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- Kontro, M, et al.
(author)
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HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia
- 2017
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In: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:2, s. 301-309
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Journal article (peer-reviewed)abstract
- Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.Leukemia advance online publication, 2 September 2016; doi:10.1038/leu.2016.222.
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- Guerreiro, R., et al.
(author)
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Heritability and genetic variance of dementia with Lewy bodies
- 2019
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 127, s. 492-501
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Journal article (peer-reviewed)abstract
- Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.
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| 4. |
- Guerreiro, R., et al.
(author)
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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
- 2018
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In: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74
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Journal article (peer-reviewed)abstract
- Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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- Harden, Jennifer W., et al.
(author)
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Networking our science to characterize the state, vulnerabilities, and management opportunities of soil organic matter
- 2018
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 24:2, s. e705-e718
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Journal article (peer-reviewed)abstract
- Soil organic matter (SOM) supports the Earth's ability to sustain terrestrial ecosystems, provide food and fiber, and retains the largest pool of actively cycling carbon. Over 75% of the soil organic carbon (SOC) in the top meter of soil is directly affected by human land use. Large land areas have lost SOC as a result of land use practices, yet there are compensatory opportunities to enhance productivity and SOC storage in degraded lands through improved management practices. Large areas with and without intentional management are also being subjected to rapid changes in climate, making many SOC stocks vulnerable to losses by decomposition or disturbance. In order to quantify potential SOC losses or sequestration at field, regional, and global scales, measurements for detecting changes in SOC are needed. Such measurements and soil-management best practices should be based on well established and emerging scientific understanding of processes of C stabilization and destabilization over various timescales, soil types, and spatial scales. As newly engaged members of the International Soil Carbon Network, we have identified gaps in data, modeling, and communication that underscore the need for an open, shared network to frame and guide the study of SOM and SOC and their management for sustained production and climate regulation.
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