Risk factors for breast cancer in women biopsied for benign breast disease: A nested case-control study

Aim: Women with a history of benign breast disease are at increased risk of subsequent breast cancer. However, few studies have examined whether established breast cancer risk factors other than histology are associated with an altered risk of breast cancer in women with benign breast disease. We used a nested case-control design within a large, multi-center cohort of women biopsied for benign breast disease (BBD) to estimate odds ratios for breast cancer in association with exposure to a range of personal and lifestyle factors. Methods: Cases were women biopsied for BBD who subsequently developed breast cancer; controls were individually matched to cases on center and age at diagnosis and were women biopsied for BBD who did not develop breast cancer in the same follow-up interval as that for the cases. After excluding women with prevalent breast cancer, 1357 records (661 case records and 696 records) were available for analysis. We used conditional logistic regression to obtain crude and multivariable-adjusted estimates of the association between specific factors and risk of breast cancer. Results: In multivariable analyses age at first live birth, number of pregnancies, and postmenopausal status were inversely associated with risk of breast cancer. The odds ratio for women with age at first birth <25 years and ≥3 pregnancies, relative to nulliparous women, was 0.49, 95% confidence interval 0.13–0.79, and that for postmenopausal women relative to premenopausal women was 0.60, 95% CI 0.37–0.99. Conclusions: Further study of personal factors influencing the risk of breast cancer in women with BBD may help to identify subgroups of the population at increased risk of invasive disease.     

Increased promoter methylation in exfoliated breast epithelial cells in women with a previous breast biopsy

Accurately identifying women at increased risk of developing breast cancer will provide greater opportunity for early detection and prevention. DNA promoter methylation is a promising biomarker for assessing breast cancer risk. Breast milk contains large numbers of exfoliated epithelial cells that are ideal for methylation analyses. Exfoliated epithelial cells were isolated from the milk obtained from each breast of 134 women with a history of a non-proliferative benign breast biopsy (Biopsy Group). Promoter methylation of three tumor suppressor genes, RASSF1, SFRP1 and GSTP1, was assessed by pyrosequencing of bisulfite-modified DNA. Methylation scores from the milk of the 134 women in the Biopsy Group were compared to scores from 102 women for whom a breast biopsy was not a recruitment requirement (Reference Group). Mean methylation scores for RASSF1 and GSTP1 were significantly higher in the Biopsy than in the Reference Group. For all three genes the percentage of outlier scores was greater in the Biopsy than in the Reference Group but reached statistical significance only for GSTP1. A comparison between the biopsied and non-biopsied breasts of the Biopsy Group revealed higher mean methylation and a greater number of outlier scores in the biopsied breast for both SFRP1 and RASSF1, but not for GSTP1. This is the first evidence of CpG island methylation in tumor suppressor genes of women who may be at increased risk of developing breast cancer based on having had a prior breast biopsy.     

Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort

Background

While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk.

Methods and Findings

We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; p _trend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, p _trend = 0.01), even after full adjustment (HR = 1.34, p _trend = 0.03; p _homogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; p _trend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; p _trend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD.

Conclusions

Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms. Please see later in the article for the Editors'' Summary     

Risk factors and risk reduction of breast cancer

Because of its increasing incidence, breast cancer is a significant burden for women worldwide. In industrialized countries, breast cancer is the second-leading cause of cancer-related deaths among women, and it is estimated that 1 in every 8 women will develop the disease during her lifetime. Sufficient evidence indicates that a number of genetic, environmental and lifestyle risk exposures during life may play important roles in the etiology of this disease. The purpose of this paper is to review some etiologic factors and underlying mechanisms in relation to breast cancer risk. Based on the published literature, there is sufficient evidence that some established factors are associated with breast cancer risk. Age, early age at menarche, late menopause, height, post-menopausal obesity, family history of breast cancer, ionizing radiation, oral contraceptives, hormonal replacement therapy, mammographic density, some gene mutations and clinical conditions, such as benign breast disease, are associated with an increased risk of breast cancer. The risk decreases with early childbearing, high parity and physical activity, and breastfeeding. Alcohol increases the risk, while caloric restriction may confer protection from breast cancer. Epidemiological evidence for other nutritional factors is insufficient. These results suggest that breast cancer is a multifactorial disease where genetic susceptibility, environment, nutrition and other lifestyle risk factors interact. Better identification of modifiable risk factors and risk reduction of breast cancer may allow implementation of useful strategies for prevention.     

