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C Bouchardy

Publications and source records attributed to C Bouchardy.

At least 37 records · Page 2Linked to original sources
PubMed2000

High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers.

Human microsomal epoxide hydrolase (mEH), encoded by the EPHX1 gene, is involved in the metabolism of tobacco carcinogens. We investigated the effect of exon 3 and 4 polymorphisms of the EPHX1 gene in 121 patients with cancers of the oral cavity/pharynx, 129 patients with cancer of the larynx, and 172 non-cancer controls, all Caucasian regular smokers. The potential modifying role of previously analyzed GSTM1, GSTM3, and GSTP1 genotypes was also examined. Compared with the putative low-activity genotypes, odds ratios (ORs) associated with predicted intermediate and high mEH activity genotypes were significantly increased for oropharyngeal cancers [OR = 1.8; 95% confidence interval (CI) = 1.0-3.3; and OR = 2.1; 95% CI = 1.0-4.5, respectively; P(trend) = 0.03] and laryngeal cancers (OR = 1.7; 95% CI = 1.0-3.1; and OR = 2.4; 95% CI = 1.1-5.1, respectively; P(trend) = 0.02). Moreover, a positive interaction was found between mEH activity and GSTM3 genotype for laryngeal cancer. The combined EPHX1 high activity-associated genotype and GSTM3 (AB or BB) genotype conferred a 13.1-fold risk (95% CI = 3.5-48.4) compared with the concurrent presence of the EPHX1 low activity-associated genotype and the GSTM3 AA genotype. Thus, EPHX1 polymorphisms may be one of the factors of importance in susceptibility to smoking-related cancers of the upper aerodigestive tract.

Adult↗
PubMed2000

Sex differences in presentation, management, and prognosis of patients with non-small cell lung carcinoma.

OBJECTIVE AND METHODS: To characterize gender differences in lung cancer, we conducted a retrospective analysis including all patients undergoing surgery for non-small cell lung carcinoma in a single institution over a 20-year period. RESULTS: Compared with men (n = 839), women (n = 198) were more likely to be asymptomatic (32% vs 20%, P =.006), nonsmokers (27% vs 2%, P <.001), or light smokers (31 pack-years vs 52 pack-years; P <.001). Squamous cell carcinoma predominated in men (65%), and adenocarcinoma predominated in women (54%). Preoperative bronchoscopy contributed more frequently to a histologic diagnosis in men (69% vs 49% in women, P <.001), and fewer pneumonectomies were performed in women (22% vs 32% in men, P =.01). After multivariate Cox regression analysis, women survived longer than men (hazard ratio, 0.72; 95% confidence interval, 0.56-0. 92; P =.009) independently of age, presence of symptoms, smoking habits, type of operation, histologic characteristics, and stage of disease. The protective effect linked to female sex was present in early-stage carcinoma (stage I and II) and absent in more advanced-stage carcinoma (stage III and IV). CONCLUSIONS: This study emphasizes strong sex differences in presentation, management, and prognosis of patients with non-small cell lung cancer.

Adult↗
PubMed2000

CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships.

Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption </=20 g/day) or heavy smokers (>20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.

Adult↗
PubMed2000

Surveys on mammography frequency in Geneva.

Two surveys were conducted in Geneva, in 1991 and 1995, to assess the coverage of mammography before the introduction of a breast cancer screening programme. Women who attended for mammographies did so at their own request, or were referred by doctors (more by gynaecologists than general practitioners). In 1995, the total female population was around 200,000, of which the target population for screening (age group 50 to 69) was 46,000 persons. The total number of mammographies observed increased by 23%, with a higher increase for "routine" mammographies (+35%). However, these figures hide certain trends, with a high proportion of educated women performing regular breast investigations. The two year coverage rate for mammography among the 50 to 69 age group is estimated at 38%, which means that about 20,000 women within this target population in Geneva still escape screening.

Adolescent↗
PubMed1999

Determinants of long term survival after surgery for cancer of the lung: A population-based study.

BACKGROUND: Even if some determinants of lung cancer (LC) prognosis have been established, their independent effect on long term survival remains to be seen. The objective of the current study was to identify the prognostic indicators of long term survival among LC patients treated by surgery. METHODS: All patients with LC recorded at the Geneva Cancer Registry between 1977 and 1987 were analyzed by logistic regression, considering as cases (n = 98) those patients alive 10 years after their initial diagnosis and as controls (n = 330) all other patients, excluding those who did not undergo putative curative surgery. The effect of each prognostic factor was evaluated after accounting for age and gender ("crude" effect) and also for other a priori confounding factors (adjusted effect). Additional models considered two staging variables simultaneously to identify the strongest staging determinant. Results were presented as relative risk estimates of long term (>/=10 years) survival. RESULTS: Age, histology, and stage of disease significantly influenced prognosis regardless of the confounding factors considered. Gender also emerged as a discriminated factor in LC outcome, with a 2.1-fold increased chance (95% confidence interval, 1.6-3.5) of long term survival for women compared with men. Method of discovery, presence of symptoms, period of diagnosis, socioeconomic status, and tumor differentiation did not appear to be associated with long term survival. Extent and size of the tumor were found to be the most reliable prognostic staging factors, whereas adenopathy had no effect after accounting for extension. CONCLUSIONS: The current population-based study quantifies the independent effect of the factors modifying the chances of curability in patients with LC. In particular, it provides additional evidence that gender strongly influences long term survival.

