Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

The association between ambient air pollutants and pancreatic cancer in the Multiethnic Cohort Study.

BACKGROUND: Prior studies examining the association between ambient air pollutants and pancreatic cancer have been conducted in racially/ethnically homogeneous samples and have produced mixed results, with some studies supporting evidence of an association with fine particulate matter. METHODS: To further investigate these findings, we estimated exposure levels of particulate matter (PM2.5, PM10) and oxides of nitrogen (NOX, and NO2) using kriging interpolation for 100,527 men and women from the Multiethnic Cohort Study, residing largely in Los Angeles County from 1993 through 2013. We measured the association between these air pollutants and incident pancreatic cancer using Cox proportional hazards models with time-varying pollutant measures, with adjustment for confounding factors. RESULTS: A total of 821 incident pancreatic cancer and 1,660,488 person-years accumulated over the study period, with an average follow-up time of over 16 years. PM2.5 (per 10 µg/m3) was associated with incident pancreatic cancer (hazard ratio [HR] = 1.61; 95% CI, 1.09, 2.37). This PM2.5 -association was strongest among Latinos (HR = 3.59; 95% CI, 1.60, 8.06) and ever smokers (HR = 1.76; 95% CI, 1.05, 2.94). There was no association for PM10 (HR = 1.12; 95% CI, 0.94, 1.32, per 10 µg/m3), NOx (HR = 1.14; 95% CI, 0.88, 1.48, per 50 ppb), or NO2 (HR = 1.14; 95% CI, 0.85, 1.54, per 20 ppb). CONCLUSIONS: Our findings support prior research identifying an association between fine particulate matter, PM2.5, and pancreatic cancer. Although not statistically heterogeneous, this association was most notable among Latinos and smokers. Future studies are needed to replicate these results in an urban setting and in a racially/ethnically diverse population.

Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians.

Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF) <0.05: rs80358978 (Gly2508Ser), rs80359065 (Lys2729Asn) and rs11571653 (Met784Val) in the BRCA2 gene, showing statistically significant associations with breast cancer risk, with P-values of 1.2 × 10-4, 1.0 × 10-3 and 5.0 × 10-3, respectively. In addition, we found four low-frequency variants (rs8176085, rs799923, rs8176173 and rs8176258) in the BRCA1 gene, one common variant in the CHEK2 gene (rs9620817), and one common variant in the PALB2 gene (rs13330119) associated with breast cancer risk at P < 0.01. Our study identified several new risk variants in BRCA1, BRCA2, CHEK2, and PALB2 genes in relation to breast cancer risk in Asian women. These results provide further insights that, in addition to the high/moderate penetrance mutations, other low-penetrance variants in these genes may also contribute to breast cancer risk.

Metabolic conditions and breast cancer risk among Los Angeles County Filipina Americans compared with Chinese and Japanese Americans.

Accumulating evidence suggests that the aggregation of common metabolic conditions (high blood pressure, diabetes and dyslipidemia) is a risk factor for breast cancer. Breast cancer incidence has risen steadily in Asian American women, and whether these metabolic conditions contribute to breast cancer risk in certain Asian American subgroups is unknown. We investigated the role of physician-diagnosed hypertension, high cholesterol and diabetes separately, and in combination, in relation to the risk of breast cancer in a population-based case-control study of 2,167 Asian Americans diagnosed with breast cancer and 2,035 age and ethnicity matched control women in Los Angeles County. Compared to Asian American women who did not have any of the metabolic conditions, those with 1, 2 or 3 conditions showed a steady increase in risk (respective odds ratios were 1.12, 1.42 and 1.62; P trend = 0.001) with adjustment for covariates including body mass index. Similar significant trends were observed in Filipina Americans (P trend = 0.021), postmenopausal women (P trend =0.001), Asian women who were born in the United States (US) (P trend = 0.052) and migrants who have lived in the US for at least 20 years (P trend = 0.004), but not migrants who lived in the US for <20 years (P trend = 0.64). These results suggest that westernization in lifestyle (diet and physical inactivity) and corresponding increase in adiposity have contributed to the rising prevalence of these metabolic conditions, which in turn, are associated with an increase in breast cancer.

Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

BACKGROUND: Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. METHODS: We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. RESULTS: We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. CONCLUSION: Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

BACKGROUND: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. METHODS: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. RESULTS: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. CONCLUSION: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

The Effect of Reduced Dietary Fat and Soy Supplementation on Circulating Adipocytokines in Postmenopausal Women: A Randomized Controlled 2-Month Trial.

