| BackgroundBreast cancer is the most common cancer among women worldwide.According to the Global Cancer Statistics Report,there are about 2.1 million new cases of breast cancer in the world in 2018,accounting for 24.2%of new cancer cases among women,and about 630 thousand cases of breast cancer deaths,accounting for 15.0%of female cancer deaths.According to the data of National Cancer Center of China,there were about 304 thousand new cases of breast cancer in Chinese women in 2015,accounting for 17.1%of new cancer cases among women.Breast cancer is also the most common cancer among women in China.In 2015,the number of female breast cancer deaths in China was 70 thousand,accounting for 8.2%of female cancer deaths.China is a traditional low-incidence area for breast cancer.However,in recent years,the incidence of breast cancer in China continues to rise rapidly at a rate of 3%to 4%per year,which is twice the average growth rate of the world.The comprehensive treatment level of breast cancer in China has been rapidly improved in recent years,but the overall survival rate of patients is still far lower than that of the developed countries.The increasing incidence of breast cancer,the huge population base,and the relatively lower survival rate have put a severe challenge on the prevention and control of breast cancer in China.The occurrence of breast cancer is related to many factors,and this process involves multi-stage,multi-step,and gene-environment interactions.Individualized interventions for each key step are important measures to reduce the incidence of breast cancer.The potential risk factors for breast cancer can be divided into controllable factors and uncontrollable factors.The controllable factors mainly include personal lifestyles,such as estrogen use,smoking,drinking,diet,and other habits.Uncontrollable factors include genetics,age,endogenous hormone exposure and so on.The successful experience of western countries reminds us that on the basis of identifying the risk factors for breast cancer,accurately screening for high-risk groups of breast cancer and giving effective intervention and monitoring are important measures to prevent breast cancer.However,due to the relatively limited and uneven health resources in China,the prevention and control system for breast cancer based on the Chinese population has not yet been established.Therefore,research on risk factors for breast cancer based on the Chinese population is needed.Identifying the environmental and genetic risk factors of breast cancer,and giving specific intervention and monitoring is a very important strategy to reduce the incidence of breast cancer.In the past few decades,with the rapid development of the economy,the eating habits and lifestyles of Chinese have undergone tremendous changes,lncluding increased meat intake,reduced vegetable intake,and changes in sleep and physical activity habits.At the same time,the incidence of breast cancer in China is rising rapidly,and there is a potential correlation between changes in living habits and the risk of breast cancer.However,there are relatively few related studies based on the Chinese population.In addition to environmental exposure factors such as living habits,individual genetic susceptibility is also closely related to the occurrence of breast cancer.With the development of molecular biology,we have made it possible to explain the genetic mechanism of carcinogenesis.Some susceptibility genes play an important role in the development of sporadic breast cancer,and the gene-environment interaction determines whether breast cancer occurs when exposed to certain environmental factors.Under the influence of endogenous and exogenous factors,human cells undergo a large number of DNA damage events every day.DNA repair,as an important defense mechanism of cells,is an important part of maintaining the normal physiological functions of the body,and its dysfunction is related to the occurrence of va rious diseases.The proteins encoded by XRCC5 and XRCC6 genes are key proteins in the NHEJ repair pathway of DNA double-strand break.Studies have shown that XRCC5 and XRCC6 gene polymorphisms are associated with the occurrence and development of various cancers,but there are few studies on XRCC5 and XRCC6 gene polymorphisms and breast cancer susceptibility based on Chinese mainland population.There are even fewer studies on its gene-environment interactions.Therefore,this study aims to clarify the