143 research outputs found
Publisher Correction: Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis (Nature Communications, (2025), 16, 1, (10769), 10.1038/s41467-025-65811-y)
No full text\ua9 The Author(s) 2026.Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-025-65811-y, published online 28 November 2025 In the version of this article initially published, members of the PanGenEU Consortium Investigators were listed inside the main author list and are now presented separately as consortium members in the HTML and PDF versions of the article
DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
No full textSingle Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be
associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose
polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p,0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03– 1.16), p = 2.761023) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21,
p = 4.861023). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/ 2 mutation carriers and should be more comprehensively studied
Midwest Research Computing and Data (MWRCD) Consortium Diversity, Equity and Inclusion Assessment
No full textThis survey instrument is distributed by the Midwest Research Computing and Data Consortium (Midwest RCD). This assessment was conducted by the principal investigators of the National Science Foundation-funded Midwest RCD project.Members of the Midwest RCD were invited to participate in a Diversity, Equity, and Inclusion (DEI) Assessment conducted by the principal investigators of the National Science Foundation-funded Midwest Research Computing and Data (MWRCD) Consortium Project. This assessment was administered on behalf of the MWRCD Consortium Project by the Indiana University Pervasive Technology Institute and was funded by the National Science Foundation.This material is based upon work supported by the National Science Foundation under Grant No. 2227627. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation
Childhood maltreatment and chronic ‘all over’ body pain in adulthood : a counterfactual analysis using UK Biobank
No full textThe investigators on the CAPE consortium are: Tim Hales, Lesley Colvin, Douglas Steele, 11 Andrew Brown (University of Dundee), Gary Macfarlane (University of Aberdeen), Bhuvaneish Selvaraj, Colin Smith (University of Edinburgh), Line Caes (Stirling University), Reecha Sofat, Suellen Walker, Debajit Sen, Madeleine Verriotis (University College London) while the Chronic Pain Advisory Group includes Carolyn Graham, Maureen O’Reilly and Debs Smith, among others. We thank Jisha Babu (University of Aberdeen) for her work involved in administration in relation to access to data as part of this programme of work. Thanks also to Marcus Beasley and John McBeth for advice on analyses. The authors do not report any conflicts of interest. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.Peer reviewe
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (Nature Genetics, (2018), 50, 1, (26-41), 10.1038/s41588-017-0011-x)
No full textIn the HTML version of this article initially published, the author groups ‘CHD Exome+ Consortium’, ‘EPIC-CVD Consortium’, ‘ExomeBP Consortium’, ‘Global Lipids Genetic Consortium’, ‘GoT2D Genes Consortium’, ‘EPIC InterAct Consortium’, ‘INTERVAL Study’, ‘ReproGen Consortium’, ‘T2D-Genes Consortium’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.</p
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
No full textCorrection to: Nature Genetics https://doi.org/10.1038/s41588-017-0011-x, published online 22 December 2017. In the HTML version of this article initially published, the author groups ‘CHD Exome+ Consortium’, ‘EPIC-CVD Consortium’, ‘ExomeBP Consortium’, ‘Global Lipids Genetic Consortium’, ‘GoT2D Genes Consortium’, ‘EPIC InterAct Consortium’, ‘INTERVAL Study’, ‘ReproGen Consortium’, ‘T2D-Genes Consortium’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article.No Full Tex
Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis
No full text: Pancreatic ductal adenocarcinoma (PDAC) genetic susceptibility is partially identified. The complement system (CS) influences carcinogenesis and participates in immunological defense and homeostasis; however, its role in PDAC genetic susceptibility and prognosis is underexplored. The association of SNPs within 111 CS-related genes with PDAC risk is assessed in the PanGenEU study and validated in the UKBiobank. We investigate the association between the CS-related gene variation and PDAC risk, followed by an in-depth functional in silico study using TCGA and ICGC data. We assess whether CS-related genes are associated with prognosis at the germline and somatic levels. We investigate the immune infiltration of PDAC tumors according to their transcriptomic profile. Genetic variation in FCN1 and PLAT is significantly associated with PDAC risk. PDAC patients with elevated expression of IGHG3, IGKC, IGHM, F2R, F2RL2, CFI, A2M, or C4A display improved survival and higher infiltration of CD8+, B cells, and Th1 cells. Individuals with high expression levels of either FGA, SERPINE1, FGG, or F3 exhibit poorer survival, higher infiltration of Tregs, and lower infiltration of CD8+ cells. Results from this study suggest that CS-related genes play a role in PDAC genetic susceptibility and survival through specific immune cell infiltration
Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression : validation and implications for clinical trial design and analysis
No full textAbstract: Background With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified fi ed as " trial-like" " based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament fi lament light (NfL) and phosphorylated neurofilament fi lament heavy (pNfH), urinary p75ECD , ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL 100 pg/mL correspond to future ALSFRS-R slopes of similar to 0.5 and similar to 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields similar to 25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD , ECD , and plasma miR-181ab is more limited. Interpretation Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined fi ned thresholds of NfL might also be used in trial design, for enrichment or stratified fi ed randomisation, to improve trial efficiency. fi ciency. Funding NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242). Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
No full textPurpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making. © 2021, The Author(s)
Metadata supporting data files of the related manuscript: The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