The reduced risk of breast cancer observed in Asia has been linked with diets rich in soy foods, and observational studies suggest that regular soy food intake is related to lower circulating levels of some inflammatory markers which have been implicated in breast cancer risk. However, short-term intervention studies with soy-based diets in small numbers of women have shown few significant changes in adipocytokine levels. This 8-wk dietary intervention study in 57 healthy postmenopausal women investigated whether soy food supplementation (50 mg isoflavones or 15 g soy protein in the form of tofu) or a very low-fat diet (11.3% of total energy), similar to the traditional Asian diet, is associated with beneficial effects on serum levels of the following adipocytokines: TNF-α, IL-6, adiponectin, and resistin. We found no statistically significant changes in the levels of these adipocytokines in association with the very low-fat diet or soy supplementation. Only the change in TNF-α levels between the very low-fat and control diet groups had borderline statistical significance. We conclude that ingestion of a very low-fat diet or a soy food supplemented diet for 8 wk does not significantly alter important circulating adipocytokines.

Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls.

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ~10% of excess familial risk of breast cancer in Asian populations.

Family history of cancer and gastroesophageal disorders and risk of esophageal and gastric adenocarcinomas: a case-control study.

BACKGROUND: There is a paucity of data on familial risk of developing esophageal adenocarcinoma, gastric cardia adenocarcinoma and distal gastric adenocarcinoma from population-based studies. METHODS: A population-based case-control study of newly diagnosed gastroesophageal adenocarcinoma was conducted in Los Angeles County. This analysis included data of case-patients whom we were able to interview directly (147 patients with esophageal adenocarcinoma, 182 with gastric cardia adenocarcinoma, and 285 with distal gastric adenocarcinoma) and 1,309 control participants. Multivariate polytomous logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the three cancer types. RESULTS: Risk of esophageal adenocarcinoma was positively associated with a family history of prostate cancer (OR = 2.84; 95% CI = 1.50-5.36) and a family history of hiatal hernia (OR = 2.04; 95% CI = 1.12-3.71). Risk of gastric cardia adenocarcinoma was strongly associated with a family history of esophageal cancer (OR = 5.18; 95% CI = 1.23-21.79) and a family history of hiatal hernia (OR = 2.31; 95% CI = 1.37-3.91). Risk of distal gastric adenocarcinoma was positively associated with a family history of gastric cancer (OR = 2.15; 95% CI = 1.18-3.91), particularly early-onset (before age 50) gastric cancer (OR = 2.82; 95% CI = 1.11-7.15). CONCLUSIONS: This study provides evidence that family history of hiatal hernia is a risk factor for esophageal adenocarcinoma and gastric cardia adenocarcinoma and that cancer in specific sites is associated with risk of esophageal adenocarcinoma, gastric cardia adenocarcinoma, and distal gastric adenocarcinoma. It is important to determine the extent to which shared environmental and genetic factors explain these familial associations.

Racial, Ethnic, and Socioeconomic Differences in a Deficit Accumulation Frailty Index in the Multiethnic Cohort Study.

BACKGROUND: Frailty status has been sparsely studied in some groups including Native Hawaiians and Asian Americans. METHODS: We developed a questionnaire-based deficit accumulation frailty index (FI) in the Multiethnic Cohort (MEC) and examined frailty status (robust, FI 0 to <0.2, prefrail, FI 0.2 to <0.35, and frail FI ≥ 0.35) among 29 026 men and 40 756 women. RESULTS: After adjustment for age, demographic, lifestyle factors, and chronic conditions, relative to White men, odds of being frail was significantly higher (34%-54%) among African American, Native Hawaiian, and other Asian American men, whereas odds was significantly lower (36%) in Japanese American men and did not differ in Latino men. However, among men who had high school or less, none of the groups displayed significantly higher odds of prefrail or frail compared with White men. Relative to White women, odds of being frail were significantly higher (14%-33%) in African American and Latino women, did not differ for other Asian American women and lower (14%-36%) in Native Hawaiian and Japanese American women. These racial and ethnic differences in women were observed irrespective of education. Risk of all-cause mortality was higher in prefrail and frail men than robust men (adjusted hazard ratio [HR] = 1.69, 1.59-1.81; HR = 3.27, 3.03-3.53); results were similar in women. All-cause mortality was significantly positively associated with frailty status and frailty score across all sex, race, and ethnic groups. CONCLUSIONS: Frailty status differed significantly by race and ethnicity and was consistently associated with all-cause mortality. The FI may be a useful tool for aging studies in this multiethnic population.