association between living habits,XRCC5,and XRCC6 polymorphisms and breast cancer risk based on a multicenter case-control study,and as well as the also the gene-gene and gene-environment interactions on the risk of breast cancer.It will provide evidence for the screening of high-risk populations of breast cancer and establishing strategies for breast cancer prevention.Part I Association between living habits and risk of breast cancer ObjectivesTo explore the relationship between living habits and the risk of breast cancer in Chinese women,and to clarify the relationship between living habits and the risk of breast cancer with different hormone receptor subtypes.Materia s and methodsThe study subjects were from a multicenter case-control study involving 22 hospitals.The case group was 25?70 years old,Han and female breast cancer patients who were newly diagnosed in each hospital.The control group was matched 1:1 based on the same hospital,the same period of visit?±2 months?,and the same age?±3 years?.All subjects underwent a survey by questionnaire-based face-to-face interview and breast clinical examination.The survey included demographic characteristics,living habits,family history of breast cancer,and anthropometric indicators.The pathological data of the case group was collected by the medical record system and pathological data database of each hospital.The database was established by Epidata 3.1 software.The general data of the case and control group were described by the composition ratio,and the x2 test was used to analyze the difference between the two groups.The multivariate unconditional logistic regression model was used to calculate the adjusted OR value and 95%CI for the exposures living habits in relation to breast cancer risk.Tests for trend were performed by treating the ordered categorical variables as continuous variables in the regression analysis.A stratified analysis of the relationship between living habits and breast cancer risk based on BMI group?<24kg/m2 and>24 kg/m2?and menstrual status?premenopausal and postmenopausal?,and Wald test was used to detect the interaction between living habits and the layer variables.According to the expression status of ER and PR,breast cancer was divided into three different subgroups:ER+PR+ group,ER+PR-group,and ER-PR-group.The multi-factor unconditional logistic regression model was used to analyze the relationship between living habits and breast cancer risk of different hormone receptor subtypes.Results1.The relationship between living habits and risk of breast cancerA total of 1489 pairs of breast cancer cases and controls were included in the study.The results show that dairy was a protective factor for breast cancer.Compared with women who consumed the lowest frequency dairy?<1 day/week?,women who consumed dairy 3-4 days/week had a 28%reduced risk of breast cancer?OR=0.72,95%CI:0.55-0.93?,and the risk of breast cancer in women who consumed dairy 5-7 days/week was reduced by 42%?OR=0.58,95%CI:0.43-0.78,P trend<0.001?.Analysis of sleep satisfaction showed that "dissatisfactory" sleep women had a 51%increased risk of breast cancer compared with women with "very satisfactory" sleep?OR=1.51,95%CI:1.09-2.08,P trend=0.011?.No other dietary habits such as soy products,smoking,drinking,exercise,and sleep time were found to be associated with breast cancer risk.2.The relationship between living habits and risk of breast cancer by different BMI groupIn the BMI<24 subgroup,dairy was a protective factor for breast cancer.Compared with women who consumed the lowest frequency dairy?<1 day/week?,the risk of breast cancer in women who consumed 1-2 days of dairy per week was reduced by 30%?OR=0.70,95%Cl:0.49-0.99?.The risk of breast cancer in women who consumed dairy 3-4 days/week was reduced by 35%?OR=0.65,95%CI:0.44-0.94?,and the risk was reduced by 53%in women who consumed dairy almost every day?5-7 days/week??OR=0.47,95%CI:0.30-0.72,P trend=0.001?.However,in the BMI?24 subgroup,no correlation was found between the consumption of dairy and the risk of breast cancer.In the BMI ? 