Metabolic oxidation phenotypes as markers for susceptibility to lung cancer

Ayesh, R.; Idle, Jeffrey R.; Ritchie, James C.; Crothers, Michael J.; Hetzel, M

doi:10.1038/312169a0

Cited by 357 publications

(141 citation statements)

References 5 publications

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“…The results of Ayesh et al (1984) were very similar; four of 245 (1.6%) cases and 21 of 234 (9.0%) controls were poor metabolisers (P<0.01). Poor metabolisers thus have one-fifth the risk of smoking-related lung cancer of extensive metabolisers.…”

supporting

confidence: 63%

Debrisoquine metabolism and genetic predisposition to lung cancer

Law

Hetzel²,

Idel³

1989

Br J Cancer

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It is usually the metabolites of environmental carcinogens that initiate a cancer (Miller & Miller, 1983), and if the metabolism were subject to genetically determined polymorphism, there could be variation between smokers in their susceptibility to smoking-related lung cancer. We report a case-control study using the drug debrisoquine as a potential marker of such genetically determined susceptibility to lung cancer.Debrisoquine has only one major metabolite, 4-hydroxy debrisoquine (Idle et al., 1979), and the extent of 4-hydroxylation before excretion is controlled by a single gene and segregates into two distinct phenotypes -autosomal recessive poor metabolisers (about 9% of white populations, hydroxylating only 1-2% of a 10mg dose of debrisoquine) and homozygous and heterozygous dominant extensive metabolisers (hydroxylating 10-99%) (Evans et al., 1980;Steiner et al., 1985). Unchanged and 4-hydroxy debrisoquine can be measured easily and with high reproducibility (r=0.88) in urine (Evans et al., 1980 We recruited consecutive caucasian inpatients with newly diagnosed lung cancer from a London hospital. Cigarette smoking histories were documented as accurately as possible and recorded in pack-years (one-twentieth the average daily number of cigarettes smoked multiplied by the number of years of smoking). Subjects whose total cigarette consumption was less than 10 pack years, or who had given up smoking more than five years previously were excluded. We also excluded patients with elevated serum bilirubin (>25mmoll-1), and those who were taking drugs known to induce oxidising enzymes (e.g. barbiturates) or to compete with debrisoquine for oxidation (Sloan et al., 1978;Eichelbaum, 1984). A total of 104 cases were included. The histological types were squamous cell (38 cases), large cell (22), small cell (31), adenocarcinoma (11) and undifferentiated (2), diagnosed histologically (92) or cytologically (12). The 104 control subjects were residents of three homes for ex-servicemen (70), inpatients with various non-malignant diseases (22) Cases and controls took a single 10mg debrisoquine tablet at 7 a.m. and made an 8 h urine collection, from which aliquots were stored at -20°C to await analysis by electroncapture gas-chromatography (Idle et al., 1979). The ratio of unchanged to 4-hydroxy debrisoquine concentration, the metabolic ratio, was used to assign phenotype, the antimode

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supporting

confidence: 63%

Debrisoquine metabolism and genetic predisposition to lung cancer

Law

Hetzel²,

Idel³

1989

Br J Cancer

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“…[46,47] We evaluated the debrisoquine hydroxylase metabolizer phenotype by measuring urinary debrisoquine metabolites after administration of 10 mg of debrisoquine in these newly-tested family members, and found no consistent relationship between metabolizer phenotype and cancer incidence. [46][47][48][49] In addition, we evaluated a previously-unreported family comprised of a father and two sons with bladder cancer (Figure 2), diagnosed at ages 71, 45 and 47, respectively. Smoking history was unavailable on the father; both sons reported substantial tobacco exposure.…”

Section: Summary Of Nci Familial Bladder Cancer Familiesmentioning

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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“…Initial CYP2D6 phenotyping studies suggested overrepresentation of the dominant EM (extensive metabolizer) phenotype in lung cancer patients when compared to patients with chronic obstructive pulmonary disease (Ayesh et al, 1984;Caporaso et al, 1989). Subsequent genotyping reports have not confirmed these findings (Sugimura et al, 1990;Tefre et al, 1994;Stucker et al, 1995).…”

mentioning

confidence: 95%

Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland

Rusin¹,

Butkiewicz²,

Małusecka³

et al. 1999

Br J Cancer

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The p53 mutation spectrum can generate hypotheses linking carcinogen exposure to human cancer. Although it is well-documented that tobacco smoking is a major cause of lung cancer, the contribution of air pollution is less well-established. We determined the molecular and immunohistochemical changes ( p53 gene mutations, p53 protein accumulation and WAF1 protein expression) and genetic polymorphisms of GSTM1, CYP1A1 and CYP2D6 genes in a case series of non-small-cell lung cancers from Silesia. This region of southern Poland is highly industrialized with considerable environmental pollution. More than 50% of lung cancers (90/164) contained p53 mutations and 75% showed the combined alteration of the p53 gene and protein accumulation. Males occupationally exposed to coal-derived substances showed a relatively high frequency of squamous and large-cell carcinomas, relatively frequent mutations in codon 298 of p53 and a low frequency of p53 immunohistochemically positive tumours. Codon 298 GAG→ →TAG mutations have rarely been found in lung cancers in other populations. We found no correlation between WAF1 protein expression and mutations in the p53 gene or p53 protein accumulation. No statistically significant relationship was found between p53 mutations and GSTM1, CYP1A1, CYP2D6 genotypes. Never smokers with lung cancers from Silesia had a higher frequency of G:C→ →T:A transversions than previously reported of the p53 mutation spectrum in never smokers (6/15 vs 4/34; P = 0.06 by χ 2 ). These data are a tentative indication that occupational and environmental exposure to polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, in polluted air contributes to the molecular pathogenesis of lung cancer in never smokers. © 1999 Cancer Research Campaign

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Metabolic oxidation phenotypes as markers for susceptibility to lung cancer

Cited by 357 publications

References 5 publications

Debrisoquine metabolism and genetic predisposition to lung cancer

Debrisoquine metabolism and genetic predisposition to lung cancer

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

Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland

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