass of the electron neutrino, we have designed an improved version of a He-cooled composite diamond bolometer with a monolithic germanium thermistor, developed at the Laboratoire de Physique Stellaire et Planetaire (LPSP)1. Our approach, based on an idea by De Rujula2, is to study the shape, near the upper end-point of the internal bremsstrahlung spectrum in electron-capture β decay. The best nucleus for a precise measurement seems to be 163Ho, for which we have determined3 the Q EC value to be 2.83±0.05 keV. A particularly interesting possibility is to use total absorption spectrometry4 (calorimetry), in which the radioactive holmium forms part of the sensitive volume of the detector. With 5–6-MeV α particles impinging on the diamond wafer of the bolometer, a full-width-at-half-maximum (FWHM) of 36 keV was obtained at a temperature of 1.3 K. The theoretical resolution at 100 mK is a few electron-volts, so this new detection technique should give greatly enhanced energy resolution compared with present solid-state conductors based on charge carrier collection.
|
|
5. |
|
|