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  1. Lorenzo JPP, Sollano MHMZ, Salido EO, Li-Yu J, Tankeh-Torres SA, Wulansari Manuaba IAR, et al.
    Int J Rheum Dis, 2022 Jan;25(1):7-20.
    PMID: 34931463 DOI: 10.1111/1756-185X.14266
    BACKGROUND: Gout is the most prevalent inflammatory arthritis in the Asia-Pacific region and worldwide. This clinical practice guideline (CPG) aims to provide recommendations based on systematically obtained evidence and values and preferences tailored to the unique needs of patients with gout and hyperuricemia in Asia, Australasia, and the Middle East. The target users of these guidelines are general practitioners and specialists, including rheumatologists, in these regions.

    METHODS: Relevant clinical questions were formulated by the Steering Committee. Systematic reviews of evidence were done, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation methodology. A multi-sectoral consensus panel formulated the final recommendations.

    RESULTS: The Asia-Pacific League of Associations for Rheumatology Task Force developed this CPG for treatment of gout with 3 overarching principles and 22 recommendation statements that covered the treatment of asymptomatic hyperuricemia (2 statements), treatment of acute gout (4 statements), prophylaxis against gout flare when initiating urate-lowering therapy (3 statements), urate-lowering therapy (3 statements), treatment of chronic tophaceous gout (2 statements), treatment of complicated gout and non-responders (2 statements), treatment of gout with moderate to severe renal impairment (1 statement), and non-pharmacologic interventions (5 statements).

    CONCLUSION: Recommendations for clinically relevant scenarios in the management of gout were formulated to guide physicians in administering individualized care.

  2. Austin A, De Silva U, Ilesanmi C, Likitabhorn T, Miller I, Sousa Fialho MDL, et al.
    Lancet Psychiatry, 2023 Dec;10(12):966-973.
    PMID: 37769672 DOI: 10.1016/S2215-0366(23)00265-1
    The effectiveness of mental health care can be improved through coordinated and wide-scale outcome measurement. The International Consortium for Health Outcomes Measurement has produced collaborative sets of outcome measures for various mental health conditions, but no universal guideline exists for eating disorders. This Position Paper presents a set of outcomes and measures for eating disorders as determined by 24 international experts from professional and lived experience backgrounds. An adapted Delphi technique was used, and results were assessed through an open review survey. Final recommendations suggest outcomes should be tracked across four domains: eating disorder behaviours and cognitions, physical health, co-occurring mental health conditions, and quality of life and social functioning. Outcomes are collected using three to five patient-reported measures. For children aged between 6 years and 12 years, the measures include the Children's Eating Attitude Test (or, for those with avoidant restrictive food intake disorder, the Eating Disorder in Youth Questionnaire), the KIDSCREEN-10, and the Revised Children's Anxiety and Depression Screener-25. For adolescents aged between 13 years and 17 years, the measures include the Eating Disorder Examination Questionnaire (EDE-Q; or, for avoidant restrictive food intake disorder, the Nine-Item Avoidant Restrictive Food Intake Disorder Screener [NIAS]), the two-item Patient Health Questionnaire (PHQ-2), the nine-item Patient Health Questionnaire (PHQ-9), the two-item Generalised Anxiety Disorder (GAD-2), the seven-item Generalised Anxiety Disorder (GAD-7), and the KIDSCREEN-10. For adults older than 18 years, measures include the EDE-Q (or, for avoidant restrictive food intake disorder, the NIAS), the PHQ-2, the PHQ-9, the GAD-2, the GAD-7, the Clinical Impairment Assessment, and the 12-item WHO Disability Assessment Schedule 2.0. These questionnaires should be supplemented by information on patient characteristics and circumstances (ie, demographic, historical, and clinical factors). International adoption of these guidelines will allow comparison of research and clinical interventions to determine which settings and interventions work best, and for whom.
  3. Brandão A, Paulo P, Maia S, Pinheiro M, Peixoto A, Cardoso M, et al.
    Cancers (Basel), 2020 Nov 04;12(11).
    PMID: 33158149 DOI: 10.3390/cancers12113254
    The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
  4. Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, et al.
    Cancer Epidemiol Biomarkers Prev, 2015 Nov;24(11):1796-800.
    PMID: 26307654 DOI: 10.1158/1055-9965.EPI-15-0543
    BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.

    METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).

    RESULTS: We observed no significant association between genetic variants and prostate cancer survival.

    CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study.

    IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.

  5. Dadaev T, Saunders EJ, Newcombe PJ, Anokian E, Leongamornlert DA, Brook MN, et al.
    Nat Commun, 2018 06 11;9(1):2256.
    PMID: 29892050 DOI: 10.1038/s41467-018-04109-8
    Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
  6. Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.
    Nat Genet, 2018 07;50(7):928-936.
    PMID: 29892016 DOI: 10.1038/s41588-018-0142-8
    Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
  7. Schumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.
    Nat Genet, 2019 02;51(2):363.
    PMID: 30622367 DOI: 10.1038/s41588-018-0330-6
    In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
  8. Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.
    Nat Genet, 2021 Jan;53(1):65-75.
    PMID: 33398198 DOI: 10.1038/s41588-020-00748-0
    Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
  9. Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, et al.
    Cancer Discov, 2016 Sep;6(9):1052-67.
    PMID: 27432226 DOI: 10.1158/2159-8290.CD-15-1227
    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.

    SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

  10. Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, et al.
    Nat Genet, 2023 Dec;55(12):2065-2074.
    PMID: 37945903 DOI: 10.1038/s41588-023-01534-4
    The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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