Cytotoxic T-lymphocyte antigen 4 polymorphisms and breast cancer susceptibility: Evidence from a meta-analysis.

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint and regulates the immune function of T cells. However, previous findings regarding the association of CTLA-4 polymorphisms and breast cancer remain inconclusive. Therefore, we performed a meta-analysis to investigate the potential effects of five polymorphisms (-1722 T/C, -1661 A/G -318 C/T, +49 A/G, and CT60 A/G) in the CTLA-4 gene on breast cancer susceptibility. METHODS: Relevant literatures were systematically searched through electronic databases including PubMed, EMBASE, and Web of Science up to October 10, 2021. Available data were extracted and odds ratios (ORs) with 95% confidence intervals were used to estimate the pooling effect size. The Newcastle-Ottawa Scale was applied for assessing the quality of included studies. We conducted subgroup analyses based on ethnicity and control sources to explore levels of heterogeneity. Moreover, sensitivity analysis and publication bias were assessed. RESULTS: Finally, a total of 12 eligible studies regarding CTLA-4 polymorphisms and breast cancer were included. For overall analyses, only the +49 A/G polymorphism was significantly associated with breast cancer under allelic (OR = 1.19), dominant (OR = 1.27), and recessive (OR = 1.27) models. Ethnicity-based subgroup analysis found that the +49 A/G polymorphism has a significant risk (OR = 2.03) of breast cancer under the recessive model in the non-Asian population. Studies with hospital-based controls showed that the +49 A/G polymorphism has significant breast cancer risks under allelic (OR = 1.44), dominant (OR = 1.86), and recessive (OR = 1.60) models. In addition, those with population-based controls found that -1722 T/C polymorphism has a significant breast cancer risk under allelic (OR = 1.19) and dominant (OR = 1.26) models. CONCLUSION: This meta-analysis suggested that CTLA-4 + 49 A/G polymorphism may significantly associate with breast cancer susceptibility. Future studies containing various populations are helpful for evaluating the impacts of CTLA-4 polymorphisms on breast cancer susceptibility.

Ultrasound Measurement of Rectus Femoris Muscle Parameters for Discriminating Sarcopenia in Community-Dwelling Adults.

OBJECTIVES: Sarcopenia patients require more medical attention and caretaking. As such, early detection of sarcopenia and appropriate interventions are crucial for decreasing medical costs and meeting the challenges of aging populations. The aim of the present study was to develop a reliable and accurate model to estimate muscle mass using ultrasound-derived parameters from the rectus femoris (RF), referenced by dual-energy X-ray absorptiometry. METHODS: Cross-sectional study was performed. The study patients were recruited by Taipei Veterans General Hospital (No. 2016-07-013C) between 2016 and 2019. A total of 91 community-dwelling adults (35 men and 56 women) were enrolled in this study. Ultrasound measurements of RF muscle thickness (MT), cross-sectional area (CSA), and muscle volume (MV) were performed in B-mode. Muscle strength and physical performance were also examined. Multivariate linear regression was used to build models for the prediction of appendicular skeletal muscle index (ASMI) based on MT, CSA, and MV values. The accuracy of ultrasound RF measurements for predicting sarcopenia was evaluated by using receiver operating characteristic (ROC) curve analysis. RESULTS: The regression equations used for ASMI prediction (adjusted body mass index, sex, and leg length) had high precision and low error. Moreover, the MV model results were close to those of the CSA model and higher than those of the MT model. The ROC analysis showed that both MV and CSA had excellent discrimination when assessing sarcopenia (AUC = 0.83 and 0.81, respectively), whereas MT showed acceptable discrimination (AUC = 0.73). CONCLUSIONS: Ultrasound-derived RF MV was accurate when predicting ASMI and diagnosing sarcopenia in community-dwelling adults.

Influence of intradialytic systolic blood pressure changes on arteriovenous access thrombosis in maintenance hemodialysis patients.

