Rafael Flores-Obando

Polymorphisms in DNA damage response genes and head and neck cancer risk

Background: Polymorphisms in DNA repair genes have been reported contributing factors in head and neck cancer risk but studies have shown conflicting results. Objective: To clarify the impact of DNA repair gene polymorphisms in head and neck cancer risk. Method: A meta-analysis including 30 case–control studies was performed. Results: Marginally statistically significant association was found for XRCC1 codon 399 (for Caucasians only), XPD Asp312Asn and XRCC1 codon 194 variants and head and neck cancer. Conclusion: Assessments of the effects of smoking, alcohol, human papillomavirus and race/ethnicity on the association between DNA repair gene polymorphisms and head and neck cancer are needed.

Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent

Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46-0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent.

HPV-associated lung cancers : an international pooled analysis

Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12-0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.

Polymorphisms in CYP17 and CYP3A4 and prostate cancer in men of African descent

A meta and pooled analysis of published and unpublished case–control studies was performed to evaluate the association of CYP17 (rs743572) and CYP3A4 (rs2740574) polymorphisms and prostate cancer (PCa) in men from the USA, Caribbean, and Africa.

A new mutation in GJC2 associated with subclinical leukodystrophy

Recessive mutations in GJC2, the gene-encoding connexin 47 (Cx47), cause Pelizaeus–Merzbacher-like disease type 1, a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype––hereditary spastic paraplegia type 44. Here, we present evidence that a novel Arg98Leu mutation causes an even milder phenotype––a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady-state junctional conductance–junctional voltage (Gj–Vj) relations differed only slightly from those for wild-type Cx47. Our data suggest that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.

The impact of genetic variants in inflammatory-related genes on prostate cancer risk among men of African Descent: a case control study

PurposeAlthough case–control studies have evaluated the role of variant inflammatory-related loci in prostate cancer, their impact is virtually unknown among men of African descent. To address this, we evaluated the impact of inflammatory cytokine single nucleotide polymorphisms (SNPs) on prostate cancer risk for men of African descent.MethodsForty-four SNPs in inflammatory cytokine-associated genes were evaluated among 814 African-American and Jamaican men (279 prostate cancer cases and 535 controls) using Illumina’s Golden gate genotyping system. Individual SNP effects were evaluated using logistic regression analysis.ResultsFour SNPs were modestly associated with prostate cancer after adjusting for age. In the total population, inheritance of the IL1R2 rs11886877 AA, IL8RB rs11574752 AA, TNF rs1800629 GA + AA, and TNF rs673 GA genotypes modestly increased prostate cancer risk by 1.45 to 11.7-fold relative to the referent genotype. Among U.S. men, age-adjusted dominant, recessive and additive genetic models for the IL1R2 rs11886877 locus were linked to an increase in prostate cancer susceptibility. However, these main effects did not persist after adjusting for multiple hypothesis testing.ConclusionOur preliminary data does not strongly support the hypothesis that inflammatory-related sequence variants influence prostate cancer risk among men of African descent. However, further evaluation is needed to assess whether other variant inflammatory-related genes may contribute to prostate cancer risk and disease progression in larger and ethnically diverse multi-center studies.

Melatonin and the Charlson Comorbidity Index (CCI): The Treviso Longeva (Trelong) Study:

Introduction It has been reported that elderly subjects have a compromised ability to produce melatonin nightly, and that reduced melatonin levels may be a risk factor for cancer. The purpose of this study was to evaluate the relationship between melatonin levels and chronic diseases in a cohort of elderly subjects using the Charlson comorbidity index (CCI). Design We performed a secondary data analysis of a longitudinal study of a representative, age-stratified, sample population. Setting The Treviso Longeva (Trelong) study, in Treviso, Italy. Participants A total of 114 men and 146 women, aged 77 years and older, still alive after 7 years of follow-up. Measurements As an estimation of serum melatonin secretion levels, urinary 6-sulfatoxymelatonin (aMT6s) was assayed in the urine of 260 elderly subjects using an enzyme-linked immunosorbent assay (ELISA) kit (product 01-EK-M6S, ALPCO Immunoassays, Windham, NH). All aMT6s levels were creatinine standardized ([aMT6s]/[creatinine]), and the CCI was calculated. Results The melatonin levels decreased with aging despite not reaching statistical significance, and the decrease was more evident in males than in females (40.5 ng vs 47.0 ng aMT6s/mg creatinine, ns). Melatonin levels were significantly lower in patients reporting insomnia (p=0.05). The CCI score was inversely correlated with the levels of melatonin (p=0.03). Melatonin levels of subjects affected by CCI pathologies were significantly lower than those of healthy subjects (p=0.03) and of subjects suffering from diseases not included in the CCI and, therefore, less severe (p=0.03). Conclusion Melatonin appears to be a marker of disease state and severity, as well as of sleep disorders, in the elderly. These early findings would confirm the protective role of melatonin against several chronic diseases. The benefits of this agent as a possible medication should be more thoroughly clinically tested.

