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1.
Carcinogenesis ; 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35605986

RESUMO

Helicobacter pylori (H. pylori) infection has been suggested to be associated with lung cancer risk. However, information is lacking on whether the association differs by H. pylori antigen. We conducted a nested case-control study within the Southern Community Cohort Study, including 295 incident lung cancer cases and 295 controls. H. pylori multiplex serology assay was performed to detect antibodies to 15 H. pylori proteins. Conditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals (95% CIs) after adjustment for covariates. Overall H. pylori  + was associated with a non-statistically significant increased risk of lung cancer (OR, 1.29; 95% CI, 0.85-1.95). Significant associations, however, were observed for H. pylori  + VacA + (OR, 1.64; 95% CI, 1.02-2.62) and H. pylori  + Catalase + (OR, 1.75; 95% CI, 1.11-2.77). The positive association of H. pylori  + Catalase + with lung cancer risk was predominantly seen among African Americans (OR, 2.09; 95% CI, 1.11-3.95) but not European Americans (OR, 1.20; 95% CI, 0.56-2.54). Among participants who smoked ≥30 pack-years, overall H. pylori  + (OR, 1.85; 95% CI, 1.02-3.35), H. pylori  + CagA + (OR, 2.77; 95% CI, 1.35-5.70), H. pylori  + VacA + (OR, 2.53; 95% CI, 1.25-5.13), and H. pylori  + HP1564 + (OR, 2.01; 95% CI, 1.07-3.77) were associated with increased risk of lung cancer. Our study provides novel evidence that associations of H. pylori infection with lung cancer risk differ by H. pylori biomarker, may be more evident among African Americans, and may be modified by smoking habits. Further studies are warranted to confirm our findings.

2.
Genet Med ; 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396981

RESUMO

PURPOSE: Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated. METHODS: We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated. RESULTS: Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer. CONCLUSION: Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.

3.
J Natl Cancer Inst ; 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35445262

RESUMO

BACKGROUND: A ban on the sale of menthol cigarettes in the United States is currently under consideration. A justification is that menthol cigarettes are harder to quit, particularly for African American smokers who use menthols much more frequently than White smokers, but epidemiologic data are limited. METHODS: In a cohort of 16,425 mostly low income African American and White current cigarette smokers enrolled during 2002-2009, we computed smoking quit and re-uptake rates at three follow ups conducted means of 4.6, 7.7 and 11 years after entry. Generalized estimation equations were used to compute odds ratios (OR) and 95% confidence intervals (CI) for quitting and resuming smoking for menthol vs non-menthol smokers adjusted for race, age, education, income, and smoking pack years. RESULTS: Crude annual quit rates among current smokers were 4.3% for menthol and 4.5% for non-menthol smokers, with adjusted ORs of quitting for menthol vs non-menthol smokers of 1.01 (95% CI = 0.91-1.11) overall, 0.99 (95% CI = 0.87-1.12) among African American and 1.02 (95% CI = 0.88-1.20) among White smokers. Crude annual smoking re-uptake rates were somewhat higher among menthol (8.4%) than non-menthol smokers (7.1%), with an adjusted OR of 1.19 (95% CI = 0.97-1.47), but net quit rates remained similar (OR = 1.01 [95% CI = 0.90-1.13] overall; OR = 1.00 [95% CI = 0.86-1.15] among African American participants; and OR = 1.04 [95% CI = 0.87-1.24] among White participants). CONCLUSIONS: This large-scale prospective survey revealed similar quit rates among menthol and non-menthol smokers. Results contribute to policy discussions, especially if, as a meta analysis suggests, lung cancer risk is higher for non-menthol smokers and a ban leads menthol smokers to switch to non-menthol cigarettes.

