Strong Impact of TGF-β1 Gene Polymorphisms on Breast Cancer Risk in Indian Women: A Case-Control and Population-Based Study

Introduction

TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.

Methods

We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA.

Results

c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001).

Conclusion

c.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.     

Association of TNF-α, TNFRSF1A and TNFRSF1B Gene Polymorphisms with the Risk of Sporadic Breast Cancer in Northeast Chinese Han Women

Background

The interaction of tumor necrosis factor-α (TNF-α) with its receptors: TNFRSF1A and TNFRSF1B is critical for the promotion of tumor growth, invasion and metastasis. To better understand the roles of single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes in the development of breast cancer, we explored the associations between SNPs in these three genes and breast cancer susceptibility in northeast Chinese Han women.

Methodology/Principal Findings

This case-control study was conducted among 1016 breast cancer patients and 806 age-matched healthy controls. Seven SNPs in the TNF-α (rs1800629, rs361525), TNFRSF1A (rs767455, rs4149577 and rs1800693) and TNFRSF1B (rs1061622 and rs1061624) genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In TNFRSF1B, the rs1061622 GT genotype and the G allele conferred a reduced susceptibility to breast cancer (P = 0.000662, OR = 0.706, 95% CI: 0.578–0.863; P = 0.002, OR = 0.769, 95% CI; 0.654–0.905, respectively). Moreover, the AG genotype, the AA genotype and the A allele in rs1061624 conferred an increased risk of breast cancer (P = 0.007, OR = 1.470, 95% CI:1.112–1.943; P = 0.00109, OR = 1.405 95% CI:1.145–1.724; P = 0.001, OR = 1.248 95% CI:1.092–1.426, respectively). These two SNPs also had associations with breast cancer risk under the dominant model. In haplotype analysis, the CTA (rs767455 C-rs4149577 T-rs1800693 A) haplotype in TNFRSF1A and the TA (rs1061622 T-rs1061624 A) haplotype in TNFRSF1B had higher frequencies in breast cancer patients (P = 0.00324; P = 0.000370, respectively), but the frequency of GG (rs1061622 G-rs1061624 G) haplotype in TNFRSF1B was lower in breast cancer patients (P = 0.000251). The associations of the three haplotypes remained significant after correcting for multiple testing. In addition, significant associations were also observed between TNFRSF1A polymorphisms and lymph node metastasis, P53, estrogen receptor (ER) and progesterone receptor (PR) statuses.

Conclusions

Our results suggest that rs1061622 and rs1061624 in TNFRSF1B may affect breast cancer risk, and SNPs in TNFRSF1A are associated with the clinical features of breast cancer.     

Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (P_interaction = 2.4×10⁻⁶) and between CASP8-rs17468277 and alcohol consumption (P_interaction = 3.1×10⁻⁴). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P_interaction = 5.3×10⁻⁵), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.     

Genetic Polymorphisms of Estrogen Receptors α and β and the Risk of Developing Prostate Cancer

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors α (ESR1) and β (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3′ of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3′ of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.     

Vitamin D Receptor Gene and Aggrecan Gene Polymorphisms and the Risk of Intervertebral Disc Degeneration — A Meta-Analysis

Background

A series of studies have been conducted to evaluate the associations between vitamin D receptor (VDR) and aggrecan variable numbers of tandem repeat (VNTR) polymorphisms and the risk of intervertebral disc degeneration (IDD), but produced conflicting results.

Objective

we performed a meta-analysis to address a more accurate estimation of the associations between the above gene polymorphisms and the risk of IDD.

Methods

A comprehensive literature search was conducted to identify all the relevant studies. The fixed or random effect model was selected based on the heterogeneity test among studies evaluated using the I ². Publication bias was estimated using Begg''s funnel plots and Egger''s regression test.

Results

A total of 9, 5, 3, and 7 studies were finally included in the analyses for the associations between the VDR TaqI (rs731236), FokI (rs2228570), ApaI (rs7975232), or aggrecan VNTR polymorphisms and the risk of IDD, respectively. The combined results showed that none of the VDR (TaqI, FokI, ApaI) polymorphisms were significantly associated with the risk of IDD. In contrast, the alleles with shorter VNTR length was found to significantly increase the risk of IDD (≦25 vs. >25: OR = 1.850, 95%CI 1.477–2.318; ≦23 vs. >23: OR = 1.955, 95%CI 1.41–2.703). Subgroup analysis confirmed the above results. After excluding studies deviated from Hardy-Weinberg equilibrium (HWE) in controls, no other studies were found to significantly influence the pooled effects in each genetic model. No potential publication bias was detected.