No full textIn this study, the authors tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk. In vitro experiments were also carried out whereby these three variants were studied functionally by measuring survival and chromosome fragility in FANCM − / − patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib.Data access: A subset of the genotype data analysed in this study (that originated from the Oncoarray Consortium project) is publicly available from the dbGaP repository. A subset of the genotype data generated as part of the BCAC studies (and analysed in the present study) can be accessed at https://identifiers.org/dbgap:phs001265.v1.p1. A subset of the genotype data generated as part of the CIMBA studies (and analysed in the present study) can be accessed at https://identifiers.org/dbgap:phs001321.v1.p1. The remaining genotype data analysed in the present study (and generated in the BCAC and CIMBA studies listed in supplementary Tables 4 and 5 of the related article respectively) are not publicly available due to restraints imposed by the ethics committees of individual studies but can be accessed from the corresponding author on reasonable request; Dr. Paolo Peterlongo, Genome Diagnostics Program, IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16 - 20139 Milano (Italy), email address: [email protected]. Datasets survivals DEB e OLAPARIB.pzfx (supporting figure 1 and supplementary tables 2 and 3 in the published article) and chromatidics breaks distribution.xlsx (supporting figure 1 in the published article) generated during this study can be accessed from the corresponding author on reasonable request as described above.Participant consent: All participating studies were approved by their ethics review boards and followed national guidelines for informed consent. However, due to the retrospective nature of the majority of the studies, not all participant individuals have provided written informed consent to take part in the present analysis. The Milan Breast Cancer Study Group (MBCSG) was approved by ethics committee from Istituto Nazionale dei Tumori di Milano and Istituto Europeo di Oncologia, in Milan.Study aims and methodology: Previous studies identified several protein-truncating variants in the FANCM gene, which encodes for a DNA translocase, that were described as moderate breast cancer risk factors with a greater risk of triple negative breast cancer (TNBC). This study aimed to investigate the effect of FANCM further, by testing three recurrent truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931*, within the OncoArray Consortium, a collaboration of consortia established to discover germline genetic variants predisposing to different human cancers (e.g., breast, colon, lung, ovary, endometrium and prostate cancers). These three variants were tested for association with breast cancer risk in 67 112 breast cancer cases, 53 766 controls and 26 662 carriers of pathogenic variants of BRCA1 or BRCA2. The individuals included in this study were women of genetically confirmed European ancestry who were originally ascertained in 73 case-control studies from 19 countries participating in the Breast Cancer Association Consortium (BCAC) or in 59 studies enrolling BRCA1 or BRCA2 pathogenic variants carrier from 30 countries participating in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). The CIMBA studies contributed 15 679 carriers of a pathogenic BRCA1 variant and 10 983 carriers of a pathogenic BRCA2 variant to this analysis. The BCAC studies contributed 67 112 invasive breast cancer cases and 53 766 controls. Genotyping of FANCM:p.Arg658*, p.Gln1701* and p.Arg1931* truncating variants was conducted using a custom-designed Illumina genotyping array (the “OncoArray”, Illumina, Inc. San Diego, CA, USA) at six independent laboratories.Additionally, the authors studied the functional effect of these three variants after their lentiviral transduction into a FANCM−/− patient-derived cell line, EGF280, in which they measured survival and chromosome fragility after exposure to diepoxybutane (DEB) or the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib.Statistical analyses of the genotype data, western blot and mRNA experiments are described in detail in the published article.Dataset description:Data supporting table 1: Data SNP Genotypes from Illumina array and variables datasets include single variant and burden analyses of FANCM:p.Arg658*, p.Gln1701* and p.Arg1931 cases and controls, a subset of which can be accessed from the dbGaP repository at https://identifiers.org/dbgap:phs001265.v1.p1. Data supporting figure 1: The datasets survivals DEB e OLAPARIB.pzfx and chromatidics breaks distribution.xlsx are in .pzfx (Graphpad) and .xlsx file formats respectively and consist of results of functional studies of the FANCM:p.Arg658*, p.Gln1701* and p.Arg1931* truncating variants using the patient derived FANCM−/− EGF280 cell line. These data include western blot analysis showing the expression of FANCM in EGF280 cells after lentiviral transduction with the three FANCM variants, expression of the FANCM protein in EGF280+p.Arg658* cells, data on diepoxybutane (DEB) sensitivity on cell survival, chromosome fragility data in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane and data of the analysis of cellular sensitivity to olaparib.Data supporting supplementary table 1: The SNP Genotypes from Illumina array and variables dataset consist of FANCM:p.Arg658*, p.Gln1701* and p.Arg1931 truncating variants in carriers of pathogenic BRCA1 or BRCA2 variants. A subset of these genotype data from the CIMBA studies can be accessed from dbGaP at https://identifiers.org/dbgap:phs001321.v1.p1.Data supporting supplementary table 2: Dataset survivals DEB e OLAPARIB.pzfx is in a. pzfx (Graphpad) file format and reports on the sensitivity of different EGF280 cell lines to diepoxybutane (DEB) treatment.Data supporting supplementary table 3: Dataset survivals DEB e OLAPARIB.pzfx is in a. pzfx (Graphpad) file format and reports on the sensitivity of different EGF280 cell lines to olaparib treatment.Supplementary tables 4 and 5 provide descriptions of the BCAC and CIMBA studies respectively, included in the present analysis. A subset of the genotype data generated in the BCAC studies can be accessed from dbGaP at https://identifiers.org/dbgap:phs001265.v1.p1. A subset of the genotype data generated in the CIMBA studies can be accessed from dbGaP at https://identifiers.org/dbgap:phs001321.v1.p1.</div
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