Alcohol and breast cancer risk among Asian-American women in Los Angeles County.

INTRODUCTION: The role of alcohol and breast cancer risk in Asians has not been well studied. Recent studies suggest that even moderate alcohol intake may be associated with an increase in breast cancer risk, and this may be particularly relevant as alcohol intake is traditionally low among Asians. METHODS: We investigated the association between lifetime alcohol intake (including frequency, quantity, duration, timing, and beverage type) and breast cancer in a population-based case-control study of 2,229 Asian Americans diagnosed with incident breast cancer and 2,002 matched control women in Los Angeles County. Additionally, we examined the relation between current alcohol intake and serum concentrations of sex-hormones and growth factors in a subset of postmenopausal control women. RESULTS: Regular lifetime alcohol intake was significantly higher in US-born than non-US-born Asian Americans (P < 0.001) and almost twice as common in Japanese- than in Chinese- and Filipino-Americans (P < 0.001). Breast cancer risk increased with increasing alcohol intake among US-born Asian Americans; the odds ratios (ORs) per 5 grams per day and per 10 years of drinking were 1.21 (95% confidence interval (CI) 1.00 to 1.45) and 1.12 (95% CI, 0.98 to 1.28), respectively. Regular alcohol intake was a significant risk factor for Japanese-, but not for Chinese- and Filipino-Americans. Current consumers compared with nondrinkers showed lower concentrations of insulin-like growth factor binding protein 3 (P = 0.03) and nonsignificantly higher concentrations of estrone and androgens. CONCLUSIONS: Regular lifetime alcohol intake is a significant breast cancer risk factor in US-born Asian Americans and Japanese Americans, emphasizing the importance of this modifiable lifestyle factor in traditionally low-risk populations.

Diabetes and risk of esophageal and gastric adenocarcinomas.

Diabetes has been consistently associated with an increased risk of liver, pancreas and endometrial cancer and has been implicated as a risk factor for esophageal and gastric cancers, although this association has been less well studied. We sought to determine the role of diabetes in the etiology of esophageal, gastric cardia and distal gastric adenocarcinomas (DGAs). This analysis included patients with esophageal adenocarcinoma (EA) (n = 209), gastric cardia adenocarcinoma (GCA) (n = 257) and DGA (n = 382), and 1,309 control participants from a population-based case-control study conducted in Los Angeles County. The study included non-Hispanic whites, African Americans, Hispanics and Asian Americans. The association of diabetes with the three tumor types was estimated using polytomous logistic regression. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. Nine percent of control participants and 13% of the case patients reported a history of diabetes. After adjustment for age, gender, race, birthplace, education, cigarette smoking status and body mass index, diabetes was associated with an increased risk of EA (OR, 1.48; 95% CI, 0.94-2.32; p = 0.089) and DGA (OR, 1.47; 95% CI, 1.01-2.15; p = 0.045), but was not associated with risk of GCA (OR, 0.96; 95% CI, 0.59-1.55; p = 0.87). However, the association between diabetes and risk of DGA was statistically significant only among patients for whom we interviewed their next of kin. Our study further investigated the association between diabetes and adenocarcinomas of the esophagus and distal stomach.

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Birth weight and other prenatal factors and risk of breast cancer in Asian-Americans.

Little is known about the role of birth weight and other prenatal factors in the etiology of breast cancer in Asian-Americans. We investigated the relation between birth weight and other prenatal factors and breast cancer risk in a population-based case-control study in Los Angeles County that included 2,259 Asian-American women with incident, histologically confirmed breast cancer and 2,019 control women, who were frequency matched to cases on age, Asian ethnicity, and neighborhood of residence. Breast cancer risk nearly doubled (odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.15-3.39) among those with high (≥ 4000 g) birth weight compared to those with low (<2500 g) birth weight after adjusting for age at menarche, parity, adult body mass index, and other covariates. Risk increased 8% per 500 g increase in birth weight (P trend = 0.10). We observed a significant relationship between birth weight and age at menarche in both cases and controls. Mean birth weight was higher (2948 g) for control women who had early menarche (age ≤ 11 years) compared to those who had menarche late (age ≥ 15 years) (2807 g) (P trend = 0.016); results were similar among case patients (P trend = 0.020). Older maternal age was also a risk factor; risk increased by 6% (95% CI = 1.01-1.12) per 5 years increase in maternal age with adjustment for parity and other risk factors. Our results support the hypothesis that high birth weight and older maternal age at pregnancy may have contributed to the rising breast cancer incidence in Asian-Americans.