Adult↗
PubMed1999

Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers.

Several polymorphic glutathione S-transferase enzymes are involved in the detoxification of active metabolites of many potential carcinogens from tobacco smoke and may therefore be important in modulating susceptibility to smoking-related cancers. As part of a hospital-based case-control study performed in France among Caucasian smokers, we studied GSTM1, GSTM3, GSTP1 and GSTT1 gene polymorphisms in 121 patients with oral cavity and pharyngeal cancers and 172 hospital controls using peripheral blood DNA. An increase in risk was found among carriers of the GSTP1 (AG or GG) genotype (OR 1.6, 95% CI 1.0-2.8, p = 0.07) or the GSTT1 null genotype (OR 2.0, 95% CI 1.0-4.0, p = 0.05). The effect of these at-risk genotypes was most marked in subjects with a history of more than 30 years of smoking, among whom the respective ORs were 2.0 (95% CI 1.0-3.9) and 3.3 (95% CI 1.3-8.1), though the interaction tests between these genotypes and duration of smoking were not significant. In contrast, neither the GSTM1 null genotype nor the GSTM3 AA genotype was associated with oropharyngeal cancer risk (OR 0.9, 95% CI 0.5-1.5 and OR = 1.3, 95% CI 0.7-2.3, respectively). Our results thus suggest that GSTP1 and GSTT1 gene polymorphisms modulate susceptibility to smoking-related cancers of the oral cavity and pharynx.

Adult↗
PubMed1999

Glutathione S-transferase GSTM3 and GSTP1 genotypes and larynx cancer risk.

Glutathione S-transferases (GSTs) are involved in detoxification of reactive metabolites of carcinogens and, therefore, could be potentially important in susceptibility to cancer. The associations between larynx cancer risk and GSTM3 and GSTP1 gene polymorphisms, either separately or in combination with GSTM1 and GSTT1 gene polymorphisms, were evaluated using peripheral blood DNA from 129 cancer patients and 172 controls, all regular smokers. The frequencies of GSTM3 AA, AB, and BB genotypes were 60.5%, 36.4%, and 3.1% in cases and 72.7%, 24.4%, and 2.9% in controls, respectively. The frequencies of GSTP1 AA, AG, and GG genotypes were 48.1%, 40.3%, and 11.6% in cases and 50.0%, 37.2%, and 12.8% in controls, respectively. Multivariate logistic regression analyses did not reveal any association between the GSTP1 (AG or GG) genotype and larynx cancer [odds ratio, 1.1; 95% confidence interval (CI), 0.7-2.0]. In contrast, a significant increase in risk was related to the GSTM3 (AB or BB) genotype (odds ratio, 2.0; 95% CI, 1.1-3.4). The combined GSTM3 (AB or BB) and GSTM1-null genotype conferred a 4-fold risk (95% CI, 1.6-10.1) of larynx cancer as compared with the combined GSTM3 AA and GSTM1-positive genotype. However, the effect of GSTM3 (AB or BB) genotype was similar among individuals with GSTM1-positive or GSTM1-null genotypes.

Carcinogens↗
PubMed1999

A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin.

Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent approximately 13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.

Alleles↗
PubMed1999

Inherent difficulties in epidemiological studies involving phenotyping.

Phenotyping studies on a possible association between genetic polymorphisms and cancer raise specific problems that are mostly related to accurate determination of enzymatic activity in individuals. These difficulties are addressed on the basis of investigations into the relationship between the CYP2D6 phenotype and lung cancer. Only the problems concerning the design and analysis of epidemiological studies and which are specifically related to the genetic polymorphism are discussed. In particular, factors likely to modify enzymatic activity are potential sources of error when assessing the relationship between cancer and genetic polymorphism. These factors are mainly related to the study population (ethnicity, co-administered drugs, underlying diseases, etc.) or to the phenotyping protocol (probe drugs, urine collection, techniques). These aspects of phenotyping-related difficulties are the key issues in the design of phenotyping studies.

Cytochrome P-450 CYP2D6↗
PubMed1998

Association between lung cancer and microsomal epoxide hydrolase genotypes.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of tobacco-derived carcinogens. Polymorphisms in exons 3 and 4 of the EPHX gene have been reported to be associated with variations in mEH activity. We examined whether the predicted mEH activity modified the lung cancer risk among 150 cases and 172 controls, all French Caucasian smokers. A significant association was found between predicted mEH activity and lung cancer (P < 0.02), with a dose-effect relationship (P < 0.005). The risks associated with intermediate and high activities, compared to low activity, were 1.65 (95% CI, 0.95-2.86) and 2.66 (95% CI, 1.33-5.33), respectively. The effect of mEH activity on lung cancer risk was not significantly modified by smoking exposure, CYP1A1 genotype, or GSTM1 genotype. mEH may thus be an important genetic determinant of smoking-induced lung cancer.

