RESUMEN
By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.
Asunto(s)
Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Femenino , Humanos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genética , Neoplasias de la Mama/genética , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Mammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women. METHODS: In this case-control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression. RESULTS: We found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42-2.99) for percent dense area and 2.21 (1.44-3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95-2.67) and 1.89 (1.22-2.96) for percent dense area and 1.24 (0.70-2.22) and 1.96 (1.19-3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume]. CONCLUSIONS: This study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals.
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Pueblo Asiatico , Densidad de la Mama , Neoplasias de la Mama , Mamografía , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Persona de Mediana Edad , Adulto , Factores de Riesgo , Mamografía/métodos , Anciano , Posmenopausia , Premenopausia , Oportunidad Relativa , Glándulas Mamarias Humanas/anomalías , Glándulas Mamarias Humanas/diagnóstico por imagen , Glándulas Mamarias Humanas/patologíaRESUMEN
PURPOSE: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown. METHOD: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls. RESULTS: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Of the remaining 40 variants with a P-value of association > 0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD. CONCLUSION: Our study confirms the associations of 21 SNPs (19/55 or 34.5% out of all known MD loci identified in women of European ancestry) with area and/or volumetric densities in Asian women, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk.
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Densidad de la Mama , Neoplasias de la Mama , Femenino , Humanos , Densidad de la Mama/genética , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Asia Oriental , MamografíaRESUMEN
BACKGROUND: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population. METHODS: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays. RESULTS: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks. CONCLUSION: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Animales , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Femenino , Mutación de Línea Germinal , Humanos , Malasia/epidemiología , Masculino , Ratones , Singapur/epidemiologíaRESUMEN
BACKGROUND: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. METHODS: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. RESULTS: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. CONCLUSIONS: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.
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Neoplasias de la Mama , Pueblo Asiatico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Medición de RiesgoRESUMEN
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.
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Neoplasias de la Mama , Teorema de Bayes , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Mutación , Adulto , Neoplasias de la Mama/etnología , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Femenino , Mutación de Línea Germinal , Humanos , Malasia , Persona de Mediana Edad , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Physical activity is a modifiable lifestyle factor associated with reduced breast cancer risk. Mammographic density is a strong, independent risk factor for breast cancer, and some breast cancer risk factors have been shown to modify mammographic density. However, the effect of physical activity on mammographic density, studied predominantly among Caucasians, has yielded conflicting results. In this study, we examined, in an Asian population, the association between physical activity and mammographic density. METHODS: We conducted a cross-sectional study of 2,377 Malaysian women aged 40-74 years. Physical activity information was obtained at screening mammogram and mammographic density was measured from mammograms by the area-based STRATUS method (n = 1,522) and the volumetric Volpara™ (n = 1,200) method. Linear regression analyses were performed to evaluate the association between physical activity and mammographic density, adjusting for potential confounders. RESULTS: We observed that recent physical activity was associated with area-based mammographic density measures among postmenopausal women, but not premenopausal women. In the fully adjusted model, postmenopausal women with the highest level of recent physical activity had 8.0 cm2 [95% confidence interval: 1.3, 14.3 cm2] lower non-dense area and 3.1% [0.1, 6.3%] higher area-based percent density, compared to women with the lowest level of recent physical activity. Physical activity was not associated to volumetric mammographic density. CONCLUSIONS: Our findings suggest that the beneficial effects of physical activity on breast cancer risk may not be measurable through mammographic density. Future research is needed to identify appropriate biomarkers to assess the effect of physical activity on breast cancer risk.
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Pueblo Asiatico/estadística & datos numéricos , Densidad de la Mama , Ejercicio Físico , Mamografía , Adulto , Mama , Neoplasias de la Mama/prevención & control , Estudios de Cohortes , Estudios Transversales , Etnicidad , Femenino , Humanos , Persona de Mediana Edad , Premenopausia , Factores de RiesgoRESUMEN
PURPOSE: Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors. METHODS: Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts. RESULTS: Compared to Caucasian women, percent density was 2.0% higher among Asian women (p < 0.001), and dense volume was 5.7 cm3 higher among pre-menopausal Asian women (p < 0.001). Dense volume was 3.0 cm3 lower among post-menopausal Asian women (p = 0.009) compared to post-menopausal Caucasian women, and this difference was attributed to population differences in height, weight, and parity (p < 0.001). CONCLUSIONS: Our analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.
