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Wake Forest, NC, United States

Simonds N.I.,U.S. National Institutes of Health | Khoury M.J.,U.S. National Institutes of Health | Khoury M.J.,Centers for Disease Control and Prevention | Schully S.D.,U.S. National Institutes of Health | And 10 more authors.
Journal of the National Cancer Institute

A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the "real-world" effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling. © 2013 Published by Oxford University Press. Source

Qu Y.,Fudan University | Chen H.,Fudan University | Gu W.,Fudan University | Gu C.,Fudan University | And 5 more authors.
Scientific Reports

Research on sex differences in renal cancer-specific mortality (RCSM), which considered the sex effect to be constant throughout life, has yielded conflicting results. This study hypothesized the sex effect may be modified by age, which is a proxy for hormonal status. Data from the Surveillance, Epidemiology and End Results database (1988-2010) were used to identify 114,539 patients with renal cell carcinoma (RCC). The study cohort was divided into three age groups using cutoffs of 42 and 58 years, which represent the premenopausal and postmenopausal periods. The cumulative incidence function and competing risks analyses were used to examine the effect of covariates on RCSM and other-cause mortality (OCM). In premenopausal period, male sex was a significant predictor of poor RCSM for both localized (adjusted subdistribution hazard ratio [aSHR] = 1.63, P = 0.002) and advanced (aSHR = 1.20, P = 0.041) disease. In postmenopausal period, the sex disparity diminished (aSHR = 1.05, P = 0.16) and reversed (aSHR = 0.95, P = 0.017) in localized and advanced disease, respectively. On the contrary, similar trend was not found for OCM across all age groups. Our results demonstrated the sex effect on RCSM was strongly modified by age. These findings may aid in clinical practice and need further evaluation of underlying biological mechanisms. Source

Zhu Y.,Fudan University | Han C.-T.,Fudan University | Chen H.-T.,Fudan University | Liu F.,Fudan University | And 5 more authors.

Background: We investigated whether age influences the predictiveness of genetic risk score (GRS) for prostate cancer (PCa) in a Chinese hospital-based biopsy cohort. Methods: We included consecutive patients who underwent prostate biopsies in two tertiary centers between 2012 and 2014. GRS was calculated using 24 PCa-associated genetic variants and its predictiveness was assessed by area under curve (AUC). Results: Of 1120 men tested, 724 with prostate-specific antigen (PSA) < 20 ng/ml were selected for further analysis. Patients were divided into 3 groups by age cutoffs at 60 and 70 years. GRS significantly predicted PCa for all patients (AUC: 0.561; 95% CI: 0.514-0.609) and was an independent predictor in multivariate analysis for the 60-70 year-olds (AUC: 0.612, 95% CI: 0.541-0.684), but not for patients aged < 60 years or ≥70 years. For PCa with Gleason score ≥7, GRS discriminative ability was 0.582 (95% CI=0.527-0.637) for all patients, and 0.647 (95% CI: 0.541-0.684) for the 60-70 year-old group. Conclusion: GRS significantly increased clinical prediction of PCa and high-grade disease in Chinese men aged 60-70 years, which implies that men in this age group would benefit most from genetic testing. Source

Lu Y.,Zhejiang University | Lu Y.,Fudan University | Lu Y.,State Key Laboratory of Genetic Engineering | Zhang Z.,Center for Cancer Genomics | And 9 more authors.

BACKGROUND The majority of established prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association studies do not fall into protein coding regions. Therefore, the mechanisms by which these SNPs affect PCa risk remain unclear. Here, we used a series of bioinformatic tools and databases to provide possible molecular insights into the actions of risk SNPs. METHODOLOGY/PRINCIPAL FINDINGS We performed a comprehensive assessment of the potential functional impact of 33 SNPs that were identified and confirmed as associated with PCa risk in previous studies. For these 33 SNPs and additional SNPs in linkage disequilibrium (LD) (r 2 ≥ 0.5), we first mapped them to genomic functional annotation databases, including the encyclopedia of DNA elements (ENCODE), 11 genomic regulatory elements databases defined by the University of California Santa Cruz (UCSC) table browser, and androgen receptor (AR)-binding sites defined by a ChIP-chip technique. Enrichment analysis was then carried out to assess whether the risk SNP blocks were enriched in the various annotation sets. Risk SNP blocks were significantly enriched over that expected by chance in two annotation sets, including AR-binding sites (P=0.003), and FoxA1-binding sites (P=0.05). About one-third of the 33 risk SNP blocks are located within AR-binding regions. CONCLUSIONS/SIGNIFICANCE The significant enrichment of risk SNPs in AR-binding sites may suggest a potential molecular mechanism for these SNPs in PCa initiation, and provide guidance for future functional studies. © 2010 Wiley-Liss, Inc. Source

Pan L.,Chinese Institute of Basic Medical Sciences | Zhang L.,U.S. Center for Disease Control and Prevention | Zhang W.,U.S. Center for Disease Control and Prevention | Wu X.,Chinese Institute of Basic Medical Sciences | And 10 more authors.
Human Molecular Genetics

Vaccination against hepatitis B virus is an effective and routine practice that can prevent infection. However, 5-10% of healthy adults fail to produce protective levels of antibody against the hepatitis B vaccination. It has been reported that host genetic variants might affect the immune response to hepatitis B vaccination. Here, we reported a genome-wide association study in a Chinese Han population consisting of 108 primary high-responders and 77 booster non-responders to hepatitis B vaccination using the Illumina HumanOmniExpress Beadchip. We identified 21 SNPs at 6p21.32 were significantly associated with non-response to booster hepatitis B vaccination (P-value <1 × 10-6). The most significant SNP in the region was rs477515, located ~12 kb upstream of the HLA-DRB1 gene. Its P-value (4.81 × 10-8) exceeded the Bonferroni-corrected genome-wide significance threshold. Four tagging SNPs (rs477515, rs28366298, rs3763316 and rs13204672) that capture genetic information of these 21 SNPs were validated in three additional ChineseHan populations, consisting of 1336 primary high-responders and420 primary non-responders. The fourSNPs continued toshowsignificant associations withnon-response to hepatitis B vaccination (P-combined = 3.98 × 10-13 - 1.42 × 10-8). Further analysis showed that the rs477515 was independently associated with non-response to hepatitis B vaccination with correction for other three SNPs in our GWAS and the known hepatitis B vaccine immunity associated SNP in previous GWAS. Our findings suggest that the rs477515 was an independent marker associated withn on-response to hepatitis B vaccination and HLA-DR region might be a critical susceptibility locus of hepatitis B vaccine-induced immunity. © The Author 2013. Published by Oxford University Press. All rights reserved. Source

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