Bhatia K.,U.S. National Cancer Institute |
Modali R.,BioServe Biotechnologies Ltd. |
Goedert J.J.,U.S. National Cancer Institute
Journal of Clinical Virology | Year: 2010
Background: Merkel cell polyomavirus (MCPyV) is the first polyoma virus consistently linked to the etiology of a human cancer. Serological studies indicate that the virus is commonly acquired in childhood, with seroprevalence reaching 50% or higher among young adults. The modes of MCPyV transmission are still unclear, but it has been identified in respiratory tract samples. Given its respiratory tropism, we examined whether MCPyV could be detected in mesothelioma tissue, a malignancy induced in animal models by another polyomavirus, SV40. Objective: To determine if MCPyV DNA can be detected in mesothelioma. Study design: DNA was extracted from 45 fresh-frozen mesothelioma samples. PCR was used to detect and quantify the abundance of MCPyV DNA, and a human control gene, in duplicates of the tissues. DNA from a sequence verified MCC tumor was used as a positive control. Results: The human control gene was detected at high levels in all but three mesothelioma tissues. MCPyV DNA was detected in only one mesothelioma, and the level of viral DNA was very low. Conclusions: These results are inconsistent with the hypothesis that MCPyV is etiologically linked to mesothelioma.
Bhatia K.,U.S. National Cancer Institute |
Goedert J.J.,U.S. National Cancer Institute |
Modali R.,Bioserve Biotechnologies Ltd. |
Preiss L.,Rti International |
Ayers L.W.,Ohio State University
International Journal of Cancer | Year: 2010
Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), a clinically and pathologically heterogeneous malignancy of dermal neuroendocrine cells. To investigate this heterogeneity, we developed a tissue microarray (TMA) to characterize immunohistochemical staining of candidate tumor cell proteins and a quantitative PCR assay to detect MCPyV and measure viral loads. MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06-1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p < 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p < 0.08). These data suggest that MCC may arise through different oncogenic pathways, including ones independent of pRb and MCPyV. © 2009 UICC.
Strong M.J.,Tulane University |
Strong M.J.,Tulane Cancer Center |
Xu G.,University of New Orleans |
Coco J.,University of New Orleans |
And 24 more authors.
PLoS Pathogens | Year: 2013
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV. © 2013 Strong et al.
Ritchie S.A.,Phenomenome Discoveries Inc |
Ahiahonu P.W.K.,Phenomenome Discoveries Inc |
Jayasinghe D.,Phenomenome Discoveries Inc |
Heath D.,Phenomenome Discoveries Inc |
And 17 more authors.
BMC Medicine | Year: 2010
Background: There are currently no accurate serum markers for detecting early risk of colorectal cancer (CRC). We therefore developed a non-targeted metabolomics technology to analyse the serum of pre-treatment CRC patients in order to discover putative metabolic markers associated with CRC. Using tandem-mass spectrometry (MS/MS) high throughput MS technology we evaluated the utility of selected markers and this technology for discriminating between CRC and healthy subjects.Methods: Biomarker discovery was performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Comprehensive metabolic profiles of CRC patients and controls from three independent populations from different continents (USA and Japan; total n = 222) were obtained and the best inter-study biomarkers determined. The structural characterization of these and related markers was performed using liquid chromatography (LC) MS/MS and nuclear magnetic resonance technologies. Clinical utility evaluations were performed using a targeted high-throughput triple-quadrupole multiple reaction monitoring (TQ-MRM) method for three biomarkers in two further independent populations from the USA and Japan (total n = 220).Results: Comprehensive metabolomic analyses revealed significantly reduced levels of 28-36 carbon-containing hydroxylated polyunsaturated ultra long-chain fatty-acids in all three independent cohorts of CRC patient samples relative to controls. Structure elucidation studies on the C28 molecules revealed two families harbouring specifically two or three hydroxyl substitutions and varying degrees of unsaturation. The TQ-MRM method successfully validated the FTICR-MS results in two further independent studies. In total, biomarkers in five independent populations across two continental regions were evaluated (three populations by FTICR-MS and two by TQ-MRM). The resultant receiver-operator characteristic curve AUCs ranged from 0.85 to 0.98 (average = 0.91 ± 0.04).Conclusions: A novel comprehensive metabolomics technology was used to identify a systemic metabolic dysregulation comprising previously unknown hydroxylated polyunsaturated ultra-long chain fatty acid metabolites in CRC patients. These metabolites are easily measurable in serum and a decrease in their concentration appears to be highly sensitive and specific for the presence of CRC, regardless of ethnic or geographic background. The measurement of these metabolites may represent an additional tool for the early detection and screening of CRC. © 2010 Ritchie et al; licensee BioMed Central Ltd.
Ritchie S.A.,Phenomenome Discoveries Inc. |
Heath D.,Phenomenome Discoveries Inc. |
Yamazaki Y.,Phenomenome Discoveries Inc. |
Grimmalt B.,Phenomenome Discoveries Inc. |
And 13 more authors.
