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Article ; Online: Uncommon Protein-Coding Variants Associated With Suicide Attempt in a Diverse Sample of U.S. Army Soldiers.

Wilkerson, Matthew D / Hupalo, Daniel / Gray, Joshua C / Zhang, Xijun / Wang, Jiawei / Girgenti, Matthew J / Alba, Camille / Sukumar, Gauthaman / Lott, Nathaniel M / Naifeh, James A / Aliaga, Pablo / Kessler, Ronald C / Turner, Clesson / Pollard, Harvey B / Dalgard, Clifton L / Ursano, Robert J / Stein, Murray B

Biological psychiatry

2023

Abstract: Background: Suicide is a societal and public health concern of global scale. Identifying genetic risk factors for suicide attempt can characterize underlying biology and enable early interventions to prevent deaths. Recent studies have described common ... ...

Abstract	Background: Suicide is a societal and public health concern of global scale. Identifying genetic risk factors for suicide attempt can characterize underlying biology and enable early interventions to prevent deaths. Recent studies have described common genetic variants for suicide-related behaviors. Here, we advance this search for genetic risk by analyzing the association between suicide attempt and uncommon variation exome-wide in a large, ancestrally diverse sample. Methods: We sequenced whole genomes of 13,584 soldiers from the Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers), including 979 individuals with a history of suicide attempt. Uncommon, nonsilent protein-coding variants were analyzed exome-wide for association with suicide attempt using gene-collapsed and single-variant analyses. Results: We identified 19 genes with variants enriched in individuals with history of suicide attempt, either through gene-collapsed or single-variant analysis (Bonferroni p Conclusions: These results advance the molecular characterization of suicide attempt behavior and support the utility of whole-genome sequencing for complementing the findings of genome-wide association studies in suicide research.
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2023.12.008
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Article ; Online: Genetic variants of PKLR are associated with acute pain in sickle cell disease.

Wang, Xunde / Gardner, Kate / Tegegn, Mickias B / Dalgard, Clifton L / Alba, Camille / Menzel, Stephan / Patel, Hamel / Pirooznia, Mehdi / Fu, Yi-Ping / Seifuddin, Fayaz T / Thein, Swee Lay

Blood advances

2022 Volume 6, Issue 11, Page(s) 3535–3540

Abstract: Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by ... ...

Abstract	Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSβ0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P < .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
MeSH term(s)	2,3-Diphosphoglycerate/metabolism ; Acute Pain/genetics ; Acute Pain/metabolism ; Adult ; Anemia, Sickle Cell/complications ; Anemia, Sickle Cell/genetics ; Child ; Erythrocytes, Abnormal/metabolism ; Hemoglobin, Sickle/metabolism ; Humans ; Pyruvate Kinase/genetics ; Pyruvate Kinase/metabolism
Chemical Substances	Hemoglobin, Sickle ; 2,3-Diphosphoglycerate (138-81-8) ; PKLR protein, human (EC 2.7.1.40) ; Pyruvate Kinase (EC 2.7.1.40)
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021006668
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Article ; Online: Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.

Braunstein, Evan M / Imada, Eddie / Pasca, Sergiu / Wang, Shiyu / Chen, Hang / Alba, Camille / Hupalo, Dan N / Wilkerson, Matthew / Dalgard, Clifton L / Ghannam, Jack / Liu, Yujia / Marchionni, Luigi / Moliterno, Alison / Hourigan, Christopher S / Gondek, Lukasz P

Leukemia

2022 Volume 37, Issue 3, Page(s) 627–635

Abstract: Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide ... ...

Abstract	Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.
MeSH term(s)	Humans ; Male ; Ataxia Telangiectasia Mutated Proteins/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Germ Cells ; Germ-Line Mutation ; Myeloproliferative Disorders/genetics ; Neoplasms ; Female
Chemical Substances	Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; ATM protein, human (EC 2.7.11.1)
Language	English
Publishing date	2022-12-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01797-6
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Article ; Online: Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease.