4.
J Epidemiol ; 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35400709

RESUMO

BACKGROUND: Ginseng, an herbal remedy, has been commonly used in Asian countries to promote longevity and health for over 2000 years. However, the association of ginseng consumption on all-cause and cause-specific mortality is still unclear. We analyzed the association of total and major cause-specific mortality (cardiovascular disease (CVD), cancer, and other death) with consumption of ginseng (primarily American and white ginseng). METHODS: This study included 56,183 female participants with an average follow-up of 14.7 years in the Shanghai Women's Health Study (SWHS), an ongoing prospective cohort study. Data were assessed via an in-person interview conducted at baseline recruitment. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ginseng-mortality associations after adjusting for confounders. RESULTS: Compared with those who never used ginseng, regular ginseng use was associated with a significantly reduced all-cause mortality (HR=0.92, 95% CI: 0.87-0.98). This inverse association was seen primarily among those who consumed ginseng for perceived general health benefit (HR=0.90, 95% CI: 0.85-0.96). A significant dose-response association was observed between duration of ginseng use and total mortality (HR=0.85, for using ≥ 6 years vs never use, P for trend < 0.001), CVD mortality (HR=0.83, P for trend = 0.019), and other-cause mortality (HR=0.76, P for trend = 0.001). However, no dose-response association was observed between amount of ginseng consumption and mortality outcomes. CONCLUSION: Regular ginseng consumption, particularly over a long duration, was associated with decreased risk of all causes of death, death due to CVD, and certain other diseases.

5.
Int J Cancer ; 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35403707

RESUMO

Many risk factors have been identified for breast cancer. The potential causality for some of them remains uncertain, and few studies have comprehensively investigated these associations by molecular subtypes. We performed a two-sample Mendelian randomization (MR) study to evaluate potential causal associations of 23 known and suspected risk factors and biomarkers with breast cancer risk overall and by molecular subtypes using data from the Breast Cancer Association Consortium. The inverse-variance weighted method was used to estimate odds ratios (OR) and 95% confidence interval (CI) for association of each trait with breast cancer risk. Significant associations with breast cancer risk were found for 15 traits, including age at menarche, age at menopause, body mass index, waist-to-hip ratio, height, physical activity, cigarette smoking, sleep duration, and morning-preference chronotype, and six blood biomarkers (estrogens, insulin-like growth factor-1, sex hormone-binding globulin [SHBG], telomere length, HDL-cholesterol and fasting insulin). Noticeably, an increased circulating SHBG was associated with a reduced risk of estrogen receptor (ER)-positive cancer (OR = 0.83, 95% CI: 0.73-0.94), but an elevated risk of ER-negative (OR = 1.12, 95% CI: 0.93-1.36) and triple negative cancer (OR = 1.19, 95% CI: 0.92-1.54) (Pheterogeneity  = 0.01). Fasting insulin was most strongly associated with an increased risk of HER2-negative cancer (OR = 1.94, 95% CI: 1.18-3.20), but a reduced risk of HER2-enriched cancer (OR = 0.46, 95% CI: 0.26-0.81) (Pheterogeneity  = 0.006). Results from sensitivity analyses using MR-Egger and MR-PRESSO were generally consistent. Our study provides strong evidence supporting potential causal associations of several risk factors for breast cancer and suggests potential heterogeneous associations of SHBG and fasting insulin levels with subtypes of breast cancer.

6.
Int J Epidemiol ; 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35229874

RESUMO

BACKGROUND: The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium. METHODS: We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol. CONCLUSION: Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended.

7.
JAMA Netw Open ; 5(3): e2149030, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35311964

RESUMO

Importance: Polygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women. Objective: To develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors. Design, Setting, and Participants: This diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study. Main Outcomes and Measures: Logistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC). Results: A total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682). Conclusions and Relevance: In this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.


Assuntos
Neoplasias da Mama , /genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
8.
Eur Heart J ; 43(18): 1702-1711, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35195259

RESUMO

AIMS: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. METHODS AND RESULTS: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS. CONCLUSION: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.


