Herng-Der Chern

Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan

SummaryThe incidence of breast cancer has been greatly increasing in Taiwan over the past two decades. Since cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens or oestrogen, we hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for breast cancer. This hypothesis was evaluated in this case control study of 150 breast cancer patients and 150 healthy controls among Chinese women. Two CYP1A1 polymorphisms were studied, one containing a new Msp1 site and the other located in axon 7 and resulting in the replacement of an isoleucine (Ile) residue by a valine (Val). After simultaneously considering the known or significant risk factors for breast cancer, including the age of study participants, positive family history of breast cancer, early menarche (≤ 13 years), nulliparity and late first full-term pregnancy (≥ 30 years), hormone replacement therapy and smoking, the CYP1A1 Msp1 polymorphism was found to be a significant factor in determining the risk of breast cancer. The homozygous variant was the most susceptible genotype with an adjusted odds ratio of 1.98 (95% confidence interval (CI) = 1.01–3.99) compared with the non-homozygous variants (the homozygous wild-type and the heterozygous variant). In contrast, the CYP1A1 Ile/Val polymorphism was not significantly associated with breast cancer development (adjusted OR = 1.07, 95% CI = 0.64–1.78). Interestingly, the Msp1 polymorphism was especially significant in postmenopausal women, but not in premenopausal women. Further stratification analysis in postmenopausal women who were non-smokers and with no history of hormone replacement therapy showed the cancer risk due to the Msp1 variant to be more significant in women with early menarche. We conclude that CYP1A1 polymorphism is a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Further study with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.

The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese

Objective: Reports suggest that catechol-O-methyltransferase (COMTL/L) (Val158/Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. Methods: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. χ2, OR, and Fisher’s exact tests were used to compare differences in allelic frequencies and genotypes. Results: The MAOB G genotype (G in men and G/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMTL and MAOB G genotypes. Conclusions: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMTL genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.

Association between N-acetyltransferase 2 (NAT2) genetic polymorphism and development of breast cancer in post-menopausal Chinese women in Taiwan, an area of great increase in breast cancer incidence.

The incidence of breast cancer has increased greatly in Taiwan over the past 2 decades. Increased exposure to environmental carcinogens, including aryl aromatic amines, as a result of the economic boom, is suspected to be one factor contributing to this increase. The enzyme N‐acetyltransferase 2 (NAT2) determines the rate of metabolism of aryl aromatic amines, and therefore the NAT2 slow acetylator genotype is associated with an increased risk of cancer. Our present case‐control study of 150 breast cancer patients and 150 healthy controls in Taiwan was performed to explore the association between NAT2 genetic polymorphism and individual susceptibility to breast cancer. A structured questionnaire was used to collect relevant information regarding all known or suspected risk factors of breast cancer. The NAT2 genotype was determined using the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in 139 cases and 133 controls, and 28.8% and 21.1%, respectively, were found to have slow acetylator genotypes. Multivariate analysis, simultaneously considering other risk factors, including age at menarche, nulliparity or age at first full‐term pregnancy, body mass index (BMI), hormone replacement therapy (HRT) and smoking status, showed that the NAT2 slow acetylator genotype was associated with an increased risk with borderline significance (Odds Ratio, 1.81; 95% CI, 1.01–3.31). Interestingly, this association was not significant in premenopausal women, but was significant in post‐menopausal women. Further stratification of our study subjects based on different risk factor status showed that the increased risk for an NAT2 slow acetylator was more marked in post‐menopausal women who were not using HRT or who had a lower BMI. Our findings suggest that NAT2 polymorphism is a susceptibility factor for breast cancer in Taiwanese women, and that NAT2‐metabolized carcinogens are probably present in the environment and may be associated with induction of breast cancer. Int. J. Cancer 82:175–179, 1999.

Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma

OBJECTIVE:Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits.METHODS:Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire.RESULTS:There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; ptrend = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007).CONCLUSIONS:Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Genetic polymorphism of the CYP2E1 gene and susceptibility to Parkinson's disease in Taiwanese

Summary. Cytochrome P450IIE1 (CYP2E1), an ethanol-inducible cytochrome P450 enzyme, is expressed in the basal ganglia and is probably involved in the activation of neurotoxicants, producing free radical metabolites and resulting in oxidative stress. To examine the association between CYP2E1 polymorphism and the risk of Parkinsons disease (PD), we performed a case-control study on a large population of Taiwanese PD patients, focusing especially on early-onset PD patients (onset at, or before, the age of 50). Two hundred and thirty-four PD patients and 251 age- and sex-matched controls were recruited. A much higher frequency of the uncommon c2 allele was seen in our control subjects than in Caucasians (0.23 vs. 0.02). There were no significant differences between PD patients and controls in the distribution of either allelic or genotype frequencies. Our results suggest that CYP2E1 is not a major or independent determinant in the occurrence of PD in Taiwanese.