BACKGROUND: Arteriovenous access (AV) thrombosis is an important and preventable problem amongst chronic hemodialysis (HD) patients. Systolic blood pressure (SBP) fluctuation relates to higher cardiovascular mortality amongst these patients. We proposed there is a close relation between SBP changes and arteriovenous (AV) access thrombosis. We also determined other risk factors and biochemical parameters related to AV access failure. METHODS: 50 HD patients with thrombosis and 50 HD patients without thrombosis were included in the study. Odds ratios and 95% confidence intervals were estimated with multivariate-adjusted logistic regression models to determine the association between potential thrombosis-related risk factors and thrombosis risk. RESULTS: Elder adults, women, and patients with AV grafts, lower intradialytic SBP and higher SBP variations during HD sessions had higher incidence of AV access thrombosis. AV access infection and decreased blood flow (BF) velocity were associated with an increased incidence of thrombotic events, whereas the use of anti-thrombotic agents was associated with a decreased incidence of thrombotic events. Further, anaemia, hypoalbuminemia, hyperlipidemia, and impaired mineral metabolism parameters were also found to be associated with AV access thrombosis. CONCLUSIONS: Close monitoring and management of intradialytic hypotension and SBP fluctuation in every HD session are important. Some important and novel modifiable risk factors related to AV access thrombosis were identified in this study (eg, AV access infection, decreased BF and abnormal biochemical parameters, etc). Earlier surveillance and modification of these risk factors is crucial to prevent AV access failure in HD patients.

Effects of Omega-3 Fatty Acids on Muscle Mass, Muscle Strength and Muscle Performance among the Elderly: A Meta-Analysis.

There is increasing evidence showing the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle mass synthesis and function. However, the role of omega-3 fatty acids remains unclear. Therefore, we conducted a meta-analysis to evaluate the potential effects of omega-3 fatty acids on sarcopenia-related performances among the elderly. Eligible literature and reports of randomized controlled trials were comprehensively searched from the PubMed, Cochrane Library, ClinicalTrials.gov, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases until July 2018. A total of 10 articles were available for the meta-analysis. There were minor benefits for muscle mass gain (0.33 kg; 95% CI: 0.05, 0.62) and timed up and go performance (-0.30 s; 95% CI: -0.43, -0.17). Subgroup analyses regarding muscle mass and walk speed indicated that omega-3 fatty acid supplements at more than 2 g/day may contribute to muscle mass gain (0.67 kg; 95% CI: 0.16, 1.18) and improve walking speed, especially for those receiving more than 6 months of intervention (1.78 m/sec; 95% CI: 1.38, 2.17). Our findings provide some insight into the effects of omega-3 fatty acids on muscle mass, especially for those taking supplements at more than 2 g/day. We also observed that a long period of omega-3 fatty acids supplementation may improve walking speed.

Dietary Patterns and Foods Associated With Cognitive Function in Taiwanese Older Adults: The Cross-sectional and Longitudinal Studies.

OBJECTIVES: To find dietary patterns and foods associated with cognitive function. DESIGN: A cross-sectional study of short-term effects and a prospective study for long-term effects. SETTING: Nutrition and Health Survey in Taiwan (NAHSIT) 2014-2016 and NAHSIT 1999-2000. PARTICIPANTS: A total of 1245 older patients enrolled in the NAHSIT 2014-2016 and 1436 in the NAHSIT 1999-2000. MEASUREMENTS: Dietary intake was appraised with a food-frequency questionnaire. Cognitive function was assessed by the Mini-Mental State Examination score (MMSE). RESULTS: Using reduced rank regression to data-mine NAHSIT 2014-2016 cross-sectional data, we found in both genders a dietary pattern associated with high MMSE score, which was characterized by higher intakes of fresh fruits, nuts and seeds, whole grains, breakfast cereals, coffee, dairy products, seafood products, and fish. Moreover, in women, the pattern included a few additional items: tea, eggs, soybean products, and vegetables. Presence of mild cognitive impairment was inversely associated with the dietary pattern score, with declined adjusted odds ratio (95% confidence interval) from tertile 1 (as reference), tertile 2, to tertile 3 in both men [1 → 0.85(0.45-1.61) → 0.32 (0.14-0.78)] and women [1→0.44 (0.25-0.76) → 0.39 (0.20-0.75)]. Using the NAHSIT 1999-2000 as a baseline, along with 11 years of follow-up, we found with the Cox proportional hazards model that higher intake (≥4 vs <1 time/wk) of either tea or fish, but not other foods, was associated with a lower risk of developing dementia. Higher intakes of both tea and fish were associated with an even lower risk. CONCLUSIONS/IMPLICATIONS: A dietary pattern characterized by high intakes of phytonutrient-rich plant foods (fruits, whole grains, nuts/seeds, and vegetables), tea and coffee, and protein-rich foods such as eggs, dairy products, and fish, was associated with the presence of better cognitive function in older adult. Higher intakes of fish and tea combined showed a long-term protective effect. Further research is warranted to understand the long- and short-term effects of diet.