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Pueblo Asiatico , Densidad de la Mama , Neoplasias de la Mama/epidemiología , Población Blanca , Neoplasias de la Mama/etiología , Estudios Transversales , Femenino , Humanos , Malasia/epidemiología , Mamografía , Persona de Mediana Edad , Vigilancia de la Población , Factores de Riesgo , Suecia/epidemiologíaRESUMEN
BACKGROUND: Genetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach. METHODS: The MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history. RESULTS: Our study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9-62.3; p = 0.06). CONCLUSIONS: Our study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Etnicidad/genética , Sustitución de Aminoácidos , Neoplasias de la Mama/etnología , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Malasia/etnología , Masculino , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
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Isquemia Encefálica/genética , Serina Endopeptidasas/genética , Accidente Cerebrovascular/genética , Adulto , Edad de Inicio , Anciano , Pueblo Asiatico/genética , Población Negra/genética , Isquemia Encefálica/complicaciones , Cromosomas Humanos Par 10 , Simulación por Computador , ADN Intergénico/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Serina Endopeptidasas/metabolismo , Accidente Cerebrovascular/etiología , Población Blanca/genéticaRESUMEN
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
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Coffea/metabolismo , Conducta Alimentaria , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Citocromo P-450 CYP1A2/genética , Humanos , FenotipoRESUMEN
Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n â= â3,175), when compared with the largest published meta-GWAS (n > 100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space.
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Algoritmos , Evolución Biológica , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo/genética , Teorema de Bayes , Exoma/genética , Expresión Génica , Humanos , Desequilibrio de Ligamiento , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: To date, because of limited budgets and lower incidence of breast cancer, the majority of Asian countries do not have population-based screening programmes, but instead offer opportunistic screening. However, there have been few studies which have assessed the motivators for women attending such programmes and the appropriateness of the programmes in terms of targeting women at risk. METHODS: We conducted a prospective cross-sectional study of 1,619 women aged 40 to 74 years attending a subsidized opportunistic screening mammogram from October 2011 to October 2013 at a private hospital in Malaysia. Breast cancer risk was estimated using the Gail Model and two-step cluster analysis was used to examine the motivators of attending screening. RESULTS: Although Malaysia comprises 54.5% Malay, 24.5% Chinese and 7.3% Indian, the majority of women in the MyMammo Study were Chinese (70.1%) and 99.2% had a <2% ten-year risk of breast cancer. The most commonly cited barriers were the perception of not being at risk and fear of painful mammography. We found that highly educated women, cited doctors, family and friends as their main motivators. Of those with only secondary school education, their main motivators were doctors. CONCLUSIONS: Taken together, our results suggest the women attending opportunistic mammography screening in Asia are at low risk of breast cancer and this poses challenges to cost-effective and equitable strategies for cancer control. We propose that to improve uptake of screening mammography, awareness programmes should target both doctors and members of the public.
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Neoplasias de la Mama/diagnóstico , Hospitales Privados , Mamografía , Motivación , Aceptación de la Atención de Salud/psicología , Adulto , Anciano , Análisis Costo-Beneficio , Estudios Transversales , Detección Precoz del Cáncer , Femenino , Humanos , Malasia , Tamizaje Masivo , Persona de Mediana Edad , Estudios Prospectivos , RiesgoRESUMEN
INTRODUCTION: Assessing breast cancer risks from lifestyle and reproductive factors is critical for developing population-specific risk prediction tools. However, limited studies have evaluated these risks in recent Asian birth cohorts. METHODS: We systematically reviewed articles published from January 2010 to December 2023, examining breast cancer risk factors in Asian women. Data were described narratively, estimates pooled, and prevalence and attributable proportions compared across Asian populations. RESULTS: Of the 128 studies reviewed, 103 reported adjusted effect sizes for meta-analysis. Lifestyle and reproductive factors were predictive of breast cancer risk in Asian women, with varying impacts on pre-menopausal and post-menopausal women. Relative risks were similar within Asian populations and in comparison to European populations, except for menarche, menopause, and hormone receptor therapy. However, risk factor distributions differed across populations. Whilst alcohol intake (21%) and oral contraceptive use (20%) emerged as the most attributable modifiable risk factors in Europeans, passive smoking (24%) and higher BMI (17%,≥24kg/m2 among post-menopausal women) were predominant in Asians. CONCLUSION: Our study shows that whilst the effects of lifestyle and reproductive breast cancer risk factors are largely similar across different populations, their distributions vary. IMPACT: Our analysis underscores the importance of considering population-specific risk factor distributions when developing risk prediction tools for Asian populations.
RESUMEN
In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency. SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.
Asunto(s)
Neoplasias de la Mama , Fosfatidilinositol 3-Quinasa Clase I , Receptor alfa de Estrógeno , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Proteína p53 Supresora de Tumor , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/etnología , Receptor alfa de Estrógeno/genética , Proteína p53 Supresora de Tumor/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Persona de Mediana Edad , Población Blanca/genética , Predisposición Genética a la Enfermedad/genética , Adulto , Polimorfismo de Nucleótido SimpleRESUMEN
Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia. Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment. Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10-5 for BRCA1 and 0.018 for BRCA2). Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management. Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).
