• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8673-8678
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• 2014

Purpose: This study aimed to determine the association between tobacco consumption (kretek) and betel quid chewing with oral cancer risk. Materials and Methods: A total of 81 cases of oral cancers were matched with 162 controls in this hospital-based study. Information on sociodemographic characteristics and details of risk habits (duration, frequency and type of tobacco consumption and betel quid chewing) were collected. Association between smoking and betel quid chewing with oral cancer were analysed using conditional logistic regression. Results: Slightly more than half of the cases (55.6%) were smokers where 88.9% of them smoked kretek. After adjusting for confounders, smokers have two fold increased risk, while the risk for kretek consumers and those smoking for more than 10 years was increased to almost three-fold. Prevalence of betel quid chewing among cases and controls was low (7.4% and 1.9% respectively). Chewing of at least one quid per day, and quid combination of betel leaf, areca nut, lime and tobacco conferred a 5-6 fold increased risk. Conclusions: Smoking is positively associated with oral cancer risk. A similar direct association was also seen among betel quid chewers.

• Toxicological Research
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• v.17
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• pp.139-144
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• 2001

Chewing betel quid is associated with an increased risk of oral cancer. The betel quid chewed in Taiwan includes the inflorescence of Piper betle, which contains high concentrations of safrole (15 mg/fresh weight). Piper betle leaf is also used in betel quid; however, the concentration of safrole in betel leaf has not been documented. Chewing betel quid may contribute to safrole exposure in man (420 mm in saliva). Using $a^{32}$P-postlabeling method, we have recently demonstrated the presence of stable safrole-like DNA adducts in human oral tissues following betel quid chewing. Safrole is a rodent hepatocar-cinogen, and the real nature of safrole-DNA adducts in human tissues beside oral has not been elucidated. In this paper, we tested the safrole DNA adducts forming potential in human hepatic and oral derived cells by the ${32}^P$-postlabeling technique. The results suggest that oral cancer derived cell OC-2 alone is not able to form safrole-DNA adduct. However, safrole DNA adducts can be detected following I'-hydroxysafrole, a proximate safrole metabolite, treatment. In addition, pretreament of cytochrome P450 inducers also enhanced the formation of previously undetectable safrole DNA adducts. This finding couples with our previous results suggest that oral may serve as a target tissue for safrole, and safrole may be involved in oral carcinogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.7
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• pp.4335-4338
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• 2013

Background: This study aimed to determine the association between betel quid chewing and the occurrence of upper aerodigestive tract (UADT) cancers. Methods: A cohort of 17,388 subjects, recruited and interviewed over the 1990-2001 period, in Khon Kaen, Thailand, was followed up until 2011. The data were linked to the Khon Kaen Population-Based Cancer Registry. Results: The prevalence of betel quid chewing was 15.9%, with a female predominance (97.7%); the mean age of chewers was 57.7 years (SD 6.6). The overall incidence of UADT cancers from the cohort was 14.7 per 100,000 person-years, whereas the incidence among the chewers was 45.7. Betel nut chewing was the only major risk factor for UADT cancers in this population (HR=5.26, 95%CI=2.51-11.0), while weak associations were found for tobacco smoking and alcohol (HR=1.16, 95%CI=0.45-3.01 and 1.47, 95%CI=0.72-3.03 respectively). Conclusions: We found betel quid chewing to be a main risk factor for UADT cancers, resulting in a higher incidence in females. However, further study is required to explore the potential risk factors among non-chewers, non-smokers, and non-drinkers.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6953-6961
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• 2015

Background: Tobacco and alcohol contain or may generate carcinogenic compounds related to cancers. CYP1A1 enzymes act upon these carcinogens before elimination from the body. The aim of this study was to investigate whether CYP1A1 T3801C polymorphism modulates the relationship between tobacco and alcohol-associated head and neck cancer (HNC) susceptibility among the northeast Indian population. Materials and Methods: One hundred and seventy histologically confirmed HNC cases and 230 controls were included within the study. The CYP1A1 T3801C polymorphism was determined using PCR-RFLP, and the results were confirmed by DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches were applied for statistical analysis. Results: The CYP1A1 CC genotype was significantly associated with HNC risk (P=0.045). A significantly increased risk of HNC (OR=6.09; P<0.0001) was observed in individuals with combined habits of smoking, alcohol drinking and tobacco-betel quid chewing. Further, gene-environment interactions revealed enhanced risks of HNC among smokers, alcohol drinkers and tobacco-betel quid chewers carrying CYP1A1 TC or CC genotypes. The highest risk of HNC was observed among smokers (OR=7.55; P=0.009) and chewers (OR=10.8; P<0.0001) carrying the CYP1A1 CC genotype. In MDR analysis, the best model for HNC risk was the three-factor model combination of smoking, tobacco-betel quid chewing and the CYP1A1 variant genotype (CVC=99/100; TBA=0.605; P<0.0001); whereas interaction entropy graphs showed synergistic interaction between tobacco habits and CYP1A1. Conclusions: Our results confirm that the CYP1A1 T3801C polymorphism modifies the risk of HNC and further demonstrated importance of gene-environment interaction.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.637-642
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• 2014