Dietary Pattern Associated with Frailty: Results from Nutrition and Health Survey in Taiwan.

OBJECTIVES: To investigate whether dietary patterns are associated with frailty phenotypes in an elderly Taiwanese population. DESIGN: Cross-sectional. SETTING: Nutrition and Health Survey in Taiwan (NAHSIT), 2014-2016. PARTICIPANTS: Noninstitutionalized Taiwanese nationals aged 65 years and older enrolled in the NAHSIT (N = 923). MEASUREMENTS: Dietary intake was assessed using a 79-item food-frequency questionnaire (FFQ). Presence of 5 frailty phenotypes was determined using modified Fried criteria and are summed into a frailty score. Using data from the NAHSIT (2014-15), reduced rank regression was used to find a dietary pattern that explained maximal degree of variation of the frailty scores. Logistic regression models were used to estimate the association between frailty and dietary pattern. The findings were validated with data from 2016. RESULTS: The derived dietary pattern was characterized with a high consumption of fruit, nuts and seeds, tea, vegetables, whole grains, shellfish, milk, and fish. The prevalence of frailty was 7.8% and of prefrailty was 50.8%, defined using the modified Fried criteria. Using data from the NAHSIT (2014-15), the dietary pattern score showed an inverse dose-response relationship with prevalence of frailty and pre-frailty. Individuals in the second dietary pattern tertile were one-third as likely to be frail as those in the first tertile (adjusted odds ratio (aOR) = 0.32, 95% confidence interval (CI) = 0.12-0.85), and those in the third tertile were 4% as likely to be frail as those in the first tertile (aOR = 0.04, 95% CI = 0.01-0.18). The dietary pattern score estimated using FFQ data from the NAHSIT 2016 was also significantly and inversely associated with frailty. CONCLUSION: Individuals with a dietary pattern with more phytonutrient-rich plant foods, tea, omega-3-rich deep-sea fish, and other protein-rich foods such as shellfish and milk had a reduced prevalence of frailty. Further research is necessary to confirm these findings and investigate whether related dietary interventions can reduce frailty in older adults.

Partial Least Square Discriminant Analysis Discovered a Dietary Pattern Inversely Associated with Nasopharyngeal Carcinoma Risk.

Evidence on the association between dietary component, dietary pattern and nasopharyngeal carcinoma (NPC) is scarce. A major challenge is the high degree of correlation among dietary constituents. We aimed to identify dietary pattern associated with NPC and to illustrate the dose-response relationship between the identified dietary pattern scores and the risk of NPC. Taking advantage of a matched NPC case-control study, data from a total of 319 incident cases and 319 matched controls were analyzed. Dietary pattern was derived employing partial least square discriminant analysis (PLS-DA) performed on energy-adjusted food frequencies derived from a 66-item food-frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with multiple conditional logistic regression models, linking pattern scores and NPC risk. A high score of the PLS-DA derived pattern was characterized by high intakes of fruits, milk, fresh fish, vegetables, tea, and eggs ordered by loading values. We observed that one unit increase in the scores was associated with a significantly lower risk of NPC (ORadj = 0.73, 95% CI = 0.60-0.88) after controlling for potential confounders. Similar results were observed among Epstein-Barr virus seropositive subjects. An NPC protective diet is indicated with more phytonutrient-rich plant foods (fruits, vegetables), milk, other protein-rich foods (in particular fresh fish and eggs), and tea. This information may be used to design potential dietary regimen for NPC prevention.