RESUMEN
The soya-breast cancer risk relationship remains controversial in Asia due to limited and inconsistent research findings and is exacerbated by difficulties in recruiting and retaining participants in intervention trials. Understanding public perceptions towards soya is important for designing effective intervention trials. Here, we administered a close-ended, quantitative survey to healthy, peri- and post-menopausal Asian women in the Malaysian Soy and Mammographic Density (MiSo) Study to assess perception towards soya and explore motivators and barriers that affect study adherence using the Capability, Opportunity, Motivation and Belief (COM-B) Model and Theoretical Domains Framework (TDF). Of 118 participants, the majority reported the belief that soya promotes good health (Supplement = 85â 7 %, Diet = 90â 0 %, Control = 87â 9 %). Most participants reported obtaining information about soya from the internet (Supplement = 61â 0 %, Diet = 55â 3 %, Control = 35â 9 %), while health professionals were least reported (Supplement = 9â 8 %, Diet = 7â 9 %, Control = 5â 1 %). Stratified analyses by study completion and adherence status yielded comparable findings. By the end of the study, dietary arm participants reported a strong belief that soya has no impact on their health (Supplement = 7â 1 % v. Diet = 20â 0 % v. Control = 0â 0 %, P = 0â 012). Motivation and opportunity strongly facilitated soya consumption, while psychological capability was the most common barrier to consumption though less evident among dietary arm participants. While most Asian women have a positive perception towards soya, theory-based intervention trials are warranted to understand the perception-study adherence relationship and to accurately inform the public of the health effects of soya.
Asunto(s)
Dieta , Conocimientos, Actitudes y Práctica en Salud , Alimentos de Soja , Humanos , Femenino , Malasia , Encuestas y Cuestionarios , Persona de Mediana Edad , Suplementos DietéticosRESUMEN
BACKGROUND: Polygenic risk scores (PRSs) for breast cancer, developed using European and Asian genome-wide association studies (GWAS), have been shown to have good discrimination in Asian women. However, prospective calibration of absolute risk prediction models, based on a PRS or PRS combined with lifestyle, clinical and environmental factors, in Asian women is limited. METHODS: We consider several PRSs trained using European and/or Asian GWAS. For each PRS, we evaluate the discrimination and calibration of three absolute risk models among 41â031 women from the Korean Cancer Prevention Study (KCPS)-II Biobank: (i) a model using incidence, mortality and risk factor distributions (reference inputs) among US women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. RESULTS: All Asian and European PRS improved discrimination over lifestyle, clinical and environmental (Qx) factors in Korean women. US-based absolute risk models overestimated the risks for women aged ≥50 years, and this overestimation was larger for models that only included PRS (expected-to-observed ratio E/O = 1.2 for women <50, E/O = 2.7 for women ≥50). Recalibrated and Korean-based risk models had better calibration in the large, although the risk in the highest decile was consistently overestimated. Absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. CONCLUSIONS: Absolute risk models incorporating PRS trained in European and Asian GWAS and population-appropriate average age-specific incidences may be useful for risk-stratified interventions in Korean women.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Estudios Prospectivos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , República de Corea/epidemiología , Medición de RiesgoRESUMEN
Soy intake is associated with lower breast cancer risk in observational studies concerning Asian women, however, no randomized controlled trials (RCT) have been conducted among Asian women living in Asia. This three-armed RCT assessed the effects of one-year soy isoflavone (ISF) intervention on mammographic density (MD) change among healthy peri- and postmenopausal Malaysian women. This study was registered at ClinicalTrials.gov (NCT03686098). Participants were randomized into the 100 mg/day ISF Supplement, 50 mg/day ISF Diet, or control arm, and assessed for change in absolute and relative dense area from digital mammograms conducted at enrolment and after 12 months, compared over time across study arms using Kruskal-Wallis tests. Out of 118 women enrolled, 91 women completed the intervention, while 27 women (23%) were lost in follow up. The ISF supplement arm participants observed a larger decline in dense area (−1.3 cm2), compared to the ISF diet (−0.5 cm2) and control arm (−0.8 cm2), though it was not statistically significant (p = 0.48). Notably, among women enrolled within 5 years of menopause; dense area declined by 6 cm2 in the ISF supplement arm, compared to <1.0 cm2 in the control arm (p = 0.13). This RCT demonstrates a possible causal association between soy ISF intake and MD, a biomarker of breast cancer risk, among Asian women around the time of menopause, but these findings require confirmation in a larger trial.