The pathogenesis of hepatocellular carcinoma (HCC) related to habitual betel quid (BQ) chewing is unclear. Risk of HCCis increased with adverse hepatic fibrosis. This study aimed to assess the impact of chronic viral hepatitis on adverse hepatic fibrosis in HCC related to BQ chewing. This hospital-based case-control study enrolled 200 pairs of age- and gender-matched patients with HCC and unrelated healthy controls. Serologic hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV), ${\alpha}$-fetoprotein (AFP), and surrogate markers for significant hepatic fibrosis were measured. Information on substance-use habits was obtained with a questionnaire. By analysis of surrogate markers for hepatic fibrosis, the prevalence of significant hepatic fibrosis in patients chewing BQ was between 45.8% and 91.7%, whereas that for patients without BQ chewing was between 18.4% and 57.9%. The difference was significant (P <0.05 for each surrogate marker). Multivariate analysis indicated that cirrhosis with Child-Pugh C (odds ratio (OR) = 3.28; 95% confidence interval (CI), 1.29-8.37), thrombocytopenia (OR = 3.92, 95% CI, 1.77-8.68), AFP >400 mg/L (OR = 2.21, 95% CI, 1.05-4.66) and male gender (OR = 4.06, 95% CI, 1.29-12.77) were independent factors associated with habitual BQ chewing. In conclusion, adverse hepatic fibrosis and severe liver damage play important roles in the pathogenesis of BQ-related HCC, which could be aggravated by chronic hepatitis B and hepatitis C. BQ-cessation programs and prevention of chronic HBV/HCV infection are needed to prevent HCC related to BQ chewing.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.5087-5090
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• 2012

Oral cancer is a common site of head and neck cancer, and is relatively frequent in Northeast Thailand. The objective of this hospital-based, case-control study was to determine associations with risk factors. A total of 104 oral cancer cases diagnosed between July 2010 and April 2011 in 3 hospitals were matched with control subjects by age, sex and hospital. Data were collected by personal interview. There were significant associations between oral cancer and tobacco smoking (OR=4.47; 95%CI=2.00 to 9.99), alcohol use among women (OR=4.16; 95%CI=1.70 to 10.69), and betel chewing (OR=9.01; 95%CI=3.83 to 21.22), and all three showed dose-response effects. Smoking is rare among Thai women (none of the control women were smokers), but betel chewing, especially among older women, is relatively common. We did not find any association between practicing oral sex and oral cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5767-5772
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• 2015

Background: Polymorphisms in the MDM2 309 (T>G) and TP53 72 (G>C) genes are reported to increase the susceptibility to head and neck cancer (HNC) in various populations. The risk for HNC is also strongly associated with etiologic habits such as smoking, alcohol consumption and/or chewing of betel quid (BQ). In a case-control study, we investigated the significance of the above polymorphisms alone, and upon interaction with one another as well as with various etiologic habits in determining HNC risk in a Northeast Indian population. Materials and Methods: Genotyping at 309 MDM2 and 72 TP53 in 122 HNC patients and 86 cancer free healthy controls was performed by PCR using allele specific primers, and the results were confirmed by DNA sequencing. Results: Individuals with the GG mutant allele of MDM2 showed a higher risk for HNC in comparison to those with the TT wild type allele (OR=1.9, 95%CI: 1.1-3.3) (p=0.022). The risk was further increased in females by ~4-fold (OR=4.6, 95% CI: 1.1-19.4) (P=0.04). TP53 polymorphism did not contribute to HNC risk alone; however, interaction between the TP53 GC and MDM2 GG genotypes resulted in significant risk (OR=4.9, 95% CI: 0.2-105.1) (p=0.04). Smokers, BQ- chewers and alcohol consumers showed statistically significant and dose-dependent increase in HNC risk, irrespective of the MDM2 genotype. Conclusions: MDM2 genotype could serve as an important predictive biomarker for HNC risk in the population of Northeast India.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.1993-1999
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• 2014