24 subgroup,compared with women who did not drink alcohol,the risk of breast cancer in drinking women was increased by 58%?OR=1.58,95%CI:1.05-2.36?.However in BMI<24 subgroup,no correlation was found between drinking behavior and the risk of breast cancer?OR=1.21,95%CI:0.83-1.78?.In the BMI<24 subgroup,compared with women with "very satisfactory"sleep,the risk of breast cancer in "dissatisfactory" sleep women was increased risks by 75%?OR=1.75,95%CI:1.08-2.85,P trend=0.024.However,in BMI>24 subgroup,no correlation was found between sleep satisfaction and the risk of breast cancer?OR?1.43,95%CI:0.92-2.23,P trend=0.108?.3.The relationship between living habits and risk of breast cancer by menstrual statusIn the premenopausal subgroup,dairy was a protective factor for breast cancer risk,and compared with women who consumed the lowest frequency dairy?<1 day/week?,women who consumed dairy 3-4 days/week had a 33%reduced risk of breast cancer?OR=0.67;95%CI:0.49-0.91?,and the risk of breast cancer in women who consumed dairy 5-7 days/week was reduced by 46%?OR=054,95%CI:0.37-0.78,P trend<0.001?,but not in the postmenopausal subgroup.In the postmenopausal subgroup,drinking alcohol increased the risk of breast cancer compared with women who did not drink alcohol?OR=2.11,95%CI:1.22-3.65?.However,in the premenopausal subgroup,no correlation was found between drinking alcohol and the risk of breast cancer?OR=1.11,95%CI:0.80-1.54?.4.The relationship between living habits and risk of breast cancer with different hormone receptor subtypesDairy was a protective factor for the risk of ER+PR+ breast cancer.Compared with women who consumed the lowest frequency dairy?<1 day/week?,women who consumed dairy 3-4 days/week had a 38%reduced risk of ER+PR+ breast cancer?OR=0.62,95%CI:0.46-0.83?,and the risk of breast cancer in women who consumed dairy 5-7 days/week was reduced by 40%?OR=0.60,95%CI:0.42-0.84,P trend<0.001?.Compared with women who did not drink alcohol,drinking alcohol increased the risk of ER+PR+?OR=1.47,95%CI:1.07-2.01?and ER-PR-?OR=1.73,95%CI:1.08-2.78?breast cancer.Compared with women with "very satisfactory" sleep,"dissatisfactory" sleep increased the risk of ER+PR+?OR=1.45,95%CI:1.00-2.11,P trend=0.049?and ER-PR-?OR=1.81,95%CI:1.02-3.23,P trend = 0.041?breast cancer.Conclusion1.Living habits were associated with the risk of breast cancer in Chinese women.Dairy was a protective factor for breast cancer,and "dissatisfactory" sleep increased the risk of breast cancer.2.Living habits had different effects on the risk of breast cancer in women with different BMI and menstrual status.Dairy consumption was a protective factor for breast cancer in premenopausal and BMI<24 women.Drinking alcohol could increase the risk of breast cancer in postmenopausal and BMI?24 women.However,sleep satisfaction was more strongly associated with breast cancer risk in BMI<24 women.3.Living habits had different effects on the risk of breast cancer with different hormone receptor subtypes.Dairy was a protective factor for ER+PR+ breast cancer.However,drinking alcohol and sleep satisfaction were associated with both ER+PR+and ER-PR-breast cancer risk.Part ? Gene polymorphism of XRCC5,XRCC6 and risk of breast cancer ObjectivesThis study aims to clarify the association between XRCC5 and XRCC6 polymorphisms and breast cancer risk based on a multicenter case-control study,as well as the also the gene-gene and gene-environment interactions on the risk of breast cancer.Materials and methodsThe study subjects were from a multicenter case-control study involving 22 hospitals.The case group was 25?70 years old,Han and female breast cancer patients who were newly diagnosed in each hospital.The control group was matched 1:1 based on the same hospital,the same period of visit?±2 months?,and the same age?±3 years?.All subjects underwent a survey by questionnaire-based face-to-face interview and breast clinical examination,and the fasting blood samples were collected.The pathological data of the ease group was collected by the medical record system and pathological data database of each hospital.Genotyping of target SNPs?XRCC5 rs3835,rs828907,rs16855458,rs9288516,rs828704 and XRCC6 rs2267437,rs5751129,rs5751131?were performed by the Sequenom MassARRAY?SNP assay.The general data of the case and control group were described by the composition ratio,and the ?2 test was used to analyze the difference between the two groups.Hardy-Weinberg equilibrium?HWE?was evaluated by ?2 fitting test for the distribution of genotypes of SNPs in the control group.The multivariate unconditional logistic regression model was used to calculate the adjusted OR value and 95%CI for the co-dominant and dominant model genotypes in relation to the risk of breast cancer.Tests for trend were performed by treating the ordered categorical variables of co-dominant as