Bhattarai, Prabesh / Gunasekaran, Tamil Iniyan / Belloy, Michael E / Reyes-Dumeyer, Dolly / Jülich, Dörthe / Tayran, Hüseyin / Yilmaz, Elanur / Flaherty, Delaney / Turgutalp, Bengisu / Sukumar, Gauthaman / Alba, Camille / McGrath, Elisa Martinez / Hupalo, Daniel N / Bacikova, Dagmar / Le Guen, Yann / Lantigua, Rafael / Medrano, Martin / Rivera, Diones / Recio, Patricia /

Nuriel, Tal / Ertekin-Taner, Nilüfer / Teich, Andrew F / Dickson, Dennis W / Holley, Scott / Greicius, Michael / Dalgard, Clifton L / Zody, Michael / Mayeux, Richard / Kizil, Caghan / Vardarajan, Badri N

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 70

Abstract: The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the ... ...

Abstract	The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b-the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.
MeSH term(s)	Aged ; Animals ; Humans ; Alzheimer Disease/genetics ; Fibronectins/genetics ; Genetic Variation/genetics ; Gliosis ; Zebrafish
Chemical Substances	Fibronectins ; ApoE protein, human ; FN1 protein, human
Language	English
Publishing date	2024-04-10
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-024-02721-1
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Article ; Online: Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

Liu, Delong / Billington, Charles J / Raja, Neelam / Wong, Zoe C / Levin, Mark D / Resch, Wulfgang / Alba, Camille / Hupalo, Daniel N / Biamino, Elisa / Bedeschi, Maria Francesca / Digilio, Maria Cristina / Squeo, Gabriella Maria / Villa, Roberta / Parrish, Pheobe C R / Knutsen, Russell H / Osgood, Sharon / Freeman, Joy A / Dalgard, Clifton L / Merla, Giuseppe /

Pober, Barbara R / Mervis, Carolyn B / Roberts, Amy E / Morris, Colleen A / Osborne, Lucy R / Kozel, Beth A

Journal of the American Heart Association

2024 Volume 13, Issue 3, Page(s) e031377

Abstract: Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable ... ...

Abstract	Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. Methods and results: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes ( Conclusions: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
MeSH term(s)	Humans ; Williams Syndrome/genetics ; Genome-Wide Association Study ; Proteomics ; Rare Diseases ; Aortic Stenosis, Supravalvular/genetics ; Aortic Stenosis, Supravalvular/metabolism ; Aortic Stenosis, Supravalvular/surgery
Language	English
Publishing date	2024-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.123.031377
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Article ; Online: Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease.

Clinical immunology (Orlando, Fla.)

2023 Volume 255, Page(s) 109732

Abstract: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving ... ...

Abstract	Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8
MeSH term(s)	Male ; Humans ; Child, Preschool ; CD8-Positive T-Lymphocytes/pathology ; Lymphocytosis ; Panniculitis/genetics ; Panniculitis/pathology ; Panniculitis/therapy ; Lymphoma, T-Cell/genetics ; Lymphoma, T-Cell/therapy ; Immunologic Deficiency Syndromes
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2023.109732
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Article: Toxicity Testing of Pristine and Aged Silver Nanoparticles in Real Wastewaters Using Bioluminescent

Mallevre, Florian / Alba, Camille / Milne, Craig / Gillespie, Simon / Fernandes, Teresa F / Aspray, Thomas J

Nanomaterials (Basel, Switzerland)

2016 Volume 6, Issue 3

Abstract: Impact of aging on nanoparticle toxicity in real matrices is scarcely investigated due to a lack of suitable methodologies. Herein, the toxicity of pristine and aged silver nanoparticles (Ag NPs) to a ... ...

Abstract	Impact of aging on nanoparticle toxicity in real matrices is scarcely investigated due to a lack of suitable methodologies. Herein, the toxicity of pristine and aged silver nanoparticles (Ag NPs) to a bioluminescent
Language	English
Publishing date	2016-03-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662255-5
ISSN	2079-4991
ISSN	2079-4991
DOI	10.3390/nano6030049
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Article ; Online: Genome-Wide Analysis of Off-Target CRISPR/Cas9 Activity in Single-Cell-Derived Human Hematopoietic Stem and Progenitor Cell Clones.

