A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

Introduction

The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.

Methods

Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer.

Results

We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk.

Conclusion

Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes.     

A prospective study of plasma prolactin levels and subsequent risk of breast cancer

Plasma prolactin was measured in 2,572 premenopausal, 628 menopausal, and 1,666 peri- and postmenopausal women who were apparently healthy. Breast cancer was subsequently diagnosed in 47 of these women at a median time of 5 years after blood collection (pre-cancer cases). Prolactin levels in pre-menopausal cases increased significantly with age whereas this was not found in matched controls. The perimenopausal cases were characterized by extreme variability in prolactin levels. In post-menopausal women who developed breast cancer, the prolactin levels were significantly elevated, being at or above the 70th percentile for the controls. In this group the results are consistent with prolactin acting as a late-stage tumour promoter.     

A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

BackgroundIntakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.Materials and methodsWe assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours.ResultsA high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4–Q1) 1.37; 95% confidence interval (CI), 1.14–1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI₁₆) (16:1n–7/16:0) [OR (Q4–Q1), 1.28; 95% C, 1.07–1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3–T1)=2.01; 95% CI, 1.03–3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.ConclusionThese findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.     

A prospective study of hemoglobin A1c concentrations and risk of breast cancer in women

Impaired glucose metabolism and hyperinsulinemia have been hypothesized to increase breast cancer risk. However, findings from observational studies relating blood concentrations of hyperinsulinemia markers to breast cancer risk have been inconsistent. We prospectively evaluated whether hemoglobin A1c (HbA1c) concentrations predict breast cancer risk in a large female cohort. We included 27,110 female participants of the Women's Health Study who were, at baseline, free of cancer and had usable blood specimens as well as sufficient information on potential risk factors for breast cancer. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazards regression models. All Ps were two sided. During an average of 10 years of follow-up, 790 incident cases of invasive breast cancer were confirmed. Higher baseline HbA1c levels were not associated with an increased risk of breast cancer. The multivariate RR for the highest relative to the lowest quintile of HbA1c levels was 0.87 (95% CI, 0.69-1.10; P(trend) = 0.22). Higher HbA1c levels were also not associated with an increased risk of breast cancer according to alternative clinical cutoff points for HbA1c or in the analyses stratified by body mass index or according to certain tumor characteristics. However, a weakly inverse association was noted among postmenopausal women, especially among those who had never used hormone therapy. There was also a weakly inverse association between HbA1c levels and estrogen receptor-negative breast tumors. These data suggest that higher HbA1c concentrations do not seem to increase risk of breast cancer among apparently healthy women.     

A prospective study of bowel motility and related factors on breast cancer risk

BACKGROUND: Estrogen is an established risk factor for breast cancer. Greater bowel motility has been associated with increased estrogen excretion and lower serum estrogen levels, suggesting that it may influence breast cancer risk. However, only one other epidemiologic study thus far, to our knowledge, has examined the relation between bowel motility and breast cancer risk. METHODS: We prospectively examined whether bowel motility, measured by self-reported frequency of bowel movements, and related factors (constipation, laxative use, water consumption, and dietary fiber intake) were associated with incidence of breast cancer among 28,586 postmenopausal women, ages 50 to 76 years, in the Vitamins and Lifestyle study. Cox proportional hazards models were used to estimate multivariate-adjusted relative risks (RR) and 95% confidence intervals (95% CI). From 2000 to 2005, 507 incident invasive breast cancers among the cohort were identified. RESULTS: Women with very frequent (> or =3/d) bowel movements had a 46% decreased risk compared with 1/d women (RR, 0.54; 95% CI, 0.31-0.92), but the test for linear trend was not significant (P(trend) = 0.41). Constipation was nonsignificantly associated with increased risk (RR, 1.30 for > or =1/wk versus <1/y; 95% CI, 0.87-1.95). No statistically significant associations were observed for the other study exposures: 10-year chemical laxative use, 10-year use of fiber laxatives, water consumption, and dietary fiber intake. CONCLUSION: This study adds limited support to the hypothesis that increased bowel motility lowers breast cancer risk.     

Estrogen receptor genotypes and haplotypes associated with breast cancer risk

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), approximately O.4; 95% confidence interval (CI), 0.2-0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2-3.8; P < 0.05). A unique risk haplotype was present in approximately 7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2-2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.     