Assuntos
Doença da Artéria Coronariana , China/epidemiologia , Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Estudos Prospectivos , Medição de Risco/métodos , Fatores de Risco
9.
HGG Adv ; 3(1): 100077, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35047862

RESUMO

Certain genetic variants are associated with risks of multiple cancers. We investigated breast cancer risk with overall genetic susceptibility to each of 16 other cancers. We constructed polygenic risk scores (PRS) for 16 cancers using risk variants identified by genome-wide association studies. We evaluated the associations of these PRSs with breast cancer risk (overall and by subtypes) using Breast Cancer Association Consortium data, including 106,278 cases and 91,477 controls of European ancestry. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated to measure the association of each PRS with breast cancer risk. Data from the UK Biobank, including 4,337 cases and 209,983 non-cases, were used to replicate the findings. A 5%-8% significantly elevated risk of overall breast cancer was associated with per unit increase of the PRS for glioma and cancers of the corpus uteri, stomach, or colorectum. Analyses by subtype revealed that the PRS for corpus uteri cancer (OR = 1.09; 95% CI, 1.03-1.15) and stomach cancer (OR = 1.07; 95% CI, 1.03-1.12) were associated with estrogen receptor-positive breast cancer, while ovarian cancer PRS was associated with triple-negative breast cancer (OR = 1.25; 95% CI, 1.01-1.55). UK Biobank data supported the positive associations of overall breast cancer risk with PRS for melanoma and cancers of the stomach, colorectum, and ovary. Our study provides strong evidence for shared genetic susceptibility of breast cancer with several other cancers. Results from our study help uncover the genetic basis for breast and other cancers and identify individuals at high risk for multiple cancers.

10.
Int J Epidemiol ; 50(6): 2070-2081, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34999862

RESUMO

BACKGROUND: Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. METHODS: Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. RESULTS: During a mean follow-up of 12.0 years, 108 287 deaths were ascertained-35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10-14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13-1.37) and 1.20 (1.02-1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15-19 years after smoking cessation [1.97 (1.41-2.73)], particularly among former heavy smokers [2.62 (1.71-4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. CONCLUSIONS: Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.


Assuntos
Abandono do Hábito de Fumar , Ásia/epidemiologia , Causas de Morte , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Tabaco
11.
Am J Clin Nutr ; 115(3): 643-651, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-34673927

RESUMO

BACKGROUND: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. METHODS: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. RESULTS: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.


Assuntos
Isoflavonas , Lignanas , Neoplasias Pulmonares , Biomarcadores/urina , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Fitoestrógenos , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos
12.
Thyroid ; 32(3): 306-314, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34915752

RESUMO

Background: Although previous meta-analyses have suggested a dose-response relationship between body mass index (BMI) and thyroid cancer risk, limited evidence has been presented about Asian populations. To assess this association among Asian populations, where underweight is more prevalent than in other regions, a pooled analysis from the Asia Cohort Consortium was conducted. Methods: Baseline height and weight were measured in five cohorts and self-reported in eight cohorts. Thyroid cancer incidence was ascertained by linkage to local cancer registries. Cohorts were treated as a stratum in the Cox proportional hazard model to estimate the pooled hazard ratios (HRs) and corresponding confidence intervals (CIs) from the estimates for each cohort. All analyses were stratified by sex. Results: A total of 538,857 men and women from 13 cohorts from mainland China, Korea, Japan, and Singapore were included in the analysis. During a mean of 15.1 years of follow-up, 1132 thyroid cancer cases were ascertained. Using a BMI of 18.5-22.9 kg/m2 as a reference, an elevated risk of thyroid cancer was observed for groups with a BMI between 25 and 29.9 kg/m2 (HR: 1.31, [CI: 0.95-1.80]) and a BMI of 30 kg/m2 and greater (HR: 1.84, [CI: 0.89-3.81]) in men. Thyroid cancer risk was elevated in women with a BMI of 23-24.9 kg/m2 (HR: 1.26, [CI: 1.07-1.48]). The HRs for 5-U increment of BMI showed a linear association among men (HR: 1.25, [CI 1.10-1.55]) but not among women (HR: 1.07, [CI: 0.97-1.18]). Although the overall thyroid cancer risk was lower among underweight men and women, the papillary cancer risk may be elevated among underweight men (HR: 2.24, [CI: 0.75-6.66]). Conclusion: While higher BMI is associated with an elevated risk of thyroid cancer in both men and women, the association of underweight BMI may differ by sex and histological subtype.


