Citations

Background and Purpose— The field of ischemic stroke genetics is moving beyond candidate gene studies into the realm of genomewide association studies. Such studies have resulted in discoveries in diverse, complex disorders. Methods— The author conducted an informal qualitative review of peer-reviewed medical literature. Results— The power of genomewide association studies to confirm prior associations and establish new ones is illustrated by recent work focusing on type 2 diabetes mellitus. A pilot genomewide association study of ischemic stroke failed to identify a single gene of major effect. Conclusions— Follow-up studies with substantially greater statistical power are essential and are being planned by the Wellcome Trust and others.

AbstractOver 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567–72)

Abstract The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and implicated in many diseases, including cancer. To evaluate whether mitochondria-related genes are associated with increased risk for prostate cancer, we genotyped 24 single-nucleotide polymorphisms (SNP) within the mitochondrial genome and 376 tagSNPs localized to 78 nuclear-encoded mitochondrial genes. The tagSNPs were selected to achieve ≥80% coverage based on linkage disequilibrium. We compared allele and haplotype frequencies in ∼1,000 prostate cancer cases with ∼500 population controls. An association with prostate cancer was not detected for any of the SNPs within the mitochondrial genome individually or for 10 mitochondrial common haplotypes when evaluated using a global score statistic. For the nuclear-encoded genes, none of the tagSNPs were significantly associated with prostate cancer after adjusting for multiple testing. Nonetheless, we evaluated unadjusted P values by comparing our results with those from the Cancer Genetic Markers of Susceptibility (CGEMS) phase I data set. Seven tagSNPs had unadjusted P ≤ 0.05 in both our data and in CGEMS (two SNPs were identical and five were in strong linkage disequilibrium with CGEMS SNPs). These seven SNPs (rs17184211, rs4147684, rs4233367, rs2070902, rs3829037, rs7830235, and rs1203213) are located in genes MTRR, NDUFA9, NDUFS2, NDUFB9, and COX7A2, respectively. Five of the seven SNPs were further included in the CGEMS phase II study; however, none of the findings for these were replicated. Overall, these results suggest that polymorphisms in the mitochondrial genome and those in the nuclear-encoded mitochondrial genes evaluated are not substantial risk factors for prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3558–66)

Abstract Prostate cancer is the second leading cause of cancer deaths among U.S. men. Early detection is associated with drastically improved 5-year survival rates. It is unclear, however, what psychosocial factors motivate or discourage men from taking advantage of both prostate-specific antigen (PSA) testing and digital rectal examination (DRE). The goal of the current study was to identify psychosocial factors that influence screening behavior for prostate cancer in a cohort of 2,447 men. In 1990, a randomly selected cohort of Caucasian men, ages 40 to 79 years, from Olmsted County, Minnesota, were enrolled in the study. These men completed a questionnaire containing queries on family history of prostate cancer, concern about getting prostate cancer, and marital status. Medical and laboratory records were reviewed to determine the number DREs (1989-1996) and PSA tests (1989-1998). Frequent screening was defined as the upper 25th percentile for number of DREs (>4) or PSAs (>3). Men who have a family history and men who worry or have concern about prostate cancer were more likely [odds ratio (OR), 1.5; 95% confidence interval (95% CI), 1.2-2.0 and OR, 1.9; 95% CI, 1.4-2.5] to seek screening compared with those without a family history or worry. The association between family history and frequent screening was similar in men who were married or living with someone (OR, 1.7; 95% CI, 1.2-2.2); however, it was reduced among men who live alone (OR, 0.6; 95% CI, 0.2-1.8). These data suggest that psychosocial factors such as family history, worry, or concern about prostate cancer and marital status may play an important role in men's decisions about prostate cancer screening. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3588–92)

AbstractDo some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.