XRCC1多态性与乳腺癌易感性

XRCC1是一个低度外显的基因，其编码的蛋白质在碱基切除修复过程中是不可缺少的。该基因多态性会导致所编码蛋白发生改变，从而影响DNA修复，可能引起肿瘤的易感性。XRCC1基因多态性与乳腺癌易感性的关系仍然存在争论，其相关性需进一步深入研究。     

A prospective study of smoking and breast cancer risk among African-American women

Purpose

Active smoking and passive smoking have been associated with increased risk of breast cancer. The purpose of the present study was to prospectively assess associations of smoking with breast cancer and identify subgroups at higher risk among African-American women.

Methods

Based on 1,377 incident cases identified during 14 years of follow-up in the Black Women’s Health Study, we assessed active and passive smoking in relation to breast cancer incidence by menopausal status, estrogen receptor status, and other factors. Incidence rate ratios (IRR) and 95 % confidence intervals (CI) for categories of smoking relative to no active or passive smoking were calculated from Cox proportional hazards models, controlling for breast cancer risk factors.

Results

Active smoking was associated with increased risk of premenopausal breast cancer. The IRR was 1.21 (95 % CI 0.90–1.62) for premenopausal breast cancer overall and 1.70 (95 % CI 1.05–2.75) for premenopausal breast cancer associated with beginning smoking before age 18 together with accumulation of ≥20 pack years. The positive association with premenopausal breast cancer was most apparent for estrogen-receptor-positive cancer. Passive smoking was also associated with increased risk of premenopausal breast cancer (IRR = 1.42, 95 % CI 1.09–1.85), based on information on passive smoking at home and work. Neither active nor passive smoking was associated with increased risk of postmenopausal breast cancer.

Conclusion

These results strengthen the evidence that both active and passive smoking increase the incidence of premenopausal breast cancer.     

A prospective study of urinary oestrogen excretion and breast cancer risk.

To test the hypothesis that high levels of endogenous oestrogens increase the risk for developing breast cancer, concentrations of oestrone, oestradiol and oestriol were measured in 24 h urine samples from 1000 women participants in a prospective study of breast cancer on the island of Guernsey. Sixty-nine subjects were diagnosed with breast cancer subsequent to urine collection. Among women who were premenopausal at the time of urine collection, cases excreted less oestrogen than controls; the odds ratios (95% CI) for breast cancer in the middle and upper thirds of the distribution of oestrogen excretion, in comparison with the lower third (reference group, assigned odds ratio = 1.0), were 0.5(0.2-1.2) and 0.4(0.2-1.1) respectively for oestrone, 0.8(0.4-1.8 and 0.4(0.2-1.1) for oestradiol, 0.7(0.3-1.6) and 0.7(0.3-1.6) for oestriol and 0.9(0.4-2.0) and 0.5(0.2-1.3) for total oestrogens. Among women who were post-menopausal at the time of urine collection, the trend was in the opposite direction, with an increase in risk associated with increased oestrogen excretion; the odds ratios were 0.9(0.3-2.2) and 1.1(0.5-2.8) for oestrone, 0.8(0.3-2.3) and 1.9(0.8-4.6) for oestradiol, 1.5(0.6-3.9) and 1.8(0.7-4.6) for oestriol and 0.9(0.4-2.6) and 1.9(0.7-4.7) for total oestrogens. The trends of increasing risk with increasing oestrogen excretion among post-menopausal women were statistically significant for oestradiol (P = 0.022) and for total oestrogens (P = 0.016). We conclude that high levels of endogenous oestrogens in post-menopausal women are associated with increased breast cancer risk, but that the relationship of oestrogens in premenopausal women with risk is unclear.     

XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study

Introduction

It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking.

Methods

The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses.

Results

No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1-399 Gln allele (OR 2.33, 95% CI 1.30–4.19, p _int 0.025) or XPD-751 Gln/Gln genotype (OR 2.52, 95% CI 1.27–5.03, p _int 0.011) compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66–10.3) and 4.41 (95% CI 1.62–12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00–2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes.