Taiwan's Experience with the Assessment of the Acceptability of the Extrapolation of Foreign Clinical Data for Registration Purposes

Several Asian countries have begun assessing the acceptability of the extrapolation of foreign clinical data for registration purposes. Some preliminary results of this evaluation process, which is intended to reduce duplication of clinical trials, have been reported. This article presents Taiwas experience with this assessment and provides some suggestions for further improvements.

Breast Cancer Risk Associated with Genotypic Polymorphism of Oxidative DNA Damage Repair Genes - A Multigenic Study of Base Excision Repair and Transcription-Coupled Repair in Cancer Susceptibility

Estrogen is suggested to play a dual role in breast cancer development, both as a promoter, triggering cell proliferation, and as an initiator, causing the DNA damage essential for driving tumorigenesis. The initiator mechanism of estrogen is suggested to involve its metabolite, catechol estrogen, which has been shown to lead to oxidative DNA damage in vitro. To test this possibility in human breast cancer, a multigenic case-control study was conducted to determine whether the association between estrogen exposure and breast cancer risk might be modified by genotypic polymorphism of the genes involved in oxidative damage repair, including those involved in base excision repair (BER)(hOGG1, APE1, and XRCC1) and transcription-coupled repair (TCR)(XPD and BRCA1). One hundred and thirty-six breast cancer patients and 232 healthy controls were recruited and the single-nucleotide polymorphisms (SNPs) and genotypes of their oxidative damage repair genes determined by PCR-based RFLP assays. Women with low-risk genotypes of repair genes (hOGG1 codon326 Ser/Ser or Cys/Ser, APE1 codon148 Glu/Glu or Glu/Asp, XRCC1 codon399 Arg/Arg or Gln/Arg, XPD codon751 Lys/Lys, or BRCA1 codon871 Pro/Pro) showed no significant association between increased cancer risk and longer estrogen exposure (＞10 years) from menarche to first full-term pregnancy, whereas women with high-risk genotypes(hOGG1 codon326 Cys/Cys, APE1 codon148 Asp/Asp, XRCC1 codon399 Gln/Gln, XPD codon751 Gln/Lys or Gln/Gln, or BRCA1 codon871 Leu/Pro or Leu/Leu) showed a consistently stronger and significant association. Furthermore, a trend to an increased risk of developing breast cancer was found in women harboring higher numbers of high-risk genotypes of the BER and TCR genes (P=0.009), particularly in those with prolonged estrogen exposure. Interestingly, this study provided supporting evidence for an interaction, during breast tumorigenesis, between BER and TCR via BRCA1, by demonstrating both an extra independent risk (aOR, 2.1;95%CI, 1.1-4.0) of breast cancer in those women in whom both the BER and TCR pathways were defective and a more pronounced risk (aOR, 1.8; 95%CI, 1.1-3.1), associated with defective BER, in women with high-risk BRCA1 genotypes. On the basis of a comprehensive profile of DNA oxidative damage repair genes, this study has not only confirmed a carcinogenic mechanism by which estrogen causes DNA lesions, but has also shed light on a connection between TCR and BER in the prevention of oxidative damage and breast cancer development.

An Overview of Bridging Study Evaluation in Taiwan

In 2001, the Bridging Study Evaluation (BSE) review process based on the ICH E5 guideline was introduced in Taiwan. The purpose of BSE is to assess the impact of ethnic factors on a drugs safety and efficacy and to determine whether pharmaceutical sponsors should conduct regional bridging studies in Taiwan. In this report, we provide the background and experience of BSE implementation in Taiwan and its influence on the global drug development process. Our BSE review process, allowing bridging studies to be waived, has successfully prevented conducting clinical trials with meaningless results. The trend of Investigational New Drug Application submission after New Drug Application (post-NDA) in other countries has also been shifted to the pre-NDA stage. The implementation of BSE in new regions has encouraged the pharmaceutical industry to consider the impact of ethnic factors in the early phase of clinical studies.

Assessment of the Extrapolation of Foreign Clinical Data for Registration Purposes

The assessment of the acceptability of the extrapolation of foreign clinical data to a new region for registration purposes, known as the process of “bridging study evaluation,” started in Taiwan on January 1, 2001. Established in compliance with the International Conference on Harmonisation E5 guidance, this process was enacted to gradually replace the “registration trial” as a basis for registration of medications in the Asian region. Since its implementation, Taiwans Center for Drug Evaluation has received and evaluated 20 applications. Of these, 12 (60%) were considered to be ethnically acceptable and 8 (40%) were considered ethnically sensitive due to reasons such as their pharmacodynamic/pharmacokinetic characteristics, concerns about their efficacy and safety in the Taiwanese population, and extrinsic factors leading to ethnic differences.

Placebo Controlled Clinical Trials are as Ethical as Active Controlled Trials Even if Effective Therapies Exist

In recent years, placebo controlled clinical trials have often been considered unethical if effective therapies are available when the trials are conducted. This concept was strengthened by the 2000 revision of the Declaration of Helsinki. This article discusses why placebo controlled clinical trials can be considered as ethical as active controlled trials, even if effective therapies are available for the medical conditions concerned.