88 research outputs found
LocusExplorer: a user-friendly tool for integrated visualization of human genetic association data and biological annotations.
Unlabelled : In this article, we present LocusExplorer, a data visualization and exploration tool for genetic association data. LocusExplorer is written in R using the Shiny library, providing access to powerful R-based functions through a simple user interface. LocusExplorer allows users to simultaneously display genetic, statistical and biological data for humans in a single image and allows dynamic zooming and customization of the plot features. Publication quality plots may then be produced in a variety of file formats.Availability and implementation LocusExplorer is open source and runs through R and a web browser. It is available at www.oncogenetics.icr.ac.uk/LocusExplorer/ or can be installed locally and the source code accessed from https://github.com/oncogenetics/LocusExplorerContact [email protected]
Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel
Background
Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis.
Objective
To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease.
Design, setting, and participants
We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60 yr) and 1160 selected controls.
Outcome measurements and statistical analysis
Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n = 201) versus nonaggressive (Gleason score ≤7, n = 1048) cases.
Results and limitations
We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR] = 1.29, 95% confidence interval [CI] 1.01–1.64, p = 0.036). Gene-level analyses selected NBN (pSKAT-O = 2.4 × 10−4) for overall risk and XPC (pSKAT-O = 1.6 × 10−4) for aggressive disease, both at candidate-level significance (p < 3.1 × 10−4 and p < 3.4 × 10−4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR = 3.2, 95% CI 2.1–4.8, pADA = 4.1 × 10−3) and four genes that increased risk of aggressive disease (OR = 11.2, 95% CI 4.6–27.7, pADA = 5.6 × 10−3), three of which overlap the predisposition gene set.
Conclusions
The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential.
Patient summary
This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice
Correction: Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease
Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study.
BACKGROUND: A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. OBJECTIVE: To determine how the number, degree, and age of a PrCa patient's affected relatives are associated with OS and PCSS of those already diagnosed with PrCa. DESIGN, SETTING, AND PARTICIPANTS: The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors. RESULTS AND LIMITATIONS: A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75-0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. CONCLUSIONS: Based on the investigation of the type and timing of relatives' cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH. PATIENT SUMMARY: We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients' diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes
CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer.
PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches
Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.
BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease
Background
Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.
Methods
We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.
Results
Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.
Conclusions
Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application
Climate Change Promotes the Emergence of Serious Disease Outbreaks of Filarioid Nematodes
Filarioid parasites represent major health hazards with important medical, veterinary, and economic implications, and considerable potential to affect the everyday lives of tens of millions of people globally (World Health Organization, 2007). Scenarios for climate change vary latitudinally and regionally and involve direct and indirect linkages for increasing temperature and the dissemination, amplification, and invasiveness of vector-borne parasites. High latitude regions are especially influenced by global climate change and thus may be prone to altered associations and dynamics for complex host-pathogen assemblages and emergence of disease with cascading effects on ecosystem structure. Although the potential for substantial ecological perturbation has been identified, few empirical observations have emanated from systems across the Holarctic. Coincidental with decades of warming, and anomalies of high temperature and humidity in the sub-Arctic region of Fennoscandia, the mosquito-borne filarioid nematode Setaria tundra is now associated with emerging epidemic disease resulting in substantial morbidity and mortality for reindeer and moose. We describe a host-parasite system that involves reindeer, arthropods, and nematodes, which may contribute as a factor to ongoing declines documented for this ungulate species across northern ecosystems. We demonstrate that mean summer temperatures exceeding 14°C drive the emergence of disease due to S. tundra. An association between climate and emergence of filarioid parasites is a challenge to ecosystem services with direct effects on public health, sustainability of free-ranging and domestic ungulates, and ultimately food security for subsistence cultures at high latitudes
Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.
Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk
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