Anthropometric, dietary, and hormonal correlates of serum adiponectin in Asian American women.

There is increasing evidence that adiponectin has a critical role in the development of breast cancer, but factors that influence adiponectin concentrations have not been well studied. We conducted a cross-sectional study among Asian-American controls who participated in a population-based case-control study of breast cancer. Participants were interviewed in-person and donated a blood specimen. Using multivariate models, we investigated the relationships between serum adiponectin concentrations and lifestyle factors (including adiposity and dietary factors) and serum sex-hormones and growth factors among postmenopausal women who were nonhormone-users at blood draw (n = 196). Adiponectin concentrations were significantly positively associated with green tea intake (P trend = 0.03); levels were 31% higher among those who drank green tea 4 or more times per wk (14.5 ± 1.10 µg/mL) compared with nongreen-tea-drinkers (11.0 ± 1.09 µg/mL); this association remained after adjustment for body mass index (BMI) and waist/hip ratio (WHR), both of which were significantly and inversely associated with adiponectin. Adiponectin concentrations were positively associated with sex-hormone-binding globulin (P trend < 0.0001) and the ratios of total testosterone (T)/total estradiol (E2) (P trend <0.004) after adjustment for BMI and WHR. Confirmation of our findings on green tea and adiponectin is needed.

Association between Airport-Related Ultrafine Particles and Risk of Malignant Brain Cancer: A Multiethnic Cohort Study.

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98-1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07-1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers. SIGNIFICANCE: Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Hormone therapy, DNA methylation and colon cancer.

Observational epidemiological studies and randomized trials have reported a protective effect of estrogen and progestin therapy (EPT) on the risk of colorectal cancer but the findings on estrogen-alone therapy (ET) are less consistent. The mechanism by which menopausal hormones influence risk of colorectal cancer has not been well studied. To further investigate the relationship between menopausal hormones and risk of colon cancer, we conducted a population-based case-control study in Los Angeles County involving 831 women with newly diagnosed colon cancer and 755 population-based control women. Risk of colon cancer decreased significantly with increasing duration of current use of ET and EPT; the adjusted relative risk was 0.83 [95% confidence interval (95% CI) = 0.76-0.99)] per 5 years of ET use and 0.88 (95% CI = 0.78-0.99) per 5 years of EPT use. Risk of colon cancer was unrelated to past ET or EPT use. We explored if current use of menopausal hormones is associated with DNA methylation of estrogen receptor (ESR1 and ESR2), progesterone receptor and other genes in the colonic tissues of a subset of colon cancer patients (n = 280) we interviewed. Our results suggest that current menopausal hormone users compared with non-current users displayed increased DNA methylation of progesterone receptor in the 'normal' colonic tissues (P = 0.055) and increased DNA methylation of ESR1 in the 'tumorous' colonic tissues (P = 0.056). These findings on DNA methylation and hormone therapy use need confirmation in larger studies.

Markers of inflammation and risk of ovarian cancer in Los Angeles County.

Factors that increase inflammation have been suggested to influence the development of ovarian cancer, but these factors have not been well studied. To further investigate this question, we studied the role of talc use, history of endometrioisis and use of non-steroidal anti-inflammatory drugs (NSAIDs) and risk of ovarian cancer in a population-based case-control study in Los Angeles County involving 609 women with newly diagnosed epithelial ovarian cancer and 688 population-based control women. Risk of ovarian cancer increased significantly with increasing frequency and duration of talc use; compared to never users risk was highest among long-duration (20+ years), frequent (at least daily) talc users (adjusted relative risk (RR) = 2.08, 95% confidence interval (CI) = 1.34-3.23). A history of physician-diagnosed endometriosis was statistically significantly associated with risk (RR = 1.66, 95% CI = 1.01-2.75). Women who were talc users and had a history of endometriosis showed a 3-fold increased risk (RR = 3.12, 95% CI = 1.36-7.22). Contrary to the hypothesis that risk of ovarian cancer may be reduced by use of NSAIDs; risk increased with increasing frequency (per 7 times/week, RR = 1.27, 95% CI = 1.14-1.43) and years of NSAID use (per 5 years of use, RR = 1.25, 95% CI = 1.10-1.42); this was consistent across types of NSAIDs. We conclude that risk of ovarian cancer is significantly associated with talc use and with a history of endometriosis, as has been found in previous studies. The NSAID finding was unexpected and suggests that factors associated with inflammation are associated with ovarian cancer risk. This result needs confirmation with careful attention to the reasons for NSAID use.

The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium.

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.