Background: This study aimed to explore the role of XRCC1 (Arg399Gln) and XPD (Lys751Gln) gene polymorphisms, lifestyle and environmental factors as well as their possible interactions in propensity to develop lung cancer in a population with high incidence from North East India. Materials and Methods: A total of 272 lung cancer cases and 544 controls were collected and XRCC1 (Arg399Gln) and XPD (Lys751Gln) genotypes were analyzed using a polymerase chain reaction based restriction fragment length polymorphism assay. Conditional multiple logistic regression analysis was used to calculate adjusted odds ratios and 95% confidence intervals after adjusting for confounding factors. Results: The combined Gln/Gln genotype of XRCC1 and XPD genes (OR=2.78, CI=1.05-7.38; p=0.040) was significantly associated with increased risk for lung cancer. Interaction of XRCC1Gln/Gln genotype with exposure of wood combustion (OR=2.56, CI=1.16-5.66; p=0.020), exposure of cooking oil fumes (OR=3.45, CI=1.39-8.58; p=0.008) and tobacco smoking (OR=2.54, CI=1.21-5.32; p=0.014) and interaction of XPD with betel quid chewing (OR=2.31, CI=1.23-4.32; p=0.009) and tobacco smoking (OR=2.13, CI=1.12-4.05; p=0.022) were found to be significantly associated with increased risk for lung cancer. Conclusions: Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smoking and betel quid chewing on lung cancer risk in the study population.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8227-8233
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• 2016

Background: To investigate polymorphisms in heat shock proteins A1B and A1L (HOM) and associated risk of oesophageal carcinoma in Northeast India. Materials and Methods: The study includes oesophageal cancer (ECA) patients attending general outpatient department (OPD) and endoscopic unit of Gauhati Medical College. Patients were diagnosed based on endoscopic and histopathological findings. Genomic DNA was typed for HSPA1B1267 and HSPA1L2437 SNPs using the polymerase chain reaction with restriction fragment length polymorphisms. Results: A total of 78 cases and 100 age-sex matched healthy controls were included in the study with a male: female ratio of 5:3 and a mean age of $61.4{\pm}8.5years$. Clinico-pathological evaluation showed 84% had squamous cell carcinoma and 16% were adenocarcinoma. Dysphagia grades 4 (43.5%) and 5 (37.1%) were observed by endoscopic and hispathological evaluation. The frequency of genomic variation of A1B from wild type A/A to heterozygous A/G and mutant G/G showed a positive association [chi sq=19.9, p=<0.05] and the allelic frequency also showed a significant correlation [chi sq=10.3, with cases vs. controls, OR=0.32, $p{\leq}0.05$]. The genomic variation of A1L from wild T/T to heterozygous T/C and mutant C/C were found positively associated [chi sq=7.02, p<0.05] with development of ECA. While analyzing the allelic frequency, there was no significant association [chi sq=3.19, OR=0.49, p=0.07]. Among all the risk factors, betel quid [OR=9.79, Chi square=35.0, p<0.05], tobacco [OR=2.95, chi square=10.6, p<0.05], smoking [OR=3.23, chi square=10.1, p<0.05] demonstrated significant differences between consumers vs. non consumers regarding EC development. Alcohol did not show any significant association [OR=1.34, chi square=0.69, p=0.4] independently. Conclusions: It can be concluded that the present study provides marked evidence that polymorphisms of HSP70 A1B and HSP70 A1L genes are associated with the development of ECA in a population in Northeast India, A1B having a stronger influence. Betel quid consumption was found to be a highly significant risk factor, followed by smoking and tobacco chewing. Although alcohol was not a potent risk factor independently, alcohol consumption along with tobacco, smoking and betel nut was found to contribute to development of ECA.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2629-2633
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• 2012

Background: Raw betel nut (RBN) chewing is an important contributing factor for esophageal squamous cell carcinoma (ESCC), although associated genomic changes remain unclear. One difficulty in assessing the effects of exclusively RBN induced genetic alterations has been that earlier studies were performed with samples of patients commonly using tobacco and alcohol, in addition to betel-quid. Both CDKN2A (at 9p21) and Rb1 gene (at 13q14.2) are regarded as tumor suppressors involved in the development of ESCC. Therefore, the present study aimed to verify the RBN's ability to induce ESCC and assess the involvement of CDKN2A and Rb1 genes. Methods: A panel of dinucelotide polymorphic markers were chosen for loss of heterozygosity studies in 93 samples of which 34 were collected from patients with only RBN-chewing habit. Promoter hypermethylation was also investigated. Results: Loss in microsatellite markers D9S1748 and D9S1749, located close to exon $1{\beta}$ of CDKN2A/ARF gene at 9p21, was noted in 40% ESCC samples with the habit of RBN-chewing alone. Involvement of a novel site in the 9p23 region was also observed. Promoter hypermethylation of CDKN2A gene in the samples with the habit of only RBN-chewing alone was significantly higher (p=0.01) than Rb1 gene, also from the samples having the habit of use both RBN and tobacco (p=0.047). Conclusions: The data indicate that the disruption of 9p21 where CDKN2A gene resides, is the most frequent critical genetic event in RBN-associated carcinogenesis. The involvement of 9p23 as well as 13q14.2 could be required in later stages in RBN-mediated carcinogenesis.