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1.
Mol Carcinog ; 54 Suppl 1: E94-E102, 2015 Jun.
Article in English | MEDLINE | ID: mdl-24976539

ABSTRACT

The tobacco-specific nitrosamine NNK is a potent carcinogen found in tobacco smoke and implicated in the development of lung cancer. The major route of NNK metabolism is carbonyl reduction by AKR1C1, AKR1C2, CBR1, and 11ß-HSD1 to form NNAL. This study investigated the potential role of variants in this pathway on lung cancer risk by examining 53 tag-SNPs representing the common variations in AKR1C1, AKR1C2, CBR1, and HSD11B1 in 456 lung cancer cases and 807 controls. One SNP in CBR1 (rs2835267) was significantly associated with overall risk of lung cancer, but did not pass multiple testing adjustment (OR: 0.76 95% CI: 0.58-0.99, P = 0.048, FDR P = 0.20). After stratification and multiple testing correction, three SNPs showed significance. One SNP (rs2835267) in CBR1 showed a significant decreased risk for smokers with a high pack-years (OR: 0.3595% CI: 0.17-0.69, P = 0.018) and in SCC (OR: 0.4895% CI: 0.29-0.76, P = 0.018). Another SNP located in CBR1 (rs3787728) also showed a significant decreased risk in SCC (OR: 0.4695% CI: 0.26-0.80, P = 0.024) and small cell carcinoma (only in current smokers) (OR: 0.06895% CI: 0.01-0.42, P = 0.028). The HSD11B1 SNP (rs4844880) showed a significant increased risk for adenocarcinoma within former smokers (OR: 3.9495% CI: 1.68-9.22, P = 0.011). Haplotype analysis found significance with six haplotypes and lung cancer risk. These findings indicate that select variants in genes in the carbonyl reduction pathway of NNK may alter the risk of lung cancer.


Subject(s)
Genetic Predisposition to Disease , Lung Neoplasms/genetics , Nitrosamines/pharmacology , Polymorphism, Single Nucleotide , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged
2.
Genes Chromosomes Cancer ; 53(6): 454-66, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24822274

ABSTRACT

UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR = 0.28, 95% CI = 0.11­0.69) and for the distal colon (OR = 0.32, 95% CI = 0.12­0.91)], and that the C-T-G haplotype in the 3' region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.10­5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI = 1.21­5.04) and in females (OR = 3.08, 95% CI = 1.08­8.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.


Subject(s)
Colorectal Neoplasms/genetics , Gene-Environment Interaction , Glucuronosyltransferase/genetics , Polymorphism, Single Nucleotide , Aged , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Case-Control Studies , Chromosomes, Human, Pair 2 , Chromosomes, Human, Pair 4 , Colorectal Neoplasms/metabolism , Female , Genetic Association Studies , Haplotypes , Humans , Male , Middle Aged , Risk , Risk Factors
3.
Cancer ; 119(13): 2477-85, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23575887

ABSTRACT

BACKGROUND: Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS: To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS: A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS: The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.


Subject(s)
Colorectal Neoplasms/genetics , DNA Copy Number Variations , Gene Deletion , Glucuronosyltransferase/genetics , Metabolic Detoxication, Phase II/genetics , Adult , Aged , Case-Control Studies , Colonic Neoplasms/genetics , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/epidemiology , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Meat/adverse effects , Meat Products/adverse effects , Middle Aged , Minor Histocompatibility Antigens , Pennsylvania/epidemiology , Rectal Neoplasms/genetics , Risk Factors , Sex Factors , Surveys and Questionnaires , White People/genetics
4.
Cancer Genet ; 205(11): 572-87, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23137772

