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- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)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.
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- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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- Valiente-Dobon, JJ, et al.
(författare)
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High-spin rotational structures in Kr-76
- 2005
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 71:3
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in Kr-76(36)40 have been populated in the Ca-40(Ca-40,4p)Kr-76 fusion-evaporation reaction at abeam energy of 165 MeV and studied using the Gammasphere and Microball multidetector arrays. The ground-state band and two signature-split negative parity bands of Kr-76 have been extended to similar to 30 (h) over bar. Lifetime measurements. using the Doppler-shift attenuation method show that the transition quadrupole moment of these three bands decrease as they approach their maximum-spin states. Two signatures of a new rotational structure with remarkably rigid rotational behavior have been identified. The high-spin properties of these rotational bands are analyzed within the framework of configuration-dependent cranked Nilsson-Strutinsky calculations.
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- Dork, T, et al.
(författare)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Tidskriftsartikel (refereegranskat)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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- Kurcewicz, W, et al.
(författare)
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The nuclear structure of Fr-227
- 1997
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Ingår i: NUCLEAR PHYSICS A. - : ELSEVIER SCIENCE BV. - 0375-9474. ; 621:4, s. 827-852
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Tidskriftsartikel (refereegranskat)abstract
- The gamma-rays following the beta(-) decay of Rn-227 have been investigated by means of gamma-ray singles and gamma gamma-coincidence measurements using an array of 12 Compton-suppressed Ge detectors. The fast-timing beta gamma gamma(t) method has been us
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- Robinson, SD, et al.
(författare)
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High-spin structures and band termination effects in Cd-104
- 2002
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899. ; 28:6, s. 1415-1431
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in the neutron-deficient isotope Cd-104 were populated using the Cr-50(Ni-58,4p)Cd-104 reaction at a beam energy of 250 MeV The level scheme has been extended using triple gamma-ray coincidences to a spin of 29h and an excitation energy of 18.2 MeV. Several collective structures involving the excitation of h(11/2) neutrons have been observed to spins approaching 30h. The high-spin structure has been compared to the results of cranked Nilsson-Strutinsky calculations.
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- Valiente-Dobon, JJ, et al.
(författare)
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Evidence for nontermination of rotational bands in Kr-74
- 2005
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Ingår i: Physical Review Letters. - 1079-7114. ; 95:23
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Tidskriftsartikel (refereegranskat)abstract
- Three rotational bands in Kr-74 were studied up to (in one case one transition short of) the maximum spin I-max of their respective single-particle configurations. Their lifetimes have been determined using the Doppler-shift attenuation method. The deduced transition quadrupole moments reveal a modest decrease, but far from a complete loss of collectivity at the maximum spin I-max. This feature, together with the results of mean field calculations, indicates that the observed bands do not terminate at I=I-max.
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- Valiente-Dobon, JJ, et al.
(författare)
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Lifetimes of high-spin states in Kr-76
- 2005
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Ingår i: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 36:4, s. 1339-1342
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Tidskriftsartikel (refereegranskat)abstract
- High-spin states in Kr-76(36)40 have been populated in the Ca-40 (Ca-40,4p) Kr-76 fusion-evaporation reaction at a beam energy of 165 MeV, and studied using the GAMMASPHERE and MICROBALL multi-detector arrays. The ground-state band and two signature-split negative-parity bands of Kr-76 have been extended to similar to 30h. Lifetime measurements using the Doppler-shift attenuation method indicate that the transition quadrupole moment of these three bands decrease as they approach their maximum-spin states.
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