Contribution of Interleukin-4 Genotypes to Lung Cancer Risk in Taiwan.

AIM: Lung cancer is the leading cause of cancer-related death worldwide. Interleukin-4 (IL-4) is a typical pleiotropic T helper 2 cytokine involved in immunology during carcinogenesis. The present study aimed at evaluating the contribution of IL-4 promoter T-1099G (rs2243248), C-589T (rs2243250), C-33T (rs2070874) genetic polymorphisms to the risk of lung cancer in Taiwan. MATERIALS AND METHODS: The contributions of the promoter IL-4 polymorphic genotypes to lung cancer risk were investigated in 358 lung cancer patients and 716 age- and gender-matched healthy controls. In addition, the interaction between IL-4 and individual smoking status was also evaluated. RESULTS: The percentages of CC, CT and TT for IL-4 C-589T genotypes were differentially represented as 69.0%, 26.5% and 4.5% in the lung-cancer patient group and 61.3%, 30.4% and 8.3% in the non-cancer control group, respectively (p=0.0156). The TT genotype carriers were of lower risk for lung cancer (odds ratio (OR)=0.48, 95% confidence interval (CI)=0.27-0.86, p=0.0106) than the CC genotype carriers. We also analyzed the allelic frequency distributions and the results showed that the T allele of IL-4 C-589T conducted a protective effect on lung cancer susceptibility (p=0.0022). On the contrary, there was no difference in the distribution of genotypic or allelic frequencies among patients and controls for the IL-4 promoter T-1099G and C-33T. CONCLUSION: The TT genotype of IL-4 C-589T compared to the CC wild-type genotype may have a protective effect on lung cancer risk in Taiwan and may serve as an early detection and prediction marker.

Risk factors for primary lung cancer among never smokers by gender in a matched case-control study.

OBJECTIVE: Lung cancers that occur in never smokers differ from those that occur in smokers. We performed an analysis of potential epidemiological risk factors for lung cancer among never smokers. METHODS: In this hospital-based matched case-control study, all 1,540 matched case-control pairs were Han Chinese in Taiwan. The data on demographic characteristics, smoking habit, exposure to environmental tobacco smoke, medical history of lung diseases, family history of lung cancer, and female characteristics were collected from a structured questionnaire. A multiple conditional logistic regression was used to estimate odds ratios and 95 % confidence intervals after adjusting for possible confounders. RESULTS: Overall, several epidemiological factors of lung cancer in never smokers were different between males and females. For the female population, subjects who were exposed to environmental tobacco smoke (OR = 1.39, 95 % CI = 1.17-1.67) with a history of pulmonary tuberculosis and with family history of lung cancer in first-degree relatives (OR = 2.44, 95 % CI = 1.79-3.32) had higher risk of lung cancer, while subjects with a history of hormone replacement therapy and using fume extractors for those who cooked were protective. For the male population, only subjects with family history of lung cancer in first-degree relatives (OR = 2.77, 95 % CI = 1.53-5.01) were significantly associated with risk of lung cancer. CONCLUSION: This study provides insights about the epidemiological factors of lung cancer in never smokers, adding to existing evidence that family history of lung cancer and environmental tobacco smoke may moderate lung cancer risk.

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

Polymorphisms of MLH1 and MSH2 genes and the risk of lung cancer among never smokers.