Abstract A70: Chemokine-associated genetic variants as predictors of prostate cancer outcomes among men of African descent

Background: African-American men in the U.S. are 1.6 and 2-fold more likely to receive a prostate cancer (PCA) diagnosis and die from the disease relative to their Caucasian counterparts, respectively. This health disparity extends beyond the U.S. For instance, men from Kingston, Jamaica have higher cancer mortality and morbidity rates compared to African-Americans. Reasons for these disparities may be attributed to differences in cancer screening practices, lifestyle factors, clinical management of the disease, detection of aggressive/advance tumors that are not responsive to available treatments, and genetic susceptibilities. Recent research efforts have focused on the identification of genetic determinants of PCA. Emphasis has been placed on genes that encode chemokines and their receptors, since they play an essential role in tumorigenesis. For instance, over expression of CCR6 is associated with lung, pancreatic, and PCA, presumably by triggering leukocyte production and promoting cell survival and metastasis. Moreover sequence variants detected in CCL5 (rs2280078, rs2107538 at positions −28 and −403, respectively) and CCR6 (rs9459883, rs3798315) were significantly associated with oral cancer, lymphoma or brain cancer in three independent studies. Research Goal and Objective: With the ultimate goal of improving PCA detection/prognosis predictions and clinical management practices, this study seeks to systematically evaluate the individual and combined effects of 41 single nucleotide polymorphisms (SNPs) in chemokine associated genes in relation to PCA risk and disease progression among 1,237 African-American, African and Caribbean men. Hypothesis: We hypothesized that individuals inheriting one or multiple chemokine associated loci (linked to increased inflammation, immune response surveillance, metastasis and cell survival) will have an increased risk of developing PCA relative to those of referent genotypes. Materials and Methods: Forty-one sequence variants detected in chemokine associated genes will be evaluated in germ-line DNA samples collected from 420 PCA cases and 735 controls using Illumina9s Veracode genotyping system. Study participants were recruited from cancer screening programs, hospitals, or cancer centers located in the Washington D.C., South Carolina, and Kingston, Jamaica. Main effects and complex SNP interactions will be evaluated using logistic regression analysis and multi-factor dimensionality reduction (MDR), respectively. All risk models will be adjusted for potential confounders (i.e., age and West African Ancestry) and multiple hypothesis testing. Results: In a pilot study, four SNPs detected in CCR6, CCL5, and CCR4 were significantly associated with PCA among 230 men of African Descent from the United States (124 PCA cases, 106 controls). Inheritance of at least one minor CCR6 rs2023305 A allele was associated with a 1.92 fold increase in the risk of developing PCA. However, a 48–63% decrease in PCA was observed among carriers of the CCL5 (rs2107538 AG+AA, rs3817655 AT+AA) and CCR4 rs6550178 AG. With the exception of the CCR4 marker, these markers remained statistically after adjusting for age and West African ancestry. Discussion: In summary, polymorphisms in chemokine associated genes modify PCA susceptibility among men of African descent in the current study. Our findings will undergo further evaluation and validation in a larger and ethnically diverse study population, including 420 PCA cases and 735 controls from the U.S. and Jamaica. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A70.

Rapid and Specific Immunomagnetic Isolation of Mouse Primary Oligodendrocytes

The efficient and robust isolation and culture of primary oligodendrocytes (OLs) is a valuable tool for the in vitro study of the development of oligodendroglia as well as the biology of demyelinating diseases such as multiple sclerosis and Pelizaeus-Merzbacher-like disease (PMLD). Here, we present a simple and efficient selection method for the immunomagnetic isolation of stage three O4+ preoligodendrocytes cells from neonatal mice pups. Since immature OL constitute more than 80% of the rodent-brain white matter at postnatal day 7 (P7) this isolation method not only ensures high cellular yield, but also the specific isolation of OLs already committed to the oligodendroglial lineage, decreasing the possibility of isolating contaminating cells such as astrocytes and other cells from the mouse brain. This method is a modification of the techniques reported previously, and provides oligodendrocyte preparation purity above 80% in about 4 h.

Inflammation polymorphisms and prostate cancer risk in Jamaican men: Role of obesity/body size

African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.