SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer.

Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.

Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk.

Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29-38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations.

The role of body weight in the relationship between physical activity and endometrial cancer: results from a large cohort of US women.

Factors influencing circulating estrogen levels, insulin-mediated pathways or energy balance through obesity-related mechanisms, such as physical activity, have been proposed as potential risk factors for endometrial cancer. We examined measures of physical activity in relation to endometrial cancer risk in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, a prospective study of cancer incidence and mortality, using information obtained at baseline in 1992. From 1992 to 2003, 466 incident endometrial cancers were identified among 42,672 postmenopausal women with intact uteri who were cancer-free at enrollment. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) while adjusting for potential confounders. To assess the role of body mass index (BMI) in this relationship, we computed multivariate RR with and without adjustment for BMI and stratifying by BMI. All measures of physical activity and the avoidance of sedentary behavior were associated with lower endometrial cancer risk. Baseline recreational physical activity was associated with 33% lower risk (RR = 0.67, 95% CI 0.44-1.03 for 31.5+ vs. <7 MET-hr/week, trend p = 0.007) in the multivariate model without BMI. However, the trend was attenuated after further adjustment for BMI (trend p = 0.18). BMI significantly modified the association between physical activity and endometrial cancer risk (heterogeneity of trends p = 0.01). The inverse relationship was seen only among overweight or obese women (trend p = 0.003) and not in normal weight women (trend p = 0.51). In summary, light and moderate physical activity including daily life activities were associated with lower endometrial cancer risk in our study, especially among women who are overweight or obese.

Paraoxonase 1 (PON1) polymorphisms and prostate cancer in the CPS-II Nutrition Cohort.

BACKGROUND: The HDL-associated enzyme paraoxonase 1 acts to decrease oxidative stress, which is thought to contribute to cancer development. PON1, which encodes paraoxonase 1, has two common, nonsynonymous SNPs that alter the activity of this enzyme and may influence cancer risk. METHODS: We investigated the association the nonsynonymous SNPs, Q192R and L55M, with prostate cancer risk in a nested case-control analysis of 1,268 cases and 1,268 matched controls from the American Cancer Society CPS-II Nutrition Cohort. RESULTS: For both the Q192R and L55MSNPs, the presence of the variant allele was associated with an increased risk of aggressive prostate cancer that approached statistical significance. The genotype combination that included one variant allele from both SNPs (QR/LM) was associated with an increased risk of more than twofold (OR = 2.18, 95% CI: 1.31, 3.64). CONCLUSIONS: These findings suggest that the Q129R and the L55M SNP may be associated with increased risk of aggressive prostate, perhaps through attenuation of paraoxonase l activity.

No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk.

One-carbon metabolism mediates the interconversion of folates for the synthesis of precursors used in DNA synthesis, repair, and methylation. Inadequate folate nutrition or compromised metabolism can disrupt these processes and facilitate carcinogenesis. In this study, we investigated associations of 39 candidate single nucleotide polymorphisms (SNP) in 9 one-carbon metabolism genes with risk of prostate cancer using 1,144 cases and 1,144 controls from the Cancer Prevention Study-II Nutrition Cohort. None of these SNPs were significantly associated with prostate cancer risk, either overall or in cases with advanced prostate cancer. Thus, our findings do not support the hypothesis that common genetic variation in one-carbon metabolism genes influences prostate cancer risk.

Nicotinic receptor gene variants influence susceptibility to heavy smoking.

Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the alpha5 nicotinic receptor in heavy smoking.

Predictors of compliance in mass drug administration for the treatment and prevention of lymphatic filariasis in Leogane, Haiti.

The global strategy for the elimination of lymphatic filariasis (LF) is based on annual mass drug administration (MDA) to interrupt transmission. Noncompliance with MDA represents a serious programmatic obstacle for the LF program because systematically noncompliant individuals may serve as a reservoir for the parasite and permit recrudescence of infection. Using a survey questionnaire concerning practices, beliefs, and attitudes towards MDA, we assessed differences between noncompliant individuals and compliant individuals in Leogane, Haiti (n = 367) after four years of treatment. A logistic regression model showed the odds of being noncompliant were significantly increased for women (odds ratio = 2.74, 95% confidence interval = 1.12-6.70), as well as for people who lacked knowledge about both LF and programs to eliminate infection. Public health programs should be designed to target people who are at risk for systematic noncompliance.

Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence.

The interconversion of folates by the one-carbon metabolism pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. Perturbations in this pathway can disrupt these processes and are hypothesized to facilitate carcinogenesis. We investigated associations of 25 candidate polymorphisms in nine one-carbon metabolism genes with risk of postmenopausal breast cancer using 502 cases and 505 controls from the Cancer Prevention II Nutrition Cohort. Four single nucleotide polymorphisms (SNP) in three different genes were significantly associated with breast cancer. The nonsynonymous R134K SNP in methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthase [MTHFD1; odds ratio (OR), 1.40; 95% confidence interval (95% CI), 1.06-1.85 for CT + TT] and an intronic SNP in formyltetrahydrofolate dehydrogenase (FTHFD; OR, 2.23; 95% CI, 1.09-4.54 for CC) were associated with a significant increase in risk. Significantly decreased risk was associated with an intronic SNP in FTHFD (OR, 0.75; 95% CI, 0.58-0.98 for CT + CC) and the A360A SNP in cystathionine beta-synthase (CBS; OR, 0.63; 95% CI, 0.41-0.96 for TT). The presence of at least one variant from both the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C SNPs was also associated with increased risk (OR, 2.16; 95% CI, 1.34-3.48 for 677 CT + TT/1,298 AC + CC). Investigations into interactions of the associated SNPs with each other and with dietary factors yielded inconclusive results. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of postmenopausal breast cancer and may involve changes in methyl donor synthesis. However, larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway.

Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals.

BACKGROUND: Although use of efficacious interventions, including antiretrovirals (ARVs), has dramatically reduced the rate of mother-to-child transmission of human immunodeficiency virus, the safety of in utero ARV exposure remains of concern. METHODS: Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis. RESULTS: Congenital anomalies were identified and confirmed in 61 of the 1112 infants, resulting in a prevalence of 5.49/100 live births (95% confidence interval, 4.22-6.99). Among the 80 anomalies identified, the organ systems involved included cardiovascular (n = 33), musculoskeletal (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial (n = 4), and central nervous system (n = 2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (odds ratio, 2.84; 95% confidence interval, 1.13-7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies. CONCLUSIONS: The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but it is consistent with rates observed in other recent studies of children born to human immunodeficiency virus-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified.

4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia.

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.