Conclusion

This meta-analysis suggested that the alleles with shorter VNTR length significantly increased the risk of IDD, while the VDR (TaqI, FokI, ApaI) gene polymorphisms were not significantly associated with the risk of IDD. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results.     

Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis

Background

HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis.

Methods

Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I ², and funnel plot.

Results

Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis.

Conclusions

Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.     

Association between TNF α Gene Polymorphisms and the Risk of Duodenal Ulcer: A Meta-Analysis

Background

Epidemiological studies have evaluated the association between tumor necrosis factor α (TNF-α) single nucleotide polymorphisms (SNPs) and duodenal ulcer (DU), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to investigate a more authentic association between TNF-α SNPs and DU.

Methods

We performed the meta-analysis by searching PubMed, Embase, and Web of Science databases from the first available year to Sep. 5, 2012. Additionally, checking reference lists from identified articles, reviews, and the abstracts presented at related scientific societies meetings were also performed. All case-control studies investigating the association between TNF-α SNPs and DU risk were included. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). Publication bias was analyzed by Begg''s funnel plot and Egger''s regression test.

Results

A total of sixteen studies reporting TNF-α −308G/A, −1031T/C, −863C/A, −857C/T, and −238G/A polymorphism were included in our final meta-analysis. There was no statistically significant association between −308G/A polymorphism and DU in the overall study population, as well as subgroup analyses by ethnicity, study design, and H. pylori status. As for −1031T/C, −863C/A, −857C/T, and −238G/A, results of our meta-analyses showed no statistical evidence of significant association. Power calculation on the combined sample size showed that the statistical powers were all lower than 80% for all the meta-analyses.

Conclusions

The data suggests that there is no statistical evidence of significant association between the studied TNF-α SNPs and DU. However, this conclusion should be interpreted with caution as low statistical powers were revealed by power calculations. In future, larger sample-size studies with homogeneous DU patients and well-matched controls are required.     

Estrogen Receptor Status in Relation to Risk of Contralateral Breast Cancer–A Population-Based Cohort Study

Background

It is unclear whether estrogen receptor (ER)-status of first primary breast cancer is associated with risk of metachronous (non-simultaneous) contralateral breast cancer (CBC), and to what extent endocrine therapy affects this association.

Methods

We studied the effect of ER-status of the first cancer on the risk of CBC overall, and for different ER-subtypes of CBC, using a large, population-based cohort. The cohort consisted of all women diagnosed with breast cancer in the Stockholm region 1976–2005; 25715 patients, of whom 940 suffered CBC. The relative risk was analyzed mainly using standardized incidence ratios (SIR).

Results

Women with breast cancer had a doubled risk of CBC compared to the risk of breast cancer in the general female population (SIR: 2.22 [2.08–2.36]), for women with a previous ER-positive cancer: SIR = 2.30 (95% CI:2.11–2.50) and for women with a previous ER-negative cancer: SIR = 2.17 (95% CI:1.82–2.55). The relative risk of ER-positive and ER-negative CBC was very similar for women with ER-positive first cancer (SIR = 2.02 [95%CI: 1.80–2.27] and SIR = 1.89 [95%CI: 1.46–2.41] respectively) while for patients with ER-negative first cancer the relative risk was significantly different (SIR = 1.27 [95% CI:0.94–1.68] for ER-positive CBC and SIR = 4.96 [95%CI:3.67–6.56] for ER-negative CBC). Patients with ER-positive first cancer who received hormone therapy still had a significantly higher risk of CBC than the risk of breast cancer for the general female population (SIR = 1.74 [95% CI:1.47–2.03]).

Conclusion

The risk of CBC for a breast cancer patient is increased to about two-fold, compared to the risk of breast cancer in the general female population. This excess risk decreases, but does not disappear, with adjuvant endocrine therapy. Patients with ER-positive first cancers have an increased risk for CBC of both ER subtypes, while patients with ER-negative first cancer have a specifically increased risk of ER-negative CBC.     

Does Hair Dye Use Increase the Risk of Breast Cancer? A Population-Based Case-Control Study of Finnish Women

Introduction

Role of hair dyes in the etiology of breast cancer has occasionally raised concern but previous research has concluded with mixed results. Remnants of prohibited aromatic amines have been found in many hair dye products, and elevated levels of DNA-adducts of these amines have been detected from breast epithelial cells of hair dye users. However, the IARC working group has concluded that there is inadequate evidence for carcinogenicity of personal hair dye use and limited evidence in experimental animals for carcinogenicity of hair colorants.

Material and Methods

We investigated whether the use of hair dyes is associated with breast cancer risk in women. The study design was a retrospective population-based case-control study in Finland, with a self-administered questionnaire from 6,567 breast cancer patients, aged 22–60 years and diagnosed in 2000–2007, and their 21,598 matched controls. We report odds ratios (OR) with 95% confidence interval (95% CI) from a conditional logistic regression model applied to the frequency matched sets of cases and controls. Bias-adjusted odds ratios from the sensitivity analysis are also presented.