Assuntos
Neoplasias da Glândula Tireoide , Ásia/epidemiologia , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia
13.
JCO Precis Oncol ; 6: e2100401, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35108035

RESUMO

PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.


Assuntos
Neoplasias do Endométrio , Genoma , Estudos de Coortes , Neoplasias do Endométrio/epidemiologia , Feminino , Genômica , Humanos , Mutação
14.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34734193

RESUMO

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

15.
Nat Commun ; 12(1): 5318, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518541

RESUMO

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.


Assuntos
Neoplasias da Mama/genética , DNA de Neoplasias/genética , Fator de Transcrição E2F1/genética , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Fator 3-alfa Nuclear de Hepatócito/genética , Transcriptoma , Sequência de Bases , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Fator de Transcrição E2F1/metabolismo , Elementos Facilitadores Genéticos , Receptor alfa de Estrogênio/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Células MCF-7 , Ligação Proteica , Risco
16.
JNCI Cancer Spectr ; 5(4)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34377936

RESUMO

Background: The cost-effectiveness of mammography screening among Chinese women remains contentious. Here, we characterized breast cancer (BC) epidemiology in Hong Kong and evaluated the cost-effectiveness of personalized risk-based screening. Methods: We used the Hong Kong Breast Cancer Study (a case-control study with 3501 cases and 3610 controls) and Hong Kong Cancer Registry to develop a risk stratification model based on well-documented risk factors. We used the Shanghai Breast Cancer Study to validate the model. We considered risk-based programs with different screening age ranges and risk thresholds under which women were eligible to join if their remaining BC risk at the starting age exceeded the threshold. Results: The lifetime risk (15-99 years) of BC ranged from 1.8% to 26.6% with a mean of 6.8%. Biennial screening was most cost-effective when the starting age was 44 years, and screening from age 44 to 69 years would reduce breast cancer mortality by 25.4% (95% credible interval [CrI] = 20.5%-29.4%) for all risk strata. If the risk threshold for this screening program was 8.4% (the average remaining BC risk among US women at their recommended starting age of 50 years), the coverage was 25.8%, and the incremental cost-effectiveness ratio (ICER) was US$18 151 (95% CrI = $10 408-$27 663) per quality-of-life-year (QALY) compared with no screening. The ICER of universal screening was $34 953 (95% CrI = $22 820-$50 268) and $48 303 (95% CrI = $32 210-$68 000) per QALY compared with no screening and risk-based screening with 8.4% threshold, respectively. Conclusion: Organized BC screening in Chinese women should commence as risk-based programs. Outcome data (e.g., QALY loss because of false-positive mammograms) should be systemically collected for optimizing the risk threshold.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mamografia/economia , Programas de Rastreamento/economia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/mortalidade , Estudos de Casos e Controles , China/epidemiologia , Análise Custo-Benefício , Feminino , Hong Kong/epidemiologia , Humanos , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Anos de Vida Ajustados por Qualidade de Vida , Sistema de Registros , Medição de Risco , Fatores de Risco , Adulto Jovem
17.
Cancer Epidemiol Biomarkers Prev ; 30(10): 1846-1857, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34272269