Adult↗
PubMed1998

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.

Alleles↗
PubMed1998

N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk.

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved in the activation/inactivation reactions of numerous xenobiotics, including tobacco-derived aromatic amine carcinogens. Several allelic variants of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenotype/genotype has been inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk was evaluated among 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. The NAT1 alleles (*3, *4, *10, *11, *14, and *15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods using DNA extracted from peripheral white blood cells. Genotypes were classified according to current knowledge of the functional activity of the variant alleles. The NAT1*10 and NAT1*11 alleles were considered as rapid alleles, the NAT1*4 and the NAT1*3 as normal alleles and NAT1*14 and NAT1*15 as slow-acetylation alleles. Logistic regression analyses were performed taking into account the age, sex, smoking and occupational exposures. A significant association was observed between lung cancer and NAT1 genotypes (P(homogeneity) < 0.02) with a gene dose effect (P(trend) < 0.01); compared with homozygous rapid acetylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-19.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence interval 1.3-106.5) for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. Similar results were obtained whatever the adjustment considered. No significant association was found between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking-induced lung cancer.

Acetyltransferases↗
PubMed1998

Role of glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes in modulating susceptibility to smoking-related lung cancer.

Glutathione S-transferases GSTM1, GSTM3, GSTP1 and GSTT1 are involved in the detoxification of active metabolites of several carcinogens in tobacco smoke. We studied the potential role of GSTM3 and GSTP1 gene polymorphisms either separately, or in combination with GSTM1 and GSTT1 gene polymorphisms, in susceptibility to lung cancer using peripheral blood DNA from 150 lung cancer patients and 172 control individuals, all regular smokers. The frequencies of GSTM3, AA, AB and BB genotypes were 70.7%, 24.0% and 5.3% in cases and 72.7%, 24.4% and 2.9% in control individuals respectively. The frequencies of GSTP1, AA, AG and GG genotypes were 44.7%, 44.0% and 11.3% in cases and 50.0%, 37.2% and 12.8% in control individuals respectively. When studied separately, neither GSTM3 nor GSTP1 genotypes contributed significantly to the risk of lung cancer. Although failing to reach statistical significance, the combined GSTM3 AA and GSTP1 (AG or GG) genotype conferred a nearly threefold risk when the GSTM1 gene was concurrently lacking (odds ratio 2.9, 95% confidence interval 0.7-12.1). Significant interactions were observed between pack-years of smoking and the combined GSTM3 AA and GSTP1 (AG or GG) genotype, or the combined GSTM3 AA, GSTP1 (AG or GG) and GSTM1 null genotype. The combination of these three a priori at risk genotypes conferred an increased risk of lung cancer among smokers with a history of at least 35 pack-years (odds ratio 2.7, 95% confidence interval 1.2-6.0), but not in lighter smokers, probable because of the lower average number of pack-years of smoking found among control individuals with this genotype combination.

Aged↗
PubMed1998

A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin.

The 4'-hydroxylation of the S-enantiomer of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism shows marked interracial heterogeneity, with the poor metabolizer (PM) phenotype representing 2 to 5% of Caucasian and 13 to 23% of Asian populations. Two defective CYP2C19 alleles, CYP2C19*2 and CYP2C19*3, have been described which account for approximately 87% of Caucasian and > 99% of Oriental PM alleles. The present study identifies a new allele (CYP2C19*4) in Caucasian PMs which contains an A-->G mutation in the initiation codon. A new polymerase chain reaction-restriction fragment length polymorphism genotyping test was developed, and the incidence of this allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. One of nine putative PMs was heterozygous for CYP2C19*2/CYP2C19*4, which suggests that CYP2C19*4 represents a defective allele. Six of the seven remaining putative PMs available for genotyping were explained by CYP2C19*2. The frequency of the CYP2C19*4 allele in Caucasians was 0.6%. An additional Caucasian PM from a separate study was also heterozygous for CYP2C19*2 and CYP2C19*4. To verify that CYP2C19*4 represented a defective CYP2C19 allele, the initiation codon of the normal CYP2C19*1 cDNA was mutated to a GTG, and both cDNAs were expressed in yeast. Recombinant CYP2C19 protein was detected by Western blot analysis of colonies transformed with CYP2C19*1 cDNA, but not in those transformed with CYP2C19*4 cDNA. The two cDNAs were also used in an in vitro coupled transcription/translation assay. CYP2C19 protein was translated only from the CYP2C19*1 allele. These data indicate that CYP2C19*4 represents a new PM allele.

Alleles↗