Results

After adjusting for potential confounders, the odds of breast cancer increased by 23% (OR: 1.23, 95% CI: 1.11–1.36) among women who used hair dyes compared to those who did not. In women born before 1950 an increase of 28% was noted (OR: 1.28, 95% CI: 1.10–1.48). We also observed a significant trend between the OR and cumulative use of hair dyes (P: 0.005). Bias-adjusted odds ratios varied between 1.04 and 2.50.

Conclusions

Our results suggest that use of hair dyes is associated with breast cancer incidence. The impact on public health may be substantial due to vast popularity of hair coloring in modern societies. It should be noted that regardless of all efforts, a possibility of bias cannot definitively be ruled out and use of a prospective design is warranted. Based on the present results, it may be concluded however that safety of hair dyes in relation to breast cancer cannot yet be fully acknowledged and lack of external safety assessment within the cosmetics industry is of major concern.     

Development and Validation of Nomograms for Predicting Overall and Breast Cancer–Specific Survival in Young Women with Breast Cancer: A Population-Based Study

INTRODUCTION: The objective of current study was to develop and validate comprehensive nomograms for predicting the survival of young women with breast cancer. METHODS: Women aged <40 years diagnosed with invasive breast cancer between 1990 and 2010 were selected from the Surveillance, Epidemiology, and End Results database and randomly divided into training (n = 12,465) and validation (n = 12,424) cohorts. A competing-risks model was used to estimate the probability of breast cancer–specific survival (BCSS). We identified and integrated significant prognostic factors for overall survival (OS) and BCSS to construct nomograms. The performance of the nomograms was assessed with respect to calibration, discrimination, and risk group stratification. RESULTS: The entire cohort comprised 24,889 patients. The 5- and 10-year probabilities of breast cancer–specific mortality were 11.6% and 20.5%, respectively. Eight independent prognostic factors for both OS and BCSS were identified and integrated for the construction of the nomograms. The calibration curves showed optimal agreement between the predicted and observed probabilities. The C-indexes of the nomograms in the training cohort were higher than those of the TNM staging system for predicting OS (0.724 vs 0.694; P < .001) and BCSS (0.733 vs 0.702; P < .001). Additionally, significant differences in survival were observed in patients stratified into different risk groups within respective TNM categories. CONCLUSIONS: We developed and validated novel nomograms that can accurately predict OS and BCSS in young women with breast cancer. These nomograms may help clinicians in making decisions on an individualized basis.     

γ-Glutamyltransferase and Breast Cancer Risk Beyond Alcohol Consumption and Other Life Style Factors – A Pooled Cohort Analysis

Objective

Elevated γ-Glutamyltransferase serum levels are associated with increased risk of overall cancer incidence and several site-specific malignancies. In the present prospective study we report on the associations of serum γ-Glutamyltransferase with the risk of breast cancer in a pooled population-based cohort considering established life style risk factors.

Methods

Two cohorts were included in the present study, i.e. the Vorarlberg (n = 97,268) and the Malmoe cohort (n = 9,790). Cox proportional hazards regression models were fitted to estimate HRs for risk of breast cancer.

Results

In multivariate analysis adjusted for age, body mass index and smoking status, women with γ-Glutamyltransferase levels in the top quartile were at significantly higher risk for breast cancer compared to women in the lowest quartile (HR 1.21, 95% CI 1.09 to 1.35; p = 0.005). In the subgroup analysis of the Malmoe cohort, γ-Glutamyltransferase remained an independent risk factor for breast cancer when additionally considering alcohol intake. A statistically significant increase in risk was seen in women with γ-Glutamyltransferase-levels in the top versus lowest quartile in a multivariate model adjusted for age, body mass index, smoking status, physical activity, parity, oral contraceptive-use and alcohol consumption (HR 1.37, 95% CI 1.11–1.69, p = 0.006).

Conclusion

Our findings identified γ-Glutamyltransferase as an independent risk factor for breast cancer beyond the consumption of alcohol and other life style risk factors.     