BMC Gastroenterology | Year: 2010
Background: Serum levels of novel hydroxy polyunsaturated ultra long-chain fatty acids (hPULCFAs) have been previously shown to be reduced in pre-treatment CRC patients compared to disease-free subjects, independent of disease stage. However, whether reduced levels of hPULCFAs result from the presence of cancer is currently unknown, as is the distribution of hPULCFAs in the general population. The following studies were carried out to assess whether conventional therapy would result in restoration of systemic hPULCFAs in CRC patients, and to investigate the relationship between hPULCFA levels and age.Methods: Tandem mass spectrometry was used to determine serum levels of the 28 carbon-containing hPULCFA C28H46O4 (CRC-446) in the following cohorts: two independent Japanese CRC populations following surgical tumor removal (n = 86), a North American Caucasian CRC cohort (n = 150) following post-surgery combination chemo/radiation therapy, 990 randomly selected anonymized serum samples from subjects ranging between 11 and 99 years of age, as well as longitudinally collected serum samples from healthy normals (n = 8, up to 90 weeks) and stage IV CRC subjects on combination therapy (n = 12, up to 63 weeks).Results: Serum CRC-446 levels in CRC subjects were significantly lower than controls (mean of 0.297 ± 0.07 ug/ml in controls versus 0.092 ± 0.03 in CRCs, p < 0.001), and were unaffected by surgical tumor removal or by chemo/radiation treatment (p > 0.05 between pre vs post surgery). CRC-446 levels showed a strong inverse association with age (p < E-11) across the randomly-selected cohort of 990 subjects, with no correlation observed in the CRC-positive subjects. Longitudinal intra-subject results, however, showed relatively stable CRC-446 levels over the short term of up to 90 weeks in both disease-free subjects and late-stage CRC patients.Conclusions: Our findings show that CRC-446 levels are not affected by conventional CRC treatment and inversely correlate with age, which suggest that reduced serum CRC-446 levels likely exist prior to the development of CRC. Extrapolation of the results to a simple screening scenario showed that, compared to fecal blood testing, pre-colonoscopy screening using serum CRC-446 levels would require 80% fewer colonoscopies, would identify risk in subjects under the age of 50, and would result in increased numbers of early cases detected. The precise role these serum metabolites play in the aetiology of cancer development remains to be determined. © 2010 Ritchie et al; licensee BioMed Central Ltd.
Minlikeeva A.N.,State University of New York at Buffalo |
Browne R.W.,Buffalo Lab |
Ochs-Balcom H.M.,State University of New York at Buffalo |
Marian C.,Ohio State University |
And 8 more authors.
PLoS ONE | Year: 2016
Purpose: There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress. Methods: We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white women randomly selected from Western New York (n = 1402). We used general linear models to calculate age-adjusted geometric means of TBARS across the variants. We also examined the associations within strata of menopausal status. Results: For MnSOD, being heterozygous was associated with lower geometric means of TBARS (less oxidative stress), 1.28 mg/dL, compared to homozygous T-allele or homozygous C-allele,1.35 mg/dL, and 1.31 mg/dL correspondingly (p for trend = 0.01). This difference remained among postmenopausal women, 1.40 mg/dL for TT, 1.32 mg/dL for TC, and 1.34mg/dL for CC (p for trend 0.015); it was attenuated among premenopausal women. SNPs in the other genes examined (GSTP1, GSTM1, GPX1, GPX3, and CAT) were not associated with TBARS. Conclusions: Our findings suggest that genetic variation in MnSOD gene may be associated with oxidative status, particularly among postmenopausal women. © 2016 Minlikeeva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PubMed | City College of New York, BioServe Biotechnologies Ltd., University of America, Ohio State University and Buffalo Lab
Type: Journal Article | Journal: PloS one | Year: 2016
There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress.We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white women randomly selected from Western New York (n = 1402). We used general linear models to calculate age-adjusted geometric means of TBARS across the variants. We also examined the associations within strata of menopausal status.For MnSOD, being heterozygous was associated with lower geometric means of TBARS (less oxidative stress), 1.28 mg/dL, compared to homozygous T-allele or homozygous C-allele,1.35 mg/dL, and 1.31 mg/dL correspondingly (p for trend = 0.01). This difference remained among postmenopausal women, 1.40 mg/dL for TT, 1.32 mg/dL for TC, and 1.34mg/dL for CC (p for trend 0.015); it was attenuated among premenopausal women. SNPs in the other genes examined (GSTP1, GSTM1, GPX1, GPX3, and CAT) were not associated with TBARS.Our findings suggest that genetic variation in MnSOD gene may be associated with oxidative status, particularly among postmenopausal women.
Roberts M.R.,State University of New York at Buffalo |
Roberts M.R.,Roswell Park Cancer Institute |
Shields P.G.,Georgetown University |
Ambrosone C.B.,Roswell Park Cancer Institute |
And 11 more authors.
Carcinogenesis | Year: 2011
Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35-79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01-1.51 and OR = 1.23; 95% CI 1.01-1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01-1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01-1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype-smoking and genotype-alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer. © The Author 2011. Published by Oxford University Press. All rights reserved.
Ratnasinghe L.D.,Cytonix |
Modali R.V.,BioServe Biotechnologies Ltd. |
Seddon M.B.,BioServe Biotechnologies Ltd. |
Lehman T.A.,BioServe Biotechnologies Ltd.
Nutrition and Cancer | Year: 2010
We evaluated the association between physical activity and breast cancer risk among 1,463 breast cancer cases and 4,862 controls in a multinational study. All subjects were asked how many times and for how long they exercised or engaged in strenuous physical labor per week. We used multivariate logistic regression to assess the association between physical activity and breast cancer risk. For all subjects combined, the multivariate-adjusted odds ratio was 50% lower (95% confidence interval = 0.4-0.6) for women who reported physical activity once per week or more after adjusting for age, race, body mass index, and pack years of smoking compared to those who reported physical activity less than once per week. Women who reported physical activity 3 times/wk or more did not gain any additional reduced risk. The amount of time spent in physical activity per session was also significantly associated with reduced risk. All ethnic groups examined including Caucasian-Americans, African-Americans, Hispanic-Americans, Tunisian-Arabs, and Polish-Caucasians were at 35% or greater reduced risk for breast cancer if they were physically active for more than 30 minutes per week. Our study shows that physical activity may reduce breast cancer risk regardless of race, weight category, or family history of breast cancer. © 2010, Taylor & Francis Group, LLC.