Shi-Yi Yang

Genetic polymorphisms of XRCC1 and risk of the esophageal cancer.

A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical‐associated carcinogenesis. We hypothesized that the polymorphic XRCC1 genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCC1 genetic polymorphisms on codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (±3 years), gender and ethnicity. The distribution of the 3 genotypes were not significantly different among patients and controls. However, among alcohol drinkers, the XRCC1399 Arg/Arg genotype was more frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCC1399 Arg/Arg was 2.78 (95% CI =1.15–6.67) as compared with the XRCC1399 Arg/Gln and XRCC1399 Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCC1 genes might modify the risk of alcohol‐associated esophageal cancers.

Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma

Background and aims: To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case–control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988–1992. Methods: The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up. Results: Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants. Conclusions: HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.

Genetic polymorphisms of p53 and GSTP1,but not NAT2,are associated with susceptibility to squamous-cell carcinoma of the esophagus.

The interaction of genetic and environmental factors can determine an individuals susceptibility to various cancers. We present a hospital‐based case‐control study, which included 90 patients of esophageal squamous‐cell carcinoma (ESCC) and 254 healthy people in Taiwan, to investigate the effects of genetic polymorphisms of p53, GSTP1 and NAT2 on the risk of ESCC. Polymorphisms of p53, NAT2 and GSTP1 were determined by PCR‐RFLP. The codon 72 p53 Pro allele was more frequently found in ESCC patients [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.04–3.35 for Arg/Pro genotype and OR 2.56, 95% CI 1.29–5.08 for Pro/Pro genotype]. In cigarette smokers, the frequency of GSTP1 Ile/Ile genotype was higher in ESCC patients (OR 2.8, 95% CI 1.4–5.7). Among alcohol drinkers, borderline significance was also found for GSTP1 Ile/Ile genotype (OR 2.0, 95% CI 0.9–4.4). Results were not similar for the NAT2 genetic polymorphism. Using logistic analyses, we found that individuals with p53 Pro/Pro genotype had a significantly higher risk of developing ESCC than those with Arg/Arg genotype (OR 2.3, 95% CI 1.1–5.1), after adjusting for other significant environmental risk factors. This result remained similar (OR 2.2, 95% CI 1.0–4.8 for p53 Pro/Pro vs. Arg/Arg), even after further adjustment for NAT2 and GSTP1 polymorphisms. The codon 72 p53 Pro/Pro genotype in the general population and GSTP1 Ile/Ile in cigarette smokers may predict a higher risk of developing ESCC. Int. J. Cancer 89:458–464, 2000.

Association of GSTP1 Polymorphism and Survival for Esophageal Cancer

Purpose: Activity of glutathione S-transferase (GST) is associated with detoxification of xenobiotics and the maintenance of cell viability. Genetically variant GSTs produce different enzymatic activities. The clinical significance of this variation is still puzzling. We investigated whether genetic polymorphisms of GST including GSTP1, GSTM1, and GSTT1 affect survival among esophageal cancer patients. Experimental Design: From 1996 to 2002, 233 patients with pathologically proven esophageal cancer were recruited from the Department of Surgery, National Taiwan University Hospital. GST genotypes, including GSTT1, GSTM1, and GSTP1, were determined by PCR or PCR-RFLP. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function and Cox proportional hazards models. Results: The mean survival times (months) of the GSTP1 Ile/Ile, Ile/Val, and Val/Val were 11, 10, and 7, respectively (P < 0.05). The more the patients carried GSTP1 variant Val alleles, the poorer the survival rate (adjusted hazard ratio, 1.36; 95% confidence interval, 1.01-1.84; Ptrend = 0.045). In contrast, no association of GSTT1 or GSTM1 genotypes with survival rate was noted. Conclusion: The presence of the GSTP1 variant allele (Val) is associated with a poorer prognosis of esophageal cancer.

