RESUMO
BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Mutação em Linhagem Germinativa , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Few genetic variants have been confirmed as being associated with prostate cancer-specific mortality (PCSM). A recent study identified 22 candidate single-nucleotide polymorphisms (SNPs) associated with PCSM in a Seattle-based patient cohort. Five of these associations were replicated in an independent Swedish cohort. METHODS: We genotyped these 22 SNPs in Physicians' Health Study (PHS) participants diagnosed with prostate cancer (PCa). Using the same model that was found to be most significant in the Seattle cohort, we examined the association of these SNPs with lethal disease with Cox proportional hazards models. RESULTS: One SNP, rs5993891 in the ARVCF gene on chromosome 22q11, which had also replicated in the Swedish cohort, was also significantly associated with PCSM in the PHS cohort (hazard ratio (HR)=0.32; P=0.01). When we tested this SNP in an additional cohort (Health Professionals Follow-up Study, HPFS), the association was null (HR=0.95, P=0.90); however, a meta-analysis across all studies showed a statistically significant association with a HR of 0.52 (0.29-0.93, P=0.03). CONCLUSIONS: The association of rs5993891 with PCSM was further replicated in PHS and remains significant in a meta-analysis, though there was no association in HPFS. This SNP may contribute to a genetic panel of SNPs to determine at diagnosis whether a patient is more likely to exhibit an indolent or aggressive form of PCa. This study also emphasizes the importance of multiple rounds of replication.
Assuntos
Variação Genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapiaRESUMO
Rowers may sacrifice on-water technique during ergonometric training in an attempt to increase stroke output. This cross-sectional study aimed to identify characteristics of ergonometric rowing technique that could be potentially detrimental to an effective and safe on-water performance. Joint excursion, handle velocity, and applied force were measured in 44 athletes while they performed a 2500 meter race on an instrumented ergometer. Results on four subjects are presented here. Their performance is compared to that of a Barcelona Olympic and World champion rower with 12 years of experience to illustrate how athletes deviate from standard on-water technique. Kinematic data showed knee joint oscillations and out-of-phase hip and knee joint reversals. Horizontal handle velocity curves indicated that higher stroke rates were achieved by a decrease in recovery time. Vertical handle velocity curves exhibited bi-directional variations. The largest amplitude occurred at the end of the drive phase during an upward displacement of the handle that was associated with a jerk in the applied force. Force-time curves at different stroke rates showed greater variability in the initial portion of the drive phase. Perpetuation of these technique deviations may be detrimental to on-water performance. Biomechanical analyses may allow coaches to better monitor technique during ergonometric training.