Mismatch repair (MMR) plays an important role in repairing nucleotide mismatches during DNA replication. Defects in MMR genes are associated with some sporadic tumors. MLH1 and MSH2 are two of the MMR genes. We conducted a case-control study to investigate the associations between the risk of lung cancer and genetic polymorphisms in the MLH1 and MSH2 genes. The SNP genotypes were determined in 730 lung cancer patients and 730 healthy controls that were frequency matched for the age, gender, and smoking status. Among the SNP polymorphisms, -93A>G (rs1800734), which is located in the promoter region of MLH1, was significantly associated with the risk of lung cancer. The GG genotype for MLH1 -93A>G was associated with a significantly increased risk of lung cancer compared with the AA genotype among the never-smoking group (adjusted OR=1.64, 95% CI=1.10-2.44; P=0.013). Consistently, the haplotype of MLH1 with one -93G risk allele was associated with the risk of lung cancer compared with the AA haplotype among the never-smoking group. Furthermore, the risk of MLH1 -93A>G polymorphism in the never-smoking group related to lung adenocarcinoma was modulated by environmental tobacco smoke (ETS) exposure status, with a significant gene-ETS interaction (P=0.042). No evidence was found of the association between MSH2 and the lung cancer risk. In conclusion, our data suggest that the MLH1 -93A>G polymorphism may contribute to the etiology of lung cancer, particularly in never smokers. This study also suggests that MLH1 -93A>G polymorphisms and ETS exposure have a role in the tumorigenesis of lung adenocarcinoma among never smokers.

The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

ATM polymorphisms and risk of lung cancer among never smokers.

The ataxia-telangiectasia mutated (ATM) gene, an important caretaker of overall genome stability, is thought to play a role in the development of human malignancy. Therefore, we hypothesized that sequence variants in ATM may influence the disposition to lung cancer. In this hospital-based matched case-control study, nine ATM single nucleotide polymorphisms (rs189037, rs228597, rs228592, rs664677, rs609261, rs599558, rs609429, rs227062, and rs664982) were genotyped in 730 lung cancer patients and 730 healthy controls. Pairwise linkage disequilibrium among nine polymorphisms in the ATM gene was very high. None of the main effects of any of the ATM polymorphisms were related to the risk of lung cancer. Interestingly, ATM polymorphisms were significantly associated with lung cancer among never smokers, and the association was modulated by low-level exposure to carcinogens such as environmental tobacco smoke. When the haplotypes of nine ATM polymorphism sites were studied, no overall association between ATM haplotypes and risk of lung cancer was found. However, the frequency distribution of haplotypes between lung cancer cases and controls was significant in the never smokers (P=0.009), demonstrating that haplotypes have a significant effect on the risk of lung cancer. In conclusion, we found that never smokers with sequence variants of the ATM gene may be at increased risk for lung cancer. Our data also suggest this association may be further modified by exposure to environmental tobacco smoke. This study suggests support to the literature that ATM polymorphisms and environmental tobacco smoke exposure have a role in lung carcinogenesis among never smokers.

A polymorphism in the APE1 gene promoter is associated with lung cancer risk.

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway, which is the primary mechanism for the repair of DNA damage caused by oxidation and alkylation. We hypothesized that polymorphisms of APE1 are associated with risk for lung cancer. In the hospital-based matched case-control study, a total of 730 lung cancer cases and 730 cancer-free controls were genotyped for four APE1 haplotype-tagging polymorphisms (that is, -656T>G, 400A>G, 630T>C, and 1350T>G). Among them, the single-nucleotide polymorphism -656T>G located in the promoter region of APE1 was significantly associated with risk for lung cancer. We found that, compared with -656 TT homozygotes, the variant genotypes were associated with a significantly decreased risk [adjusted odds ratio, 0.51; 95% confidence interval (95% CI), 0.33-0.79 for -656 TG; adjusted odds ratio, 0.43; 95% CI, 0.25-0.76 for -656 GG, respectively]. Furthermore, we found a statistically significant reduced risk of -656T>G variants among heavy smokers (adjusted odds ratio, 0.52; 95% CI, 0.30-0.93 for -656 TG; adjusted odds ratio, 0.27; 95% CI, 0.13-0.57 for -656 GG, respectively), with a significant gene-smoking interaction (P = 0.013). A similar gene-smoking interaction in the context of APE1 haplotypes was also observed. The in vitro promoter assay revealed that the -656 G allele had a significantly higher transcriptional activity than that of the -656 T allele. Together, our results suggest that polymorphisms of the APE1 gene possibly interact with smoking and may contribute to the development of lung cancer.

