Browsing by Author "Smith, AH"

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    Arsenic-related chromosomal alterations in bladder cancer
    (2002) Moore, LE; Smith, AH; Eng, C; Kalman, D; DeVries, S; Bhargava, V; Chew, K; Moore, D; Ferreccio, C; Rey, OA; Waldman, FM
    Background: Previous studies have demonstrated that ingestion of arsenic in drinking water is a strong risk factor for several forms of cancer, including bladder cancer. It is not known whether arsenic-related cancers are genetically similar to cancers in unexposed individuals or what mechanisms of carcinogenesis may underlie their formation. This study was designed to compare chromosomal alterations in bladder cancers of arsenic-exposed individuals to provide insight into the mechanism of how arsenic may induce or promote cancer. Methods: A case-case study was conducted in Argentina and Chile examining chromosomal alterations in bladder tumor DNA in 123 patients who had been exposed to arsenic in their drinking water. Patients were placed into one of four arsenic exposure categories according to their average 5-year peak arsenic exposure. Patients were also classified as ever smokers or never smokers. Comparative genomic hybridization was used to identify chromosomal alterations throughout the genome. All statistical tests were two-sided. Results: The total number of chromosomal alterations was higher in individuals exposed to higher arsenic levels (5.7 +/- 5.1, 5.6 +/- 5.1, 7.3 +/- 7.4, and 9.1 +/- 6.5 [mean standard deviation] chromosomal alterations per tumor with increasing arsenic exposure; P-trend = .02, adjusted for stage and grade). The trend was stronger in high-grade (G2-G3) tumors (6.3 +/- 5.5, 8.3 +/- 4.7, 10.3 +/- 7.8, and 10.5 +/- 6.4 alterations per tumor; P-trend = .01) than it was in low-grade (G1) tumors (3.5 +/- 3.1, 1.1 +/- 1.1, 2.5 +/- 2.5, and 3.6 +/- 3.2 alterations per tumor; P-trend = .79). The mean number of chromosomal alterations also increased with tumor stage and grade (P-trend<.001) independently of arsenic exposure but was not associated with smoking history. Deletion of part or all of chromosome 17p (P-trend<.001) showed the strongest association with arsenic exposure. Conclusions: Bladder tumors in patients with higher levels of arsenic exposure showed higher levels of chromosomal instability. Most of the chromosomal alterations associated with arsenic exposure were also associated with tumor stage and grade, raising the possibility that bladder tumors from arsenic-exposed patients may behave more aggressively than tumors from unexposed patients.
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    Childhood exposure to arsenic in water in Chile and increased mortality from chronic pulmonary disease
    (LIPPINCOTT WILLIAMS & WILKINS, 2005) Smith, AH; Marshall, G; Yuan, Y; Ferreccio, C; Liaw, J; von Ehrenstein, O; Steinmaus, C
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    P53 alterations in bladder tumors from arsenic and tobacco exposed patients
    (2003) Moore, LE; Smith, AH; Eng, C; DeVries, S; Kalman, D; Bhargava, V; Chew, K; Ferreccio, C; Rey, OA; Hopenhayn, C; Biggs, ML; Bates, MN; Waldman, FM
    Previous studies demonstrated that tobacco and arsenic exposure are risk factors for bladder cancer. A case-case study was conducted to compare p53 mutations in 147 bladder tumors from South American patients by tobacco and arsenic exposure. Information on residential history and lifestyle factors was collected. The prevalence of p53 mutations and protein expression was examined in relation to tumor stage, grade, patient age, gender, tobacco and arsenic exposure. Smokers were grouped as ever/never smokers and by pack years of exposure (0, 1-20, >20). Patients were also grouped into four arsenic exposure categories based on the average of the five highest years arsenic concentration in their drinking water: group 1, non-detectable to <10 mug/l (n=50); group 2, 10-99 mug/l (n=31); group 3, 100-299 mug/l (n=35); group 4, >300 mug/l (n=30). The proportion of tumor samples with p53 mutations and P53 immunopositivity increased strongly with both stage and grade, but not with arsenic exposure or smoking. The prevalence of tumors containing mutational transitions increased markedly with tumor stage (from 14 to 52%, P-trend=0.005) and grade (from 11 to 48%, P-trend=0.004) and was higher in smokers than in non-smokers (34 versus 18%, respectively, P=0.10). An increasing trend was observed with pack years of smoking (P=0.09). The majority of mutations in tumors from both smokers and non-smokers were G-->A transitions, however, in smokers a preference for G-->A transitions at CpG sites was observed (P=0.07, two-tailed) and a positive trend was observed with pack years of exposure (P=0.04). A hotspot was found at codon 273 in 12% of the tumors from smokers but was not observed in never smokers (P=0.05) and a positive trend was observed with pack years of tobacco exposure (P=0.001). Neither stage nor grade demonstrated a preference for CpG site mutation, suggesting that these changes may be early exposure-related events in carcinogenesis and are not related to tumor progression. Arsenic exposure was not associated with an increased prevalence of p53 mutation or P53 immunopositivity and there was no evidence of interaction between arsenic and smoking with these outcome variables.