Association of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism With Serum Level and Development of Pulmonary Complications Following Esophagectomy

Background:Pulmonary complications remain the major cause of postoperative mortality in patients with esophageal cancer undergoing esophagectomy. It was unclear whether this dismal complication has a genetic predisposition. We therefore investigated the role of an angiotensin-converting enzyme (ACE) insertion/deletion polymorphism in developing these complications. Methods:We conducted a prospective study including 152 patients with esophageal cancer who underwent esophagectomy in National Taiwan University Hospital between 1996 and 2002. The ACE genotype was determined by polymerase chain reaction amplification of leukocyte DNA obtained before surgery. The serum ACE concentration was determined by enzyme-linked immunosorbent assay. Results:Thirty-five patients (23%) developed pulmonary complications following esophagectomy. As compared with patients with the I/I and I/D genotypes, those with the D/D genotype had a higher risk for pulmonary complications (adjusted odds ratio [OR], 3.12; 95% confidence interval [CI], 1.01–9.65). The risk was additively enhanced by combination of the ACE D/D genotype with other clinical risk factors (old age, hypoalbuminemia, and poor pulmonary function). The circulating ACE level was also dose-dependently with the presence of ACE D allele. As compared with the patients with circulating ACE less than 200 ng/mL, the patients with circulating ACE of 200 to 400 ng/mL and over 400 ng/mL had ORs (95% CI) of 2.75 (1.12–6.67) and 15.00 (4.3–52.34) to present with ACE D allele, respectively. Conclusions:An ACE insertion/deletion polymorphism might modulate the function of ACE gene and play a role in affecting individual susceptibility to pulmonary injury following esophagectomy in patients of esophageal cancer.

Genetic variants in DNA repair predicts the survival of patients with esophageal cancer.

Objective: To investigate the association of the genetic variants in excision repair cross-complementation group 2 (ERCC2) R156R and ERCC4 rs3136038 with survival duration for patients with esophageal cancer. Background: ERCC2 and ERCC4 are important molecules participating nucleotide excision repair system. The clinical relevance of the genetic variants of these genes is largely unknown currently. Patients and Methods: A total of 400 patients with a diagnosis of esophageal cancer were included. The genetic variants in the promoter regions of ERCC2 on R156R and ERCC4 on rs3136038 were analyzed with the TaqMan assay from leukocyte DNA collected before treatment and correlated to survival of the patients. Results: Presence with ERCC2 R156R C/C or ERCC4 rs3136038 C/T genotype of the patients could additively increase risk of death and disease progression. Under multivariate analysis, T, N staging and simultaneous presentation of these unfavorable genotypes were found significant for prognosis (P < 0.05). Accumulation of each unfavorable genotype would associate with adjusted HRs [95% CI] of 1.35 [1.10–1.65] and 1.37 [1.12–1.68] (P ⩽ 0.05) for death and disease progression respectively. The prognostic impact of these genotypes were more evident in the subgroup of patients with early disease status including T staging (II or less), free from lymph node metastasis or being able to undergo surgical resection (P < 0.05 for both overall and disease progression-free survival duration, respectively). Conclusion: Genetic variants in ERCC2 and ERCC4 may provide further survival prediction in addition to TNM staging system of esophageal cancer, which is more evident in the patients with early disease status.

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.

A wireless flexible temperature and tactile sensing array for robot applications

The development of a flexible 8x8 temperature and tactile sensing array, which will serve as the artificial skin for robot applications, is presented in this work. Pressure conductive rubber is employed as the tactile sensing material, and discrete temperature sensor chips are employed as the temperature sensing cells. Small disks of pressure conductive rubber are bonded on pre-defined interdigital copper electrode pairs which are patterned on a flexible copper-PI substrate which is fabricated by micromachining techniques. This approach can effectively reduce the crosstalk between each tactile sensing element. The mechanical and electrical properties of tactile sensing elements are measured. Also, scanning circuits are designed and implemented. The temperature and tactile sensing elements are heterogeneously integrated on the flexible substrate. By using the integrated 8x8 sensing arrays, temperature and tactile images induced by the heaters/stamps of different shapes have been successfully measured. Radio-frequency (RF) wireless modules are also developed and integrated on the skin system.

The Association of GSTT1 Genetic Polymorphism with the Risk of Esophageal Cancer-Interactive with Environmental Exposure

In this study, we investigated the association of the genetic polymorphisms of CYPlAl, CYP2E1, GSTMl and GSTTl with the risk of esophageal cancer in Taiwan. We recruited 105 cases of esophageal squamous cell carcinoma and 266 persons of healthy controls during 1996-1999. The genotypes of the xenobiotic metabolizing enzymes were determined by PCR or PCR-RFLP. There was no significant difference in distribution of these genotypes between the patients and controls. However, among the cigarette smokers, GSTTl null genotype was found to associate a higher risk of esophageal cancer, after adjustment with other environmental confounders (OR: 2.44;95% CI:1.17-5.08). Our results revealed that the GSTTl genetic polymorphism might interact with cigarette smoke to modulate the risk of esophageal cancer in Taiwan.