Single-nucleotide polymorphism of the Exo1 gene: association with gastric cancer susceptibility and interaction with smoking in Taiwan.

Exonuclease 1 (Exo1) is an important nuclease involved in the mismatch repair system that contributes to the maintenance of genomic stability, modulation of DNA recombination and mediation of cell cycle arrest. Potential polymorphisms in Exo1 may alter cancer risks by influencing the repair activity of Exo1. We hypothesized that single-nucleotide polymorphisms (SNPs) in Exo1 might be associated with risks of gastric cancer. In this hospital-based study, the association of Exo1 A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with gastric cancer risk in a central Taiwanese population was investigated. In total, 179 patients with gastric cancer and 179 age- and gender-matched healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped. A significantly different distribution was found in the frequency of the Exol K589E genotype, but not the other genotypes, between the gastric cancer and control groups. The A allele Exol K589E conferred a significant (P = 0.0094) increased risk of gastric cancer. Gene-environment interactions with smoking were significant for Exo1 K589E polymorphism, which showed that the Exo1 K589E AG/AA genotype in association with smoking conferred an increased risk of 2.07-fold (95% confidence interval = 1.22-3.50) for gastric cancer. Our results provide the first evidence that the A allele of the Exo1 K589E may be associated with the development of gastric cancer and may be a novel and useful marker for primary prevention and anticancer intervention.

Association of an EGFR intron 1 SNP with never-smoking female lung adenocarcinoma patients.

Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of a variety of malignant tumors. To test single nucleotide polymorphisms (SNPs) and haplotypes of the EGFR in modulating the lung cancer susceptibility, we conducted a matched case-control study of 730 lung cancer patients and 730 healthy controls for examining the association in Taiwanese population. Fourteen tag SNPs distributed in EGFR were selected for genotyping and one SNP 8227G>A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer (P=0.009). Interestingly, the increase of lung cancer risk is significantly associated with never-smoking female adenocarcinoma patients harboring 8227A allele. In never-smoking female population, ORs for 8227G>A were significantly increased in adenocarcinoma subtype (adjusted odds ratio (OR) for GA genotype=1.23, 95% confidence interval (CI)=0.87-1.75; and adjusted OR for AA genotype=3.52, 95% CI=1.32-9.37, respectively). The ORs in dominant or recessive genetic model were also significantly increased in female lung adenocarcinoma subtype (adjusted OR=1.35, 95% CI=1.05-1.90; and adjusted OR=3.26, 95% CI=1.24-8.62, respectively). Haplotype analyses of 14 EGFR SNPs revealed that haplotype comprising the rare allele of 8227G>A and the common allele of the other 13 SNPs was associated with a significantly increased risk of female adenocarcinoma (OR=2.81, 95% CI=1.02-7.77). Together, our results suggest that polymorphisms or haplotypes of the EGFR play an important role in the development of lung cancer in Taiwan, particularly in never-smoking female lung adenocarcinoma.

Association of p53 and p21(CDKN1A/WAF1/CIP1) polymorphisms with oral cancer in Taiwan patients.

BACKGROUND: The tumor suppressor gene p53 and its downstream effector p21(CDKN1A/WAF1/CIP1) are thought to play major roles in the development of human malignancy. Polymorphic variants of p53, at codon 72, and CDKN1A, at codon 31, have been associated with cancer susceptibility, but few studies have investigated their effect on oral cancer risk. MATERIALS AND METHODS: In this hospital-based case-control study, the association of p53 codon 72 and CDKN1A codon 31 polymorphisms with oral cancer risk in a Taiwanese population were investigated. In total, 137 patients with oral cancer and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. RESULTS: We found a significant difference in the frequency of the p53 genotype, but not the CDKN1A genotype, between the oral cancer and control groups. Those who had Arg/Arg at p53 codon 72 showed a 2.68-fold (95% confidence interval = 1.19-6.01) increased risk of oral cancer compared to those with Pro/Pro. The distribution of the combination of p53 codon 72 and CDKN1A codon 31 was different in the oral cancer and control groups. The percentages of three subgroups with the p53 GG homozygote were all higher in the oral cancer group, and the risky double homozygote, p53/CDKN1A GG/CC form, was almost 9-fold higher than the control group. CONCLUSION: Our findings suggest that the homozygous Arg allele of the p53 codon 72 may be associated with the development of oral cancer and be a useful marker for primary prevention and anticancer intervention.