Maternal Smoking and the Risk of Cancer in Early Life – A Meta-Analysis

BackgroundIn spite of the well-known harmful effects on the fetus, many women continue smoking during pregnancy. Smoking as an important source of toxic chemicals may contribute to the developmental origin of diseases.ObjectivesThe aim of this work was to pursue the possible association between maternal smoking and cancer in early life. Specifically, we wanted to identify the associated early life cancer types, and to quantify the associations.MethodsIn a systematic literature search 825 articles were identified in PubMed and Web of Science, and 55 more through the reference lists. Of these 62 fulfilled the criteria for inclusion in meta-analyses. Using Mantel-Haenszel or DerSimonian and Laird method, depending on heterogeneity of the studies, pooled estimates and 95% confidence intervals for eight cancer types were calculated.ResultsSmoking during pregnancy was associated with an increased risk for for brain and central nervous system tumors (OR = 1.09; 95% CI = 1.02–1.17). Although the risk for lymphoma was also associated (OR = 1.21; 95% CI = 1.05–1.34), it did not hold up in subgroup analyses. Leukemia was not found to be associated with maternal smoking. Five other cancer types (bone, soft tissue, renal, hepatic, and germ cell cancer) were also examined, but the number of studies was too limited to exclude the possibility of maternal smoking as a risk factor for cancer in offspring.ConclusionsAccording to our meta-analyses, maternal smoking is associated with nervous system cancers, but not with leukemia in early life. Confirming or rejecting associations of maternal smoking with lymphoma and the five other cancer types requires further studies.     

Association between β2-Adrenoceptor Gene Polymorphisms and Asthma Risk: An Updated Meta-Analysis

Background

Evidence is increasingly accumulated about multiple roles for the β2-adrenoceptor gene in asthma. The results were inconsistent partly due to small sample sizes. To assess the association between β2-adrenoceptor gene polymorphisms and asthma risk, a meta-analysis was performed.

Methods

We comprehensively searched the PubMed, EMBASE, BIOSIS Previews databases and extracted data from all eligible articles to estimate the association between β2-adrenoceptor gene polymorphisms and asthma risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.

Results

Thirty-seven studies involving 6648 asthma patients and 15943 controls were included in the meta-analysis. Overall, significant associations were found in allelic genetic model (OR = 1.06, 95% CI = 1.01∼1.12), recessive genetic model (OR = 1.11, 95% CI = 1.02∼1.21) for Arg/Gly16. Stratified by ethnicity and age, significant associations were also found in Asian population in allelic genetic model, recessive genetic model and addictive model. For Gln/Glu27, no significant association was found when we combined all eligible studies. Age stratification showed significant associations in adults in allelic genetic model and recessive genetic model, but no significant association was found among Asians and Caucasians in ethnicity stratification.

Conclusions

This meta-analysis implied that the β2-adrenoceptor Arg/Gly16 polymorphism was likely to contribute to asthma risk in Asian population. Gln/Glu27 polymorphism might be a contributor to asthma susceptibility for adults.     

Meta-Analysis of the Association between COX-2 Polymorphisms and Risk of Colorectal Cancer Based on Case–Control Studies

Objective

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Ten studies with 6,774 cases and 9,772 controls were included for −1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for −765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to −765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113–1.760, P = 0.004) and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295–3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297–3.970, P = 0.004). In subgroup analysis according to source of control, no significant association was detected. With respect to −1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses.

Conclusions

The present meta-analysis suggests that the COX-2 −765G>C polymorphism may be a risk factor for CRC in Asians and rectum cancer patients. Further large and well-designed studies are needed to confirm this association.     

Innate Immunity Pathways and Breast Cancer Risk in African American and European-American Women in the Women’s Circle of Health Study (WCHS)

African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women’s Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.     

Socioeconomic Disparity in Breast Cancer Detection in Hong Kong – A High Income City: Retrospective Epidemiological Study Using the Breast Cancer Registry

Background

It is not known whether socioeconomic disparities affect the detection of breast cancer in Asian countries where the incidence of breast cancer is a rising trend. In this study, we explore the socioeconomic profiles of women and the stage of the disease at the time of diagnosis in breast cancer patients aged 40 or over in Hong Kong.

Method

During the period 2008 to 2011, 5393 breast cancer patients registered with the Hong Kong Breast Cancer Registry. Participants and their clinicians were asked to complete standardised questionnaires including patient socio-demographics, health history and risk factors, the course of the disease, post-treatment physical discomfort and psychosocial impact, follow-up recurrence and survival status.

Results

Monthly household incomes, educational levels and the practice of regular screening are independently associated with the stage of the disease at diagnosis. Higher socioeconomic status and a higher educational level were associated with an earlier stage of the disease at the time of diagnosis. Yearly clinical examinations, ultrasound and mammographic screening every 2 to 3 years were significantly associated with the earlier detection of breast cancer.

Conclusion

There were socioeconomic disparities among Hong Kong women who were found to have breast cancer. Population-based screening policies, including raising awareness among women at risk, should be implemented.     

Treatment Strategies and Survival of Older Breast Cancer Patients – An International Comparison between the Netherlands and Ireland

ObjectivesForty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland.ResultsOverall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients.ConclusionTreatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.