Dataset Information

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

ABSTRACT: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09).Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

SUBMITTER: Amin Al Olama A

PROVIDER: S-EPMC4491026 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

Amin Al Olama Ali A Benlloch Sara S Antoniou Antonis C AC Giles Graham G GG Severi Gianluca G Neal David E DE Hamdy Freddie C FC Donovan Jenny L JL Muir Kenneth K Schleutker Johanna J Henderson Brian E BE Haiman Christopher A CA Schumacher Fredrick R FR Pashayan Nora N Pharoah Paul D P PD Ostrander Elaine A EA Stanford Janet L JL Batra Jyotsna J Clements Judith A JA Chambers Suzanne K SK Weischer Maren M Nordestgaard Børge G BG Ingles Sue A SA Sorensen Karina D KD Orntoft Torben F TF Park Jong Y JY Cybulski Cezary C Maier Christiane C Doerk Thilo T Dickinson Joanne L JL Cannon-Albright Lisa L Brenner Hermann H Rebbeck Timothy R TR Zeigler-Johnson Charnita C Habuchi Tomonori T Thibodeau Stephen N SN Cooney Kathleen A KA Chappuis Pierre O PO Hutter Pierre P Kaneva Radka P RP Foulkes William D WD Zeegers Maurice P MP Lu Yong-Jie YJ Zhang Hong-Wei HW Stephenson Robert R Cox Angela A Southey Melissa C MC Spurdle Amanda B AB FitzGerald Liesel L Leongamornlert Daniel D Saunders Edward E Tymrakiewicz Malgorzata M Guy Michelle M Dadaev Tokhir T Little Sarah J SJ Govindasami Koveela K Sawyer Emma E Wilkinson Rosemary R Herkommer Kathleen K Hopper John L JL Lophatonanon Aritaya A Rinckleb Antje E AE Kote-Jarai Zsofia Z Eeles Rosalind A RA Easton Douglas F DF

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20150402 7

<h4>Background</h4>Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.<h4>Methods</h4>We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different ri ...[more]

PMID: 25837820

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Project description:BACKGROUND:Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS:Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS:We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION:Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

Dataset Information

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

Publications

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

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