Hormonal factors in association with lung cancer among Asian women: A pooled analysis from the International Lung Cancer Consortium.

Two thousand sixty-four lung cancer cases and 5342 controls were evaluated in this International Lung Cancer Consortium (ILCCO) pooled analysis on estrogen-related hormonal factors and lung cancer in Asian women. Random effect of study site and fixed effect of age, smoking status, comprehensive smoking index and family history of lung cancer were adjusted for in the multivariable logistic regression models. We found that late onset of menarche conferred elevated odds of lung cancer with adjusted odds ratio (OR) of 1.24 (95% confidence interval [CI] = 1.05, 1.45) for 17 years or older, compared to 14 years or younger. Late onset of menopause at 55 years old or older was associated with lung cancer with OR = 1.24 (95% CI = 1.02, 1.51). Nonnatural menopause was associated with an OR of 1.39 (95% CI = 1.13, 1.71). More live births showed reversed association with lung cancer (ORs of 5 or more live births: 0.71 (95% CI = 0.60, 0.84), compared to 0-2 live births (Ptrend < 0.001). A later first child delivery seemed associated with an increased susceptibility: OR of 21 to 25 years old: 1.23 (95% CI = 1.06, 1.40), 26 or older: 1.27 (95% CI = 1.06, 1.52), Ptrend = .010). The use of oral contraceptives appeared to be protective with an OR of 0.69 (95% CI = 0.57, 0.83). Stronger for adenocarcinoma than squamous cell carcinoma, these relationships were not clearly modified by smoking status, probably because of lower prevalence of smoking. This is a first and largest pooling study of lung cancer among Asian women and the results suggested potential roles of hormone-related pathways in the etiology of this disease.

Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Genome-wide association study of Parkinson's disease in East Asians.

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.

Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data.

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.

Characterization of large structural genetic mosaicism in human autosomes.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO).

While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke-lung cancer relationship by histological type based on pooled data from 18 case-control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 control who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack-years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17-1.45) for all histological types combined, 1.26 (95% CI: 1.10-1.44) for adenocarcinoma, 1.41 (95% CI: 0.99-1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89-2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62-5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for nonsmall cell lung cancers (OR=2.11, 95% CI: 1.11-4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention.

Types and distribution of congenital heart defects associated with trisomy 21 in Singapore.

AIM: Atrioventricular septal defect (AVSD) is widely accepted as the most common type of congenital heart defect in trisomy 21. Most of these studies, however, were conducted in Caucasian communities. The few Asian studies that had been conducted on this subject yielded different results. In the largest study of its kind in Asia, we described the distribution of types of congenital heart defects associated with trisomy 21 in Singapore. METHODS: Five hundred and eighty-eight patients with trisomy 21 born in 1996-2010, and confirmed by karyotyping, were included in the study. The diagnosis of congenital heart defects were made on echocardiography. Variables extracted for analysis were demographics (race and gender) and the types of congenital heart defects. Except for complex cyanotic heart defects, haemodynamically significant lesions were accounted for separately in cases where more than one type of congenital heart defect coexisted in a patient. RESULTS: Ventricular septal defect (VSD) (39.2%) was the most common congenital heart defect associated with trisomy 21 in our study, followed by patent ductus arteriosus (34.3%), secundum atrial septal defect (23.4%) and AVSD (15.6%). This study validates previous smaller Asian studies identifying VSD as the most common cardiac lesion associated with trisomy 21. A high proportion (25.0%) of trisomy 21 patients with tetralogy of Fallot also had AVSDs. Coarctation of the aorta was uncommon. CONCLUSION: VSD was the most common congenital heart defect seen in trisomy 21 in our study. A high proportion (25.0%) of trisomy 21 patients with tetralogy of Fallot also had AVSDs.

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.

Female reproductive factors, gene polymorphisms in the estrogen metabolism pathway, and risk of lung cancer in Chinese women.