RESUMO

BACKGROUND: Various carotenoids in circulation, including isomers, may have different influences on cancer risk. METHODS: We conducted a nested case-control study including 343 incident prostate cancer cases and 640 controls individually matched on age, race, study site, and time of blood collection. Carotenoids investigated were carotene, cryptoxanthin, lycopene, dihydrolycopene, lutein, anhydrolutein, and zeaxanthin, including α versus ß configurations and cis versus trans isomers. General linear model and conditional logistic regression were applied to evaluate associations for prostate cancer risk, with adjustment for potential confounders. We conducted additional analyses with further stratification by race, multivitamin use, and smoking status. RESULTS: Case-control differences were found in carotenoid subtype levels, although not all reached the multiple comparison adjusted threshold for significance. Plasma lycopene [ORT1 vs. T3 = 0.51; 95% confidence interval (CI), 0.29-0.87; P trend = 0.014], dihydrolycopene (ORT1 vs. T3 = 0.37; 95% CI, 0.18-0.74; P trend = 0.006), and cis-anhydrolutein (ORT1 vs. T3 = 0.57; 95% CI, 0.33-0.96; P trend = 0.037) were inversely, while ß-trans-carotene (ORT1 vs. T3 = 2.13; 95% CI, 1.32-3.43; P trend = 0.002) and trans-lutein (ORT1 vs. T3, 1.86; 95% CI, 1.20-2.88; P trend = 0.006) were positively associated with prostate cancer risk. Stratified analyses showed inverse associations of lycopene, dihydrolycopene, and cis-anhydrolutein with prostate cancer risk in subjects without multivitamin use; lycopene and dihydrolycopene in African-Americans and current smokers; and dihydrolycopene in nonsmokers. Positive associations of ß-trans-carotene and trans-lutein were observed in African-Americans, nonsmokers, and multivitamin users. CONCLUSIONS: The associations of carotenoids with risk of prostate cancer differed by carotenoid subtypes. IMPACT: Public health recommendations on carotenoid intakes for prostate cancer prevention should take subtypes and isomers into consideration.


Assuntos
Carotenoides/sangue , Pobreza , Neoplasias da Próstata/sangue , Idoso , Estudos de Casos e Controles , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/epidemiologia , Fatores de Risco , /estatística & dados numéricos
18.
Cancers (Basel) ; 13(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069208

RESUMO

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.

19.
Int J Epidemiol ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34009320

RESUMO

BACKGROUND: Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. METHODS: Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. RESULTS: During a mean follow-up of 12.0 years, 108 287 deaths were ascertained-35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10-14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13-1.37) and 1.20 (1.02-1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15-19 years after smoking cessation [1.97 (1.41-2.73)], particularly among former heavy smokers [2.62 (1.71-4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. CONCLUSIONS: Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

20.
Breast Cancer Res ; 23(1): 62, 2021 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-34051827

RESUMO

BACKGROUNDS: In contrast to developed countries, breast cancer in China is characterized by a rapidly escalating incidence rate in the past two decades, lower survival rate, and vast geographic variation. However, there is no validated risk prediction model in China to aid early detection yet. METHODS: A large nationwide prospective cohort, China Kadoorie Biobank (CKB), was used to evaluate relative and attributable risks of invasive breast cancer. A total of 300,824 women free of any prior cancer were recruited during 2004-2008 and followed up to Dec 31, 2016. Cox models were used to identify breast cancer risk factors and build a relative risk model. Absolute risks were calculated by incorporating national age- and residence-specific breast cancer incidence and non-breast cancer mortality rates. We used an independent large prospective cohort, Shanghai Women's Health Study (SWHS), with 73,203 women to externally validate the calibration and discriminating accuracy. RESULTS: During a median of 10.2 years of follow-up in the CKB, 2287 cases were observed. The final model included age, residence area, education, BMI, height, family history of overall cancer, parity, and age at menarche. The model was well-calibrated in both the CKB and the SWHS, yielding expected/observed (E/O) ratios of 1.01 (95% confidence interval (CI), 0.94-1.09) and 0.94 (95% CI, 0.89-0.99), respectively. After eliminating the effect of age and residence, the model maintained moderate but comparable discriminating accuracy compared with those of some previous externally validated models. The adjusted areas under the receiver operating curve (AUC) were 0.634 (95% CI, 0.608-0.661) and 0.585 (95% CI, 0.564-0.605) in the CKB and the SWHS, respectively. CONCLUSIONS: Based only on non-laboratory predictors, our model has a good calibration and moderate discriminating capacity. The model may serve as a useful tool to raise individuals' awareness and aid risk-stratified screening and prevention strategies.


Assuntos
/estatística & dados numéricos , Neoplasias da Mama/epidemiologia , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/patologia , China/epidemiologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Saúde da Mulher
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