Conclusion

Our results do not indicate a major role for XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women.     

p53 genotypes and haplotypes associated with risk of breast cancer

INTRODUCTION: The biological significance of sequence variants in form of SNPs needs to be carefully evaluated, as conflicting associations with cancer predisposition have been reported. Haplotypes, the combination of closely linked alleles on a chromosome, play key roles in the study of the genetic basis of disease. There is strong evidence that different polymorphisms within a single gene in cis position can interact to create a large effect on the observed phenotype. Several polymorphisms have been reported in the p53 gene. Some of these are within the coding region and may affect the function of the p53 protein, others are within introns or non-coding regions, and their significance is unclear. In this study, we investigated the association of specific p53 genotypes and haplotypes with risk of breast cancer. METHODS: One hundred and fifteen patients with breast cancer and 63 healthy individuals were analyzed. DNA was isolated by salting out. The polymorphic sites were analyzed by PCR RFLP. Pearson's chi(2) and Kolmogorof Simirnow tests were used for statistical analyses. Extended haplotype frequencies were estimated. RESULTS: The distribution of the genotypes was similar for all three polymorphisms in the cases and the controls. Our estimated haplotype results indicate that the intron 3 (+16bp)|exon 4 (Arg) diplotype and the intron 3 (+16bp)|exon 4 (Arg)|intron 6 (G) haplotype combinations are overrepresented in the breast cancer group, suggesting that the intron 3 (+16bp)|exon 4 (Arg) alleles may play a role in breast carcinogenesis. CONCLUSION: We conclude that two haplotypes harboring the intron 3 polymorphic (+16bp) allele are associated with a higher risk of breast cancer in the Turkish population.     

Dietary carotenoids and the risk of invasive breast cancer

Certain classes of vitamins and nutrients found in fruits and vegetables have been of particular interest in relation to cancer prevention, owing to their potential anticarcinogenic properties. We examined the association between certain fruits, vegetables, carotenoids, and vitamin A and breast cancer risk in a large population‐based case‐control study of women residing in the states of Massachusetts, New Hampshire and Wisconsin. The study was comprised of 5,707 women with incident invasive breast cancer (2,363 premenopausal women and 3,516 postmenopausal women) and 6,389 population controls (2,594 premenopausal women and 3,516 postmenopausal women). In an interview, women were asked about their intake of carotenoid rich fruits and vegetables 5 years prior to a referent date. An inverse association observed among premenopausal women was for high levels of vitamin A (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.01), β‐carotene (OR: 0.81, 95% CI 0.68–0.98, p for trend = 0.009), α‐carotene (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.07) and lutein/zeaxanthin (OR: 0.83, 95% CI 0.68–0.99, p for trend = 0.02). An inverse association was not observed among postmenopausal women. Among premenopausal women who reported ever smoking, these results were stronger than among never smokers, although tests for interaction were not statistically significant. Results from this study are comparable to previous prospective studies, and suggest that a high consumption of carotenoids may reduce the risk of premenopausal but not postmenopausal breast cancer, particularly among smokers. © 2009 UICC     

Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women

Carotenoids have antioxidant and antiproliferative properties and may reduce the risk of breast cancer. We examined the association between dietary carotenoids and risk of invasive breast cancer in the Swedish Mammography Cohort, a population-based cohort of 36,664 women who completed a questionnaire in 1997. During a mean follow-up of 9.4 years, 1008 women were diagnosed with incident breast cancer. Dietary carotenoids were not significantly associated with the risk of breast cancer overall or with any subtype defined by oestrogen receptor (ER) and progesterone receptor (PR) status. However, dietary α-carotene and β-carotene were inversely associated with the risk of ER–PR-breast cancer among ever smokers. Among ever smokers, the multivariable relative risks of ER–PR-breast cancer comparing the highest with the lowest quintile of intake were 0.32 (95% confidence interval (CI): 0.11–0.94; P_trend = 0.01) for α-carotene and 0.35 (95% CI: 0.12–0.99; P_trend = 0.03) for β-carotene. The risk of breast cancer also decreased with increasing intakes of α-carotene (P_trend = 0.02) and β-carotene (P_trend = 0.01) among women who did not use dietary supplements. These findings suggest that dietary α-carotene and β-carotene are inversely associated with the risk of breast cancer among smokers and among women who do not use dietary supplements.     

A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer

Objective  

We used a nested case–control design within a large, multi-center cohort of women who underwent a biopsy for benign breast disease (BBD) to assess the association of broad histologic groupings and specific histologic entities with risk of breast cancer.     