The authors examined relations between reproductive factors and 5 estrogen pathway gene polymorphisms (CYP17 rs743572, CYP19A1 rs10046, ERß rs1256049, ERß rs4986938, and COMT rs4680) among 702 Singapore Chinese female lung cancer cases and 1,578 hospital controls, of whom 433 cases (61.7%) and 1,375 controls (87.1%) were never smokers. Parity (per child, odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.87, 0.97) and menstrual cycle length (for ≥30 days vs. <30 days, OR = 0.50, 95% CI: 0.32, 0.80) were inversely associated with lung cancer in never smokers, while age at first birth (for ages 21-25, 26-30, and ≥31 years vs. ≤20 years, ORs were 1.54, 2.17, and 1.30, respectively), age at menopause (for ages 49-51 and ≥52 years vs. ≤48 years, ORs were 1.37 and 1.59; P(trend) = 0.003), and reproductive period (for 31-33, 34-36, 37-39, and ≥40 years vs. ≤30 years, ORs were 1.06, 1.25, 1.45, and 1.47; P(trend) = 0.026) were positively associated. Among smokers, parity was inversely associated with lung cancer, but there was no association with other reproductive factors. The COMT rs4680 A allele was positively associated with lung cancer in never smokers (for G/A or A/A vs. G/G, OR = 1.46, 95% CI: 1.12, 1.90) but not in ever smokers. No associations were seen with other polymorphisms. These results support a risk-enhancing role of estrogens in lung carcinogenesis among never smokers.

Sun exposure and risk of lymphoid neoplasms in Singapore.

BACKGROUND: Epidemiologic studies have reported an inverse association between sun exposure and non-Hodgkin lymphoma (NHL), but these have been almost exclusively conducted in Western populations residing in temperate locations. We evaluated the association between personal outdoor sun exposure and risk of malignant lymphomas in Singapore. METHODS: A hospital-based case-control study of 541 incident cases of lymphoid neoplasms and 830 controls were recruited during 2004-2008. Participants were interviewed regarding recreational or occupational outdoor activities during childhood and in adulthood. Basic demographics and potential confounders were also collected. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression analysis. RESULTS: Compared with individuals who did not have regular sun exposure, a lower risk of NHL was observed for those who reported regular exposure on non-school days during childhood [OR, 0.62; 95 % CI, 0.46-0.83] and non-working days in adulthood [OR, 0.70; 95 % CI, 0.51-0.97]. The protective effect was more evident among women. CONCLUSION: Our findings support an inverse relationship between intermittent sun exposure and the risk of NHL. These findings are consistent with the growing evidence from various countries, but further studies, especially prospective studies, are needed in Asian populations.

Biomass fuels and lung cancer.

It is estimated that about 2.4 billion people around the world, or about 40% of the world's population, depend on biomass fuels (wood, charcoal, dung, crop residue) to meet their energy needs for cooking and heating. The burden is especially high in Asia. Studies suggest that levels of pollutants including particulate matter <10 µm and polycyclic aromatic hydrocarbons indoors in homes where biomass fuels are used far exceed levels recommended as safe. While in vitro and in vivo studies in animal models suggest that wood smoke emission extracts are mutagenic and carcinogenic, epidemiologic studies have been inconsistent. In this review, we discuss possible carcinogenic mechanisms of action of biomass fuel emissions, summarize the biological evidence for carcinogenesis, and review the epidemiologic evidence in humans of biomass fuel emissions as a risk factor for lung cancer. Finally, we highlight some issues relevant for interpreting the epidemiologic evidence for the relationship between biomass fuel exposure and lung cancer: these include methodologic considerations and recognition of possible effect modification by genetic susceptibility, smoking status, age of exposure and histologic type.

Dietary factors and the risk of lung cancer by epidermal growth factor receptor mutation status and histological subtypes.

Background: Previous studies have reported differential associations of certain dietary factors such as soy consumption by epidermal growth factor receptor mutant (EGFR +) subtype of non-small cell lung cancer (NSCLC). However, whether the other dietary factors including meat, fruits, and vegetables have differential risks on different histological and molecular subtypes of lung cancer remains unclear. Therefore, we conducted a case-control study to evaluate these associations. Methods: A total of 3,170 cases and 4,238 controls from three different studies (Genes and Environment in Lung Cancer Study, Lung Cancer Consortium Singapore Study, and Multi-ethnic Cohort Study) were included. Information on demographics, lifestyle, and dietary consumption was obtained using questionnaires. Diet was assessed by using the number of standard servings of each item consumed per week. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between meat, vegetables, and fruits consumption with lung cancer risk after adjusting for potential confounders. Results: We identified a significant inverse association between higher consumption of fruits and the risk of lung cancer (2nd tertile: OR = 0.54, 95%CI = 0.46-0.65; 3rd tertile: OR = 0.77, 95%CI = 0.65-0.91), compared with the lower (1st tertile) consumption of fruits. Higher vegetable consumption was significantly associated with a lower risk of EGFR + lung cancer (OR = 0.69, 95% CI = 0.54-0.88), however, this association was not significant among EGFR wild-type (-) lung cancer. Conversely, higher consumption of total meat (OR = 2.10, 95%CI = 1.58-2.79) was significantly associated with higher lung cancer risk, as compared with the lower consumption group. Conclusions: Differential associations between vegetable consumption with EGFR mutation status in NSCLC were found. Further prospective studies are warranted to assess this association and elucidate the biological mechanisms.

Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers.

Inflammation appears to be important in lung carcinogenesis among smokers, but its role among never-smokers is not well established. We hypothesized that inflammatory medical conditions and gene polymorphisms interact to increase lung cancer risk in never-smokers. We interviewed 433 Singaporean female never-smoker lung cancer patients and 1375 hospital controls, and evaluated six polymorphisms in the interleukin 1-ß, interleukin 6 (IL6), cyclooxygenase-2, peroxisome proliferator-activated receptor-γ and interleukin 1-ß receptor antagonist (IL1RN) genes. Tuberculosis was associated with a non-significant elevated risk of lung cancer [odds ratio (OR) 1.58, 95% confidence interval (CI) 0.95-2.62]. There was no effect of asthma, atopy or chronic productive cough individually. However, the presence of one or more of these conditions (asthma, cough or atopy) increased risk (OR 2.24, 95%CI 1.15-4.38) in individuals possessing the T/T genotype at interleukin 1-ß -31T/C, but not in those possessing the C/T (OR 0.87, 95%CI 0.51-1.57) or C/C genotypes (OR 0.58, 95%CI 0.27-1.27), and in individuals having the *2 variable number of tandem repeat allele of IL1RN [OR 5.09 (1.39-18.67)], but not in those without (OR 0.93, 95%CI 0.63-1.35). The IL6-634 G allele increased the risk of lung cancer (OR 1.44, 95%CI 1.07-1.94). Lung cancer risk also increased with the number of polymorphism sites where at least 1 'risk' allele was present [interleukin 1-ß -31T/C (T allele), IL1RN (*2 allele) and IL6-634C/G (G allele)] among those with asthma, cough or atopy (Ptrend 0.001) but not in those without (Ptrend 0.47). Our results suggest that the effect of inflammatory medical conditions on lung cancer in never-smokers is modulated by host genetic susceptibility and will need to be confirmed in other studies conducted in similar populations.

Meat consumption and risk of lung cancer among never-smoking women.

The relationship between diet and lung cancer, apart from the protective effect of fruit and vegetables, is poorly understood. Reports on the role of dietary components such as meat are inconsistent, and few studies include sufficient numbers of nonsmokers. We examined the relationship between meat consumption and never-smoking lung cancer in a hospital-based case-control study of Singapore Chinese women, a population with low smoking prevalence. Three hundred and ninety-nine cases and 815 controls were recruited, of whom 258 cases and 712 controls were never smokers. A standardized questionnaire (which included a food frequency questionnaire module) was administered by trained interviewers. Among these never smokers, fruit and vegetable intake were inversely associated with lung cancer risk. Seventy-two percent of meat consumed was white meat (chicken or fish). Meat consumption overall was inversely associated with lung cancer [adjusted odds ratio (OR), 0.88, 0.59 for second, third tertiles, P (trend) = .012]. An inverse relationship between fish consumption and lung cancer (adjusted OR, 0.81, 0.47 for 2nd, 3rd tertiles, P (trend) < .001) was observed. No association was seen between consumption of processed meats and lung cancer, nor between dietary heterocyclic amines and lung cancer. Our data suggest that fish consumption may be protective against lung cancer in never smokers.

Association between family history and lung cancer risk among Chinese women in Singapore.

Risk factors of lung cancer unrelated to smoking are not well-studied, especially among women. Family history has been shown to play a role in predisposing individuals to lung cancer, but this relationship has not been investigated in the Southeast Asian population. A total of 1159 women were recruited in a case-control study conducted in public hospitals in Singapore from 2005 to 2008. After excluding participants with incomplete family history information, 374 cases and 785 controls remained in the final analysis. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for potential confounders. Overall, family history of lung cancer was associated with a higher risk for lung cancer (aOR 2.08, 95% CI 1.25-3.47). When stratified by smoking status, a significant association was observed among never-smokers (aOR 2.78, 95% CI 1.57-4.90). Further stratification by fruit consumption identified a significant association between family history of lung cancer and higher risk of lung cancer among never-smokers who had low fruit consumption (aOR 3.09, 95% CI 1.37-7.01). Our findings suggest that family history of lung cancer is a significant risk factor for lung cancer in Singaporean Chinese women, especially among never-smokers.

International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

BACKGROUND: Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). METHODS: Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. RESULTS: Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)]. CONCLUSION: This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.

Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore.

BACKGROUND: Single nucleotide polymorphism (SNP) 309 resulting in a T or G allele in the promoter of MDM2, the negative regulator of p53, has been suggested to affect cancer predisposition and age of onset, primarily in females. However, findings have been inconsistent in various cancers, and ethnicity appears to be a critical factor influencing the effects of the SNP on cancer risk. An increasing trend has been observed in the prevalence of lung cancers in non-smokers, especially females, though the underlying genetic basis is unclear. METHODS: We therefore examined the role of the SNPs in the p53 pathway (p53 codon 72 and MDM2 SNP309) on lung cancer risk and prognosis of a life-time non-smoking female Chinese population, in a hospital-based case-control study of 123 cases and 159 age-matched controls, by PCR analysis. RESULTS: Our findings reveal that the risk of lung cancer among individuals with the MDM2 SNP309 TT genotype was 2.1 (95% CI 1.01-4.36) relative to the GG genotype, contrary to initial expectations that the GG genotype with elevated MDM2 levels will increase cancer risk. Those who had this genotype in combination with the p53 Pro allele had a risk of 2.5 (95% CI 1.2-5.0). There was however no effect of either polymorphism on age at diagnosis of lung cancer or on overall survival. CONCLUSIONS: The results thus demonstrate that the MDM2 SNP309 TT rather than the GG genotype is associated with increased risk of lung cancer in this population, suggesting that other mechanisms independent of increased MDM2 levels can influence cancer susceptibility.

The Breast Cancer Working Group presentation was divided into three sections: the epidemiology, pathology and treatment of breast cancer.

EPIDEMIOLOGY OF BREAST CANCER: The incidence and mortality of breast cancer are lower in Asia than in the West, particularly in post-menopausal women, but they are increasing. The age patterns of the incidence of breast cancer in Asia differ from in the West: in most Asian countries the peak incidence of breast cancer is at about age 45-50, whereas in western countries the incidence continues to increase even at older ages. Mortality is decreasing in western countries, whereas it is still increasing in Asian nations. There are many epidemiological factors involved in breast cancer, and important known risk factors include diet, obesity and diabetes. Asian studies found that high intake of isoflavones reduced the risk of breast cancer. PATHOLOGY OF BREAST CANCER: With regard to the pathology of breast cancer, for the molecular subtype, luminal A and luminal B are being used, while HER2 expression and rapid proliferation are also employed. Study results showed a somewhat higher prevalence of luminal A in Japanese compared with Americans. Ductal carcinoma in situ breast cancer is less frequent in Asian breast cancer patients than in Americans. The Working Group resolved to establish an international committee for pathological assessment of breast cancer in Asia. TREATMENT OF BREAST CANCER: Pharmacokinetics-pharmacodynamics studies are needed between ethnic backgrounds, investigating aromatase inhibitors and tamoxifen (endoxifen), as well as the effects of demographic factors such as diet, medical care, body mass index, etc. Correlations between adverse events and the clinical outcome also need to be studied.

Reproductive variables, soy intake, and lung cancer risk among nonsmoking women in the Singapore Chinese Health Study.

Lung cancer among nonsmokers has emerged as a distinct clinicopathologic entity for which the etiology is still poorly understood, but which accounts for a significant proportion of the lung cancers among women. Although estrogens have been shown to have mitogenic effects in lung cells and interact with growth factor pathways in tumorigenesis, epidemiologic evidence for a link between reproductive hormones and lung cancer is sparse and inconsistent. We examined the effect of parity, age at menarche/menopause, cycle length and use of exogenous hormones, and dietary soy and soy isoflavonoid intake on lung cancer risk in a prospective cohort of middle-aged and elderly Chinese women in Singapore among whom 91% were lifetime nonsmokers. Among 35,298 women (mean follow-up time, 9.6 years), 298 cases of incident lung cancer were recorded, of which 189 (63.4%) occurred in nonsmokers. Compared with nulliparous women, those with one to two, three to four, and more than five livebirths had relative risks of between 0.49 and 0.59 (P for trend<0.01) for all lung cancers, and between 0.32 and 0.42 (P for trend<0.001) for adenocarcinomas. This relationship was observed in both smokers and nonsmokers. Age at menarche and menopause did not seem to influence risk. Dietary soy isoflavonoid intake was associated with a statistically significant inverse trend among nonsmokers only (relative risks, 0.59 for highest versus lower quartile; P for trend, 0.021). These findings add support for the role of hormonal factors in the etiology of lung cancer among nonsmoking women, and are consistent with emerging experimental evidence in this regard.