continuous variables in the regression analysis.According to ER and PR status,breast cancer patients were divided into hormone receptor-positive?ER+PR+?and hormone receptor-negative?ER-PR-?breast cancer and multi-factor unconditional logistic regression model was used to analyze the relationship between co-dominant and dominant model genotypes and risk of breast cancer by each hormone receptor subtype.The Lewontin coefficient D' was used as the linkage disequilibrium detection index,and the linkage disequilibrium between the SNPs and the haplotypes were calculated by SHEsisPlus software.The possible gene-gene,gene-environment interactions were analyzed using the fork analysis method,and logistic regression model.Resu ts1.Genotype and allele distribution of XRCC5,XRCC6 SNPs and HWE testIn this part,1039 breast cancer cases and 1040 controls were included.The ?2 fitting test found that XRCC5 rs828704 and XRCC6 rs5751129 did not satisfy the Hardy-Weinberg equilibrium?P = 0.013 and<0.001 respectively?,and hence they were discarded in the subsequent analysis,and other SNPs genotypes were consistent with Hardy-Weinberg equilibrium?P>0.05?.The frequency of XRCC5 rs16855458 AA genotype of the case group was 5.4%,and 36.8%for CA genotype,23.8%for A allele,and the frequency of control group was 3.3%,32.4%and 19.4%,respectively?P<0.05?.There were no statistical differences in the distribution of genotypes and alleles in the remaining SNPs between the case group and the control group.2.Genotypes and haplotypes of XRCC5,XRCC6 SNPs and the risk of breast cancerMultivariate unconditional logistic regression analysis revealed that the polymorphism of XRCC5 rs16855458 was associated with the risk of breast cancer.Compared with the XRCC5 rs16855458 CC genotype,CA genotype increased the risk of breast cancer by 240%?OR=1.24,95%CI:1.02-1.51?,and the OR values of AA genotype and CA+AA genotype were 1.78?95%CI:1.12-2.82?and 1.29?95V%CI:1.07-1.56?,and P trend of the co-dominant model was 0.003.Further analysis found that the polymorphism of XRCC5 rs16855458 was associated with the risk of ER+PR+and ER-PR-breast cancer.Compared with the XRCC5 rs16855458 CC genotype,the AA genotype increased the risk of ER+PR+ breast cancer by 84%?OR=1.84,95%Cl:1.10-3.07?,and the OR value was 2.25?95%Cl:1.14-4.46?for ER-PR-breast cancer.Compared with the XRCC6 rs2267437 CC genotype,the CG genotype increased the risk of ER-PR-breast cancer by 660%?OR=1.66,95%CI:1.20-2.31?,CG+GG gene in the dominant model increased the risk of ER-PR-breast cancer by 150%?OR=1.15,95%Cl:1.12-2.13?.The XRCC5 "GGAT"?sequence rs3835-rs828907-rs16855458-rs9288516?haplotype increased the risk of breast cancer by 27%?OR=1.27,95%Cl:1.09-1.49?.3.Gene-gene and gene-environment interactions of XRCC5,XRCC6 SNPs and the risk of breast cancerXRCC5 rs16855458 and drinking alcohol had an interactive effect on the risk of breast cancer.Compared with drinking women with XRCC5 rs16855458 CC genotype,the risk of breast cancer in non-drinking women with CA+AA genotype increased by 41%OR=1.41,95%CI:1.16-1.42?,and the breast cancer risk of drinking women with CC genotype was also increased?OR=1.63,95%CI:1.12-2.38?,however the risk of breast cancer in drinking women with the CA+AA genotype was not increased?OR=1.08,95%CI:0.66-1.75?.The antagonistic interaction was found?Interaction OR=0.47,95%CI:0.25-0.87?.XRCC6 rs2267437 and sleep satisfaction had an interaction in the risk of breast cancer.Compared with "satisfactory" sleep women with XRCC6 rs2267437 CC genotype,"dissatisfaction" sleep women with CG+GG genotype had an increased risk of breast cancer with?OR=1.72,95%CI:1.13-2.61?.The multiplication interaction was found(Interaction OR=1.71,950/CI:1.01-2.91.There was no gene-gene interaction between the SNPs of XRCC5 and XRCC6.Conclusion1.The polymorphism of XRCC5 rs16855458 was associated with the risk of breast cancer,and the AA genotype and CA+AA genotype might increase the risk of breast cancer.The "GGAT" haplotype of XRCC5?the sequence is rs3835-rs828907-rs16855458-rs9288516?was associated with an increased risk of breast cancer.2.The polymorphism of XRCC6 rs2267437 was associated with the risk of ER-PR-breast cancer,and the CG genotype and CG+GG genotype were associated with increased risks of ER-PR-breast cancer.3.The gene-environment interaction of rs16855458 and drinking alcohol,and also rs2267437 and sleep satisfaction,influenced the risk of breast cancer. |
PDF Full Text Request