| 1. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 2. |
- Cirulli, Elizabeth T., et al.
(författare)
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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
- 2019
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Ingår i: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 156:6, s. 1707-1716
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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| 3. |
- Gonzalez-Maurel, Osvaldo, et al.
(författare)
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The great escape : Petrogenesis of low-silica volcanism of Pliocene to Quaternary age associated with the Altiplano-Puna Volcanic Complex of northern Chile (21 degrees 10 '-22 degrees 50 ' S)
- 2019
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Ingår i: Lithos. - : ELSEVIER. - 0024-4937 .- 1872-6143. ; 346/347
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Tidskriftsartikel (refereegranskat)abstract
- The Pliocene to Quaternary volcanic arc of the Central Andes formed on 70-74 km thick continental crust. Physical interaction between mafic and acid magmas for this arc are therefore difficult to recognize due to the differentiation of mantle-derived magma during ascent through the thickened crust and a corresponding lack of erupted primitive lavas. However, a rare concentration of less evolved rocks is located marginal to the partially molten Altiplano-Puna Magma Body (APMB) in the Altiplano-Puna Volcanic Complex of northern Chile, between 21 degrees 10'S and 22 degrees 50'S. To unravel the relationship between this less evolved magmatism and the APMB, we present major and trace element data, and Sr and Nd isotope ratios of fourteen volcanoes. Whole-rock compositional and Sr and Nd isotope data reveal a large degree for compositional heterogeneity, e.g., SiO2 = 53.2 to 63.2 wt%, MgO = 1.74 to 6.08 wt%, Cr = 2 to 382 ppm, Sr = 304 to 885 ppm, (87)sr/(86)sr = 0.7055 to 0.7088, and Nd-143/Nd-144 = 0.5122 to 0.5125. The combined dataset points to magma spatial compositional changes resulting from magma mixing, fractional crystallization and crustal assimilation. The least evolved products erupted along the periphery of the APMB and are likely equivalent to the replenishing magmas that thermally sustain the large APMB system. We suggest that the mafic to intermediate eruptives we have investigated reflect mafic melt injections that underplate the APMB and escape along the side of the large felsic body to avoid significant compositional modifications during ascent, which helps to assess the evolution of the APMB through space and time. (C) 2019 Elsevier B.V. All rights reserved.
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