• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.647-653
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• 2016

Background: Breast cancer is the most common type of cancer affecting Malaysian women. Recent statistics revealed that the cumulative probability of breast cancer and related deaths in Malaysia is higher than in most of the countries of Southeast Asia. Single nucleotide polymorphisms (SNPs) in CYP2E1 (rs6413432 and rs3813867), STK15 (rs2273535 and rs1047972) and XRCC1 (rs1799782 and rs25487) have been associated with breast cancer risk in a meta-analysis but any link in Southeast Asia, including Malaysia, remained to be determined. Hence, we investigated the relationship between these SNPs and breast cancer risk among Malaysian women in the present case-control study. Materials and Methods: Genomic DNA was isolated from peripheral blood of 71 breast cancer patients and 260 healthy controls and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results: Our study showed that the c1/c2 genotype or subjects with at least one c2 allele in CYP2E1 rs3813867 SNP had significantly increased almost 1.8-fold higher breast cancer risk in Malaysian women overall. In addition, the variant Phe allele in STK15 rs2273535 SNP appeared to protect against breast cancer in Malaysian Chinese. No significance association was found between XRCC1 SNPs and breast cancer risk in the population. Conclusions: This study provides additional knowledge on CYP2E1, STK15 and XRCC1 SNP impact of risk of breast cancer, particularly in the Malaysian population. From our findings, we also recommend Malaysian women to perform breast cancer screening before 50 years of age.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.1925-1931
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• 2016

Background: The XRCC1 protein facilitates various DNA repair pathways; single-nucleotide polymorphisms (SNPs) in this gene are associated with a risk of gastrointestinal cancer (GIC) with inconsistent results, but no data have been previously reported for the Sabah, North Borneo, population. We accordingly investigated the XRCC1 Arg194Trp and Arg399Gln SNPs in terms of GIC risk in Sabah. Materials and Methods: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction-restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing. Results: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects ${\geq}50years$ and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC. Conclusions: Our findings suggest that inheritance of variant alleles in XRCC1 Arg194Trp and Arg399Gln SNPs may act as biomarkers for the early detection of GIC, especially for gastric and colorectal cancers in the Sabah population.

• Journal of Environmental Health Sciences
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• v.37 no.6
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• pp.429-439
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• 2011

Objectives: Ethylene oxide (EtO) is classified as a human carcinogen, but EtO is still widely used to sterilize heat-sensitive materials in hospitals. Employees working around sterilizers are exposed to EtO after sterilization. The aim of the present study was to assess the exposure of EtO level, coupled with occupationally induced micronuclei from hospital workers. The influence of genetic polymorphisms of detoxifying genes (GSTT1 and GSTM1) and DNA repair genes (XRCC1 and XRCC3) on the frequencies of micronuclei in relation to exposure of EtO was also investigated. Methods: The study population was composed of 35 occupationally exposed workers to EtO, 18 student controls and 44 unexposed hospital controls in Korea. Exposure to EtO is measured by passive personal samplers. We analyzed the frequencies of micronuclei by performing cytokinesis-block micronucleus assay (CBMN assay) and GSTM1, GSTT1, XRCC1, and XRCC3 were also genotyped by performing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequencies of micronuclei in EtO exposure group, student controls and hospital controls were $18.00{\pm}7.73$, $10.47{\pm}7.96$ and $13.86{\pm}6.35$ respectively and their differences were statistically significant, but no significant differences according to the level of EtO were observed. There was a dose-response relationship between the frequencies of micronuclei and cumulative dose of EtO, but no significantly differences were observed. We also investigated the influence of genetic polymorphisms (GSTM1, GSTT1, XRCC1, and XRCC3) on the frequencies of micronuclei, but there were no differences in the frequencies of micronuclei by genetic polymorphisms. Conclusions: The frequencies of micronuclei in EtO exposure group was significantly higher than control groups. A dose-response relationship was found between the level of EtO exposure and the frequencies of micronuclei, but no statistically differences were observed. We also found that the frequencies of micronuclei were increased according to cumulative EtO level. There was no association of the genetic GSTM1, GSTT1, XRCC1, and XRCC3 state with the frequency of micronuclei induced by EtO exposure.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.941-946
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• 2013

Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox's multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.sup3
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• pp.323-335
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• 2016

Breast cancer risk assessment has developed during years and evaluation of genetic factor affecting risk of breast cancer is an important component of this risk assessment. The aim of this meta-analysis was to investigate the role of XRCC1 polymorphisms (Arg194Trp, Arg280His and Arg399Gln) in risk of breast cancer among different population and categories of menopausal status.PubMed, Medline, Web of Science, and PubMed Central were systematically searched to identify studies evaluating association between breast cancer and XRCC1 gene polymorphisms (Arg194Trp, Arg280His and Arg399Gln). Two authors independently extracted required information. Odds Ratios were pooled for four genetic inheritance models using both fixed and the DerSimonian and Laird random-effect models. Egger's test and contour-enhanced funnel plot was used to evaluate publication bias and small study effect. Additional subgroup analysis was performed for menopausal status, ethnicity, and source of controls. After evaluation and applying inclusion criteria on extracted studies, fifty three studies were included in this meta-analysis. For polymorphisms of Arg194Trp and Arg280His, no significant association was observed in all genetic models. Arg194Trp had a protective effect in post-menopausal status only in homozygote model (OR=0.57 [0.37-0.88]). Arg399Gln showed significant association with breast cancer in homozygote (OR=1.21 [1.10-1.34]), dominant (OR=1.09 [1.03-1.15]) and recessive (OR=1.21 [1.09- 1.35]) genetic models. Arg399Gln was associated with higher risk in post-menopausal status for homozygote and heterozygote models. Our findings suggest that XRCC1 gene polymorphisms modify breast cancer risk in different populations and different categories of menopausal status.