Menopausal age and XRCC1 gene polymorphisms: role in breast cancer risk

BACKGROUND: Recent evidence that some DNA-repair functions are haploinsufficient adds weight to the notion that variants in DNA-repair genes constitute part of the spectrum of defects contributing to cancer risk. X-ray repair cross-complementing group 1 gene (XRCC1) is involved in base excision repair (BER) pathway, acting on spontaneous and induced DNA damage. This gene encodes for a scaffolding protein that brings together different proteins involved in the repair process. Among the non-synonymous polymorphisms in XRCC1 gene, codons 194 and 399 lead to amino acid changes at evolutionary conserved regions, and seem to alter the efficiency of the protein. METHODS: A hospital based case-control study was carried out in a Caucasian Portuguese population (241 cancer patients and 457 controls matched for sex and age) in order to evaluate the potential modifying role of the XRCC1 polymorphisms on the individual susceptibility to breast cancer. RESULTS: Our data did not reveal a positive association between the polymorphisms individually and breast cancer, or with the combination of the different genotypic associations. However, after stratification to the menopausal status, it was observed that carriers of the Gln/Gln genotype of the R399Q polymorphism with a menopausal age above 55 years are at increased risk for breast cancer (OR=4.074; CI=1.562-10.626; P=0.004). Concerning the Arg194Trp polymorphism, after stratification by menopausal status, it was observed that heterozygous individuals (Arg/Trp) with a menopausal age between 45 and 54 are at increased risk for breast cancer (adjusted OR=1.964; CI=1.174-3.288; P=0.01) as well as carriers of the variant allele (Arg/Trp+Trp/Trp) (adjusted OR=1.932; CI=1.156-3.228; P=0.012). CONCLUSIONS: Our results suggest that menopausal age together with Arg194Trp and Arg399Gln XRCC1 gene polymorphisms might be involved in individual susceptibility to breast cancer.     

Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus

Population-based studies have reported significant associations between specific genetic polymorphisms and breast cancer susceptibility. A number of studies have demonstrated that common variants of genes involved in the DNA repair pathway act as low penetrance breast cancer susceptibility alleles. We aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the DNA repair genes XRCC1, XRCC2 and XRCC3 and breast cancer in MASTOS, a population-based case–control study of 1,109 Cypriot women with breast cancer diagnosed between 40 and 70 years and 1,177 age-matched healthy controls. Five coding SNPs were genotyped including rs1799782, rs25489 and rs25487 in XRCC1, rs3218536 in XRCC2 and rs861539 in XRCC3. Homozygous XRCC1 280His carriers had an increased risk of breast cancer (odds ratio 4.68; 95% CI 1.01–21.7; P = 0.03). The XRCC2 188His allele was associated with a marginal protective effect for breast cancer (odds ratio 0.79; 95% CI 0.62–1.00; P = 0.05). No significant associations were observed between the other three SNPs and breast cancer. This study suggests that genetic variation in SNPs in XRCC1 and XRCC2 genes may influence breast cancer susceptibility.     

Association of XRCC1 polymorphisms with thyroid cancer risk

Due to the important role in the DNA repair pathways, numerous studies have been carried out to explore the relationship between the polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene and thyroid cancer risk. But previous reports have produced conflicting results. Thus, we performed an updated comprehensive meta-analysis to better investigate the association of the XRCC1 polymorphisms with thyroid cancer risk. There were a total of nine studies included with 1,621 cases and 3,669 controls examining the effects of the XRCC1 Arg280His, Arg399Gln, and Arg194Trp polymorphisms on the susceptibility of thyroid cancer. In our study, the XRCC1 Arg280His polymorphism was found to be associated with an increased thyroid cancer risk in the Caucasian population [allelic contrast: odds ratio (OR)?=?1.38, 95 % CI?=?1.05–1.80, P(Z)?=?0.02, P(Q)?=?0.61; dominant model: OR?=?1.43, 95 % CI?=?1.08–1.89, P(Z)?=?0.01, P(Q)?=?0.57]. The Arg399Gln polymorphism was associated with a significant decreased risk [allelic contrast: OR?=?0.73, 95 % CI?=?0.59–0.92, P(Z)?=?0.006, P(Q)?=?0.31; dominant model: OR?=?0.73, 95 % CI?=?0.55–0.97, P(Z)?=?0.03, P(Q)?=?0.33; recessive model: OR?=?0.56, 95 % CI?=?0.34–0.93, P(Z)?=?0.02, P(Q)?=?0.59], while the Arg194Trp SNP conferred an increased risk for thyroid cancer in the mixed populations [allelic contrast: OR?=?1.49, 95 % CI?=?1.02–2.17, P(Z)?=?0.04]. To conclude, the present meta-analysis demonstrated that the polymorphisms in the XRCC1 gene may be associated with developing of thyroid cancer.