ABSTRACT

Molecular cytogenetic evaluation of human osteosarcoma (OS) has revealed the characteristically high degree of genomic reorganization that is the hallmark of this cancer. The extent of genomic disorder in OS has hindered identification of the genomic aberrations driving disease progression. With pathophysiological similarities to its human counterpart, canine OS represents an ideal model for comparison of conserved regions of genomic instability that may be disease-associated rather than genomic passengers. This study used high-resolution oligonucleotide array comparative genomic hybridization and a variety of informatics tools to aid in the identification of disease-associated genome-wide DNA copy number aberrations in canine and human OS. Our findings support and build upon the high level of cytogenetic complexity, through the identification of shared regions of microaberration (<500 kb) and functional analysis of possible orthologous OS-associated genes to pinpoint the cellular processes most commonly affected by aberration in human and canine OS. Aberrant regions contained previously reported genes such as CDC5L, MYC, RUNX2, and CDKN2A/CDKN2B, while expanding the gene of interest list to include ADAM15, CTC1, MEN1, CDK7, and others. Such regions of instability may thus have functional significance in the etiology of OS, the most common primary bone tumor in both species.


Subject(s)
Bone Neoplasms/genetics , Bone Neoplasms/veterinary , Chromosome Aberrations , Dog Diseases/genetics , Osteosarcoma/genetics , Osteosarcoma/veterinary , Adolescent , Adult , Algorithms , Animals , Child , Comparative Genomic Hybridization/methods , DNA Copy Number Variations , Dogs , Female , Genome, Human , Genomics/methods , Humans , Male , Species Specificity
5.
Bone ; 50(1): 171-81, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22037351

ABSTRACT

Osteosarcoma (OS) is the common histological form of primary bone cancer and one of the leading aggressive cancers in children under age fifteen. Although several genetic predisposing conditions have been associated with OS the understanding of its molecular etiology is limited. Here, we show that microRNAs (miRNAs) at the chr.14q32 locus are significantly downregulated in osteosarcoma compared to normal bone tissues. Bioinformatic predictions identified that a subset of 14q32 miRNAs (miR-382, miR-369-3p, miR-544 and miR-134) could potentially target cMYC transcript. The physical interaction between these 14q32 miRNAs and cMYC was validated using reporter assays. Further, restoring expression of these four 14q32 miRNAs decreased cMYC levels and induced apoptosis in Saos2 cells. We also show that exogenous expression of 14q32 miRNAs in Saos2 cells significantly downregulated miR-17-92, a transcriptional target of cMYC. The pro-apoptotic effect of 14q32 miRNAs in Saos2 cells was rescued either by overexpression of cMYC cDNA without the 3'UTR or with miR-17-92 cluster. Further, array comparative genomic hybridization studies showed no DNA copy number changes at 14q32 locus in OS patient samples suggesting that downregulation of 14q32 miRNAs are not due to deletion at this locus. Together, our data support a model where the deregulation of a network involving 14q32 miRNAs, cMYC and miR-17-92 miRNAs could contribute to osteosarcoma pathogenesis.


Subject(s)
Bone Neoplasms/genetics , Chromosomes, Human, Pair 14/genetics , Gene Regulatory Networks , MicroRNAs/genetics , Osteosarcoma/genetics , Proto-Oncogene Proteins c-myc/genetics , Adolescent , Bone Neoplasms/pathology , Bone and Bones/anatomy & histology , Bone and Bones/pathology , Bone and Bones/physiology , Cell Line, Tumor , Child , DNA Copy Number Variations , Gene Expression Profiling , Humans , Microarray Analysis , Multigene Family , Osteosarcoma/pathology
6.
Genes Chromosomes Cancer ; 50(11): 859-74, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21837709

ABSTRACT

Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10-20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts.


Subject(s)
Bone Neoplasms/genetics , Bone Neoplasms/veterinary , Dog Diseases/genetics , Osteosarcoma/genetics , Osteosarcoma/veterinary , Animals , Comparative Genomic Hybridization , Core Binding Factor Alpha 1 Subunit/genetics , DNA Copy Number Variations , Dogs , Female , Gene Dosage , Genomic Instability , Humans , In Situ Hybridization, Fluorescence , Male , Membrane Proteins/genetics , PTEN Phosphohydrolase/genetics , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Tumor Suppressor Proteins/genetics
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