Breast cancer risk associated with genotypic polymorphism of the mitotic checkpoint genes: a multigenic study on cancer susceptibility.

Aneuploidy occurs early during tumorigenesis and may contribute to tumor formation. Tumor cells become aneuploid as a result of aberrant mitotic divisions, suggesting a tumorigenic contribution of the mechanisms in maintaining chromosomal number stability. We therefore speculated that the genes TTK, MAD2L1, BUB1, BUB1B and PTTG1 (Securin), jointly implicated in the regulation of mitotic checkpoint, might be associated with breast tumorigenesis. To test this hypothesis, this case-control study of 698 primary breast cancer patients and 1492 healthy controls examined single-nucleotide polymorphisms (SNPs) in these mitotic checkpoint genes to define their tumorigenic contribution. Because estrogen is known to promote breast cancer development via its mitogenic effect leading to malignant proliferation of breast epithelium and the mitotic checkpoint genes are involved in regulating mitosis, we were also interested in knowing whether any association between genotypes and breast cancer risk was modified by reproductive risk factors. Support for these hypotheses came from the observations that (i) two SNPs in TTK and PTTG1 were associated with breast cancer risk; (ii) haplotype and haplotype combination analyses in TTK, BUB1B and PTTG1 revealed a strong association with breast cancer risk; (iii) a trend to an increased risk of breast cancer was found in women harboring a greater number of putative high-risk genotypes/haplotypes of mitotic checkpoint genes and (iv) a significant interaction between high-risk genotypes/haplotypes and reproductive risk factors in determining breast cancer risk was defined. This study provides new support for the mutator role of mitotic checkpoint genes in breast cancer development, suggesting that breast cancer could be driven by genomic instability associated with variant mitotic checkpoint genes, the tumorigenic contribution of which could be enhanced as a result of increased mitosis due to estrogen exposure.

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit.

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.

Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene Aurora-A/STK15/BTAK.

Aneuploidy, an abnormal number of chromosomes, is relatively common and occurs early in breast cancer development. This observation supports a breast tumorigenic contribution of mechanisms responsible for maintaining chromosome number stability in which centrosomes play an essential role. We therefore speculated that the Aurora-A/STK15/BTAK gene, implicated in the regulation of centrosome duplication, may be associated with breast tumorigenesis. To test this hypothesis, we conducted a case-control study of 709 primary breast cancer patients and 1,972 healthy controls, examining single-nucleotide polymorphisms (SNPs), including a suggested functional Phe31Ile SNP, in Aurora-A. We were also interested in knowing whether any association between Aurora-A and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that, since estrogen is known to promote breast cancer development via its mitogenic effect leading to malignant proliferation on breast epithelium and since Aurora-A is involved in regulating mitosis, the discovery of a joint effect between the Aurora-A genotype and reproductive risk factors on cancer risk might yield valuable clues to the association of breast tumorigenesis with estrogen. Support for this hypothesis came from the following observations. (i) Two SNPs in Aurora-A were significantly associated with breast cancer risk (p < 0.05). (ii) Haplotype analyses, based on different combinations of multiple SNPs in Aurora-A, revealed a strong association with breast cancer risk; interestingly, the genotypic distribution of the suggested functional Phe31Ile SNP was not significantly different between breast cancer patients and controls, but the specific haplotype containing the putative at-risk Ile allele was more common in patients. (iii) This association between risk and putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with a longer interval between menarche and first full-term pregnancy. (iv) The protective effect conferred by a history of full-term pregnancy was significant only in women with a putative low-risk genotype of Aurora-A. Our study provides new findings supporting the mutator role of Aurora-A in breast cancer development, suggesting that breast cancer could be driven by genomic instability associated with variant Aurora-A, the tumorigenic contribution of which could be enhanced as a result of increased mitosis due to estrogen exposure.