Smith, Richard H / Chen, Yun-Ching / Seifuddin, Fayaz / Hupalo, Daniel / Alba, Camille / Reger, Robert / Tian, Xin / Araki, Daisuke / Dalgard, Clifton L / Childs, Richard W / Pirooznia, Mehdi / Larochelle, Andre

Genes

2020 Volume 11, Issue 12

Abstract: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9)-mediated genome editing holds remarkable promise for the treatment of human genetic diseases. However, the possibility of off-target Cas9 activity remains ...

Abstract	CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9)-mediated genome editing holds remarkable promise for the treatment of human genetic diseases. However, the possibility of off-target Cas9 activity remains a concern. To address this issue using clinically relevant target cells, we electroporated Cas9 ribonucleoprotein (RNP) complexes (independently targeted to two different genomic loci, the
MeSH term(s)	Adult ; CRISPR-Cas Systems ; Chromosomes, Human, Pair 19/genetics ; Chromosomes, Human, Pair 2/genetics ; Clone Cells ; Female ; Gene Editing ; Genetic Loci ; Hematopoietic Stem Cells ; Humans ; Receptors, CXCR4/genetics
Chemical Substances	CXCR4 protein, human ; Receptors, CXCR4
Language	English
Publishing date	2020-12-13
Publishing country	Switzerland
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11121501
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Article: Genome-Wide Analysis of Off-Target CRISPR/Cas9 Activity in Single-Cell-Derived Human Hematopoietic Stem and Progenitor Cell Clones

Genes. 2020 Dec. 13, v. 11, no. 12

2020

Abstract	CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9)-mediated genome editing holds remarkable promise for the treatment of human genetic diseases. However, the possibility of off-target Cas9 activity remains a concern. To address this issue using clinically relevant target cells, we electroporated Cas9 ribonucleoprotein (RNP) complexes (independently targeted to two different genomic loci, the CXCR4 locus on chromosome 2 and the AAVS1 locus on chromosome 19) into human mobilized peripheral blood-derived hematopoietic stem and progenitor cells (HSPCs) and assessed the acquisition of somatic mutations in an unbiased, genome-wide manner via whole genome sequencing (WGS) of single-cell-derived HSPC clones. Bioinformatic analysis identified >20,000 total somatic variants (indels, single nucleotide variants, and structural variants) distributed among Cas9-treated and non-Cas9-treated control HSPC clones. Statistical analysis revealed no significant difference in the number of novel non-targeted indels among the samples. Moreover, data analysis showed no evidence of Cas9-mediated indel formation at 623 predicted off-target sites. The median number of novel single nucleotide variants was slightly elevated in Cas9 RNP-recipient sample groups compared to baseline, but did not reach statistical significance. Structural variants were rare and demonstrated no clear causal connection to Cas9-mediated gene editing procedures. We find that the collective somatic mutational burden observed within Cas9 RNP-edited human HSPC clones is indistinguishable from naturally occurring levels of background genetic heterogeneity.
Keywords	CRISPR-Cas systems ; bioinformatics ; genes ; genetic heterogeneity ; genome-wide association study ; genomics ; humans ; loci ; ribonucleoproteins ; statistical analysis ; stem cells
Language	English
Dates of publication	2020-1213
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11121501
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.

Kohaar, Indu / Zhang, Xijun / Tan, Shyh-Han / Nousome, Darryl / Babcock, Kevin / Ravindranath, Lakshmi / Sukumar, Gauthaman / Mcgrath-Martinez, Elisa / Rosenberger, John / Alba, Camille / Ali, Amina / Young, Denise / Chen, Yongmei / Cullen, Jennifer / Rosner, Inger L / Sesterhenn, Isabell A / Dobi, Albert / Chesnut, Gregory / Turner, Clesson /

Dalgard, Clifton / Wilkerson, Matthew D / Pollard, Harvey B / Srivastava, Shiv / Petrovics, Gyorgy

Nature communications

2022 Volume 13, Issue 1, Page(s) 1361

Abstract: In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs ( ...

Abstract	In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.
MeSH term(s)	African Americans/genetics ; DNA Damage/genetics ; Germ-Line Mutation ; Humans ; Male ; Mutation ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology
Language	English
Publishing date	2022-03-15
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28945-x
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