Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility

Cr, Wolf; Ca, Smith; Gough, AC; Je, Moss; Vallis, Katherine A.; Howard, G.; Fj, Carey; Mills, Ken I.; McNee, W.; Carmichael, James

doi:10.1093/carcin/13.6.1035

Cited by 90 publications

(40 citation statements)

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“…It is estimated that the extreme poor-and ultra-rapid-metabolizer debrisoquine phenotypes are present in 5-10% and 5% of Caucasians, respectively, [81] but the poor metabolizer phenotype has been inconsistently associated with reduced bladder cancer susceptibility. [82,83] Interestingly, it has been suggested that the extensive metabolizer phenotype may contribute to tobacco addiction. [84] The presence of single low-penetrance genetic variants alone are not likely to result in familial aggregations of TCCUT, although they could potentially act together, and/or interact with environmental exposures, and/or modify the penetrance of a major cancer susceptibility gene.…”

Section: Low-penetrance Genesmentioning

confidence: 99%

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Mueller¹,

Caporaso²,

Greene³

2008

Urologic Oncology: Seminars and Original Investigations

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Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a two-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation. Polymorphisms in genes involved in the metabolism of environmental toxins (e.g., NAT2) clearly modify individual susceptibility to bladder cancer. A genetic predisposition has also been suggested by case reports describing multiple-case families, and the development of bladder cancer in association with several well-described Mendelian disorders (e.g., HNPCC, retinoblastoma). Here we update a previouslyreported family, report a new multiple-case kindred, critically review previously-reported bladder cancer families and the epidemiologic literature related to family history of transitional cell carcinoma of the urinary tract (TCCUT) as a risk factor, as well as provide a brief summary of genetic factors that have been implicated in TCCUT risk. We conclude that familial TCCUT is either very uncommon or significantly under-reported, perhaps on the assumption that this is an environmental rather than a genetic disorder. The interaction between multiple genetic and environmental factors has made it challenging to identify genetic components responsible for many common diseases; therefore, a proposed genome-wide association study (GWAS) for urinary bladder cancer may help to clarify the etiologic role of the candidate genetic pathways reviewed here, as well as characterize gene/environment interactions that contribute to TCCUT carcinogenesis.

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Section: Low-penetrance Genesmentioning

confidence: 99%

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Mueller¹,

Caporaso²,

Greene³

2008

Urologic Oncology: Seminars and Original Investigations

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“…The two mutant CYP2D6 alleles (G-*A transition at intron 3/exon 4 and base pair deletion in exon 5) were identified (Gough et al, 1990;Wolf et al, 1992). Together these assays are about 90% predictive of phenotype (Wolf et al, 1992).…”

mentioning

confidence: 99%

“…GSTT1 null and expressing subjects were identified by PCR using the primer set and reaction conditions described by Pemble et al (1994) and Warwick et al (1994). The two mutant CYP2D6 alleles (G-*A transition at intron 3/exon 4 and base pair deletion in exon 5) were identified (Gough et al, 1990;Wolf et al, 1992). Together these assays are about 90% predictive of phenotype (Wolf et al, 1992).…”

mentioning

confidence: 99%

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender

Heagerty¹,

Smith²,

English³

et al. 1996

Br J Cancer

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Summary The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTTI and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTMI A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM I A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTMI null, GSTTI null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.

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“…Accordingly, there is much interest in the significance of polymorphism in the cytochrome P450 (CYP) and glutathione S-transferase (GST) supergene families, as these enzymes metabolise exogenous and endogenous molecules involved in cellspecific functions, such as proliferation and apoptosis (Nebert, 1994). Thus, alleles associated with inappropriate detoxification appear promising candidates for cancer risk (Wolf et al, 1992;Bell et al, 1993;Heagerty et al, 1994;Elexpuru-Camiruaga et al, 1995). Mu and theta class GST appear important in the detoxification of products of oxidative stress, such as lipid hydroperoxides, alkenals and DNA hydroperoxides, as well as potential carcinogens, such as methyl halides and benzo(a)pyrene epoxides (Smith et al, 1995;Strange, 1996).…”

mentioning

confidence: 99%

“…Two mutant CYP2D6 alleles (G-A transition at intron 3/exon 4 and exon 5 base pair deletion) were identified. Together these assays are approximately 90% predictive of phenotype in British Caucasians (Wolf et al, 1992;Smith et al, 1995). DNA from immunohistochemically positive samples (using one or both antibodies) was first screened by SSCP analysis of exons 4-9 in an attempt to identify exons containing mutations and, thereby, reduce the number of exons that required sequencing.…”

mentioning

confidence: 99%

Epithelial ovarian cancer: influence of polymorphism at the glutathione S-transferase GSTM1 and GSTT1 loci on p53 expression

Sarhanis

Redman²,

Perrett³

et al. 1996

Br J Cancer

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Summary The importance of polymorphism in the glutathione S-transferase GSTM1, GSTT1 and, cytochrome P450, CYP2D6 loci in the pathogenesis of epithelial ovarian cancer has been assessed in two studies; firstly, a case-control study designed to determine the influence of these genes on susceptibility to this cancer, and secondly, the putative role of these genes in the protection of host cell DNA has been studied by comparing p53 expression in patients with different GSTM1, GSTT1 and CYP2D6 genotypes. The frequencies of GSTM1, GSTT1 and CYP2D6 genotypes in 84 cases and 325 controls were not different. Immunohistochemistry was used to detect p53 expression in 63 of these tumours. Expression was found in 23 tumours. Of the patients demonstrating immunopositivity, 20 (87%) were GSTM1 null. The frequency distributions of GSTM1 genotypes in p53-positive and -negative samples were significantly different (P= 0.002) and those for GSTT1 genotypes approached significance (exact P=0.057). The proportion of patients with both GSTM1 null and GSTT1 null was also significantly greater in the immunopositive (4/22) than in the immunonegative group (1/40) (P=0.0493). Single-strand conformational polymorphism (SSCP) analysis was used to detect mutations in the 23 tumour samples demonstrating p53 positivity. A shift in electrophoretic mobility of amplified fragments was found in 11 patients (exons 5, 6, 7 and 8) and these exons were sequenced. In eight samples a mutation was found. No SCCP variants were identified in the other 12 immunopositive patients. Sequencing of exons 4-9 of p53 from these tumours resulted in the detection of mutations in two patients (exons 5 and 7). Thus, in 23 patients who demonstrated immunopositivity, p53 mutations were found in nine patients with GSTM1 null (90.0%). In the 13 patients in whom no mutations were identified, 11 were GSTM1 null (84.6%). The data show that overexpression of p53 is associated with the GSTM1 null genotype. We propose the data are compatible with the view that GSTM1 and GSTT1 are critical in the detoxification of the products of oxidative stress produced during the repair of the ovarian epithelium. Thus, failure to detoxify products of this stress may result in damage to various genes in the host cell, including to p53, resulting in persistent expression of mutant protein. In other patients, oxidative stress effects damage to various genes, but not including p53, resulting in overexpression of wild-type p53.

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Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility

Cited by 90 publications

References 0 publications

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender

Epithelial ovarian cancer: influence of polymorphism at the glutathione S-transferase GSTM1 and GSTT1 loci on p53 expression

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