• Radiation Oncology Journal
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• v.36 no.3
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• pp.218-226
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• 2018

Purpose: Standard treatment for locally advanced rectal cancer consists of neoadjuvant radiochemotherapy with concomitant fluoropyrimidine or oxaliplatin and surgery with curative intent. Pathological complete response has shown to be predictive for better outcome and survival; nevertheless there are no biological or genetic factors predictive for response to treatment. We explored the correlation between the single nucleotide polymorphisms (SNPs) GSTP1 (A313G) and XRCC1 (G28152A), and the pathological complete response and survival after neoadjuvant radiochemotherapy in locally advanced rectal cancer patients. Materials and Methods: Genotypes GSTP1 (A313G) and XRCC1 (G28152A) were determined by pyrosequencing technology in 80 patients affected by locally advanced rectal cancer. Results: The overall rate of pathological complete response in our study population was 18.75%. Patients homozygous AA for GSTP1 (A313G) presented a rate of pathological complete response of 26.6% as compared to 8.5% of the AG+GG population (p = 0.04). The heterozygous comparison (AA vs. AG) showed a significant difference in the rate of pathological complete response (26.6% vs. 6.8%; p = 0.034). GSTP1 AA+AG patients presented a 5- and 8-year cancer-specific survival longer than GSTP1 GG patients (87.7% and 83.3% vs. 44.4% and 44.4%, respectively) (p = 0.014). Overall survival showed only a trend toward significance in favor of the haplotypes GSTP1 AA+AG. No significant correlations were found for XRCC1 (G28152A). Conclusion: Our results suggest that GSTP1 (A313G) may predict a higher rate of pathological complete response after neoadjuvant radiochemotherapy and a better outcome, and should be considered in a more extensive analysis with the aim of personalization of radiation treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.2
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• pp.713-718
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• 2015

Background: A number of association studies have been carried out to investigate the relationship between genetic polymorphisms in DNA repair genes and response to radiotherapy-based multimodality treatment of patients with rectal cancer. However, their conclusions were inconsistent. The objective of the present study was to assess the role of DNA repair gene genetic polymorphisms in predicting genetic biomarkers of the response in rectal cancer patients treated with neoadjuvant chemoradiation. Materials and Methods: Studies were retrieved by searching the PubMed database, Cochrane Library, Embase, and ISI Web of Knowledge. We conducted a meta-analysis to evaluate the association between genetic polymorphisms and the response in rectal cancer treated with neoadjuvant chemoradiation by checking odds ratios (ORs) and 95% confidence intervals (CIs). Results: Data were extracted from 5 clinical studies for this meta-analysis. The results showed that XRCC1 RS25487, XRCC1 RS179978, XRCC3 RS861539, ERCC1 RS11615 and ERCC2 RS13181 were not associated with the response in the radiotherapy-based multimodality treatment of patients with rectal cancer (p>0.05). Conclusions: This study shows that DNA repair gene common genetic polymorphisms are not significantly correlated with the radiotherapy-based multimodality treatment in rectal cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1553-1556
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• 2012

Introduction: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. Patients and Methods: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5´UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. Results: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. Conclusion: Pharmacogenetics might contribute to tailored therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1799-1802
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• 2012

Objective: We aimed to analyze the association between excision repair cross-complementing rodent repair deficiency complementation group 1 (XRCC1) and ovarian cancer risk. Methods: We performed a hospital-based case-control study with 155 cases and 313 controls in China. All Chinese cases with newly diagnosed primary ovarian cancer between May 2005 to May 2010 in our hospital were invited to participate within 2 months of diagnosis. Controls were randomly selected from people who requested general health examinations in the same hospital during the same period. SNPs in EXCC1, ERCC1 C8092A and ERCC1 T19007C, were analyzed by PCR-RFLP method. Results: We observed a non-significantly increased risk of ovarian cancer among individuals with ERCC1 8092TT compared with those with the 8092CC genotype (adjusted OR=1.55, 95% CI%=0.74-2.97). Moreover, 19007TT genotype carriers also showed a non-significant increased risk of ovarian cancer over those with the 19007CC genotype (adjusted OR=1.78, 95% CI%=0.91-3.64). Conclusion: Our firstly investigation of links between polymorphisms in the ERCC1 gene and the risk of ovarian cancer in Chinese population demonstrated no significant association. Further large sample studies in Chinese populations are needed.