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans

Differences in the composition of the gut microbial community have been associated with diseases such as obesity, Crohn''s disease, ulcerative colitis and colorectal cancer (CRC). We used 454 titanium pyrosequencing of the V1–V2 region of the 16S rRNA gene to characterize adherent bacterial communities in mucosal biopsy samples from 33 subjects with adenomas and 38 subjects without adenomas (controls). Biopsy samples from subjects with adenomas had greater numbers of bacteria from 87 taxa than controls; only 5 taxa were more abundant in control samples. The magnitude of the differences in the distal gut microbiota between patients with adenomas and controls was more pronounced than that of any other clinical parameters including obesity, diet or family history of CRC. This suggests that sequence analysis of the microbiota could be used to identify patients at risk for developing adenomas.     

Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients

Early onset in bipolar disorder (BPD) has been associated with greater familial risk and unfavorable clinical outcomes. We pooled data from seven international centers to analyze the relationships of family history and symptomatic as well as functional measures of adult morbidity to onset age, or onset in childhood (age <12), adolescence (12-18), or adulthood (19-55 years). In 1,665 adult, DSM-IV BPD-I patients, onset was 5% in childhood, 28% in adolescence, and 53% at peak ages 15-25. Adolescent and adult onset did not differ by symptomatic morbidity (episodes/year, percentage of months ill, co-morbidity, hospitalization, suicide attempts) or family history. Indications of favorable adult functional outcomes (employment, living independently, marriage and children, and a composite measure including education) ranked, by onset: adult > adolescent > child. Onset in childhood versus adolescence had more episodes/year and more psychiatric co-morbidity. Family history was most prevalent with childhood onset, similar over onset ages 12-40 years, and fell sharply thereafter. Multivariate modeling sustained the impression that family history and poor functional, but not symptomatic, outcomes were associated with younger, especially childhood onset. Early onset was more related to poor functional outcomes than greater symptomatic morbidity, with least favorable outcomes and greater family history with childhood onset.     

Obesity in post menopausal women with a family history of breast cancer: prevalence and risk awareness

Background

Obesity and physical activity are modifiable risk factors in the development of post-menopausal breast cancer. The aim of this study was to assess the level of awareness and prevalence of these factors in women attending family history clinics.

Methods

Women attending the breast cancer family history clinic from 2004 to 2006 completed a questionnaire (SP15 format) about their knowledge of and exposure to various diet and lifestyle factors. All women had been counselled by a Consultant Cancer Geneticist and were given verbal and written information on the effect of life style on breast cancer risk. Responses were analysed using SPSS? software.

Results

The response rate was 70% and two thirds of women were post-menopausal. The prevalence of obesity in post-menopausal women was 37% with 40% being overweight. The majority of women consumed a healthy balanced diet. Only 15% of post-menopausal women exercised for more than 4 hours per week. Two-thirds of women correctly stated that obesity increases their breast cancer risk and 73% of these were overweight or obese. Over 87% were correctly aware of the role of family history, 68% of a high fat diet, and 57% of hormone replacement therapy in the development of breast cancer.

Conclusion

Women attending family history clinics lead a high risk lifestyle for the development of breast cancer with high prevalence of obesity and low levels of physical activity. A campaign of patient education is needed to promote healthy lifestyle choices, especially physical activity, in these high-risk women.

     

Understanding breast cancer risk ‐ where do we stand in 2005?

Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.     

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

Value of the history in the office diagnosis of breast cancer.

A review of the histories of 1059 patients with breast problems seen consecutively in office consultation revealed an incidence of breast cancer of 13%. Patients over 50 years of age or whose mother or sister had had breast cancer had a substantially greater likelihood of having breast cancer. The finding of the problem on routine examination, a family history of breast cancer in a relative other than the mother or a sister, or prominent breast pain or nipple discharge made the diagnosis of cancer less likely. Menstrual status, a history of previous benign disease, nulliparity, current hormone therapy and duration of symptoms did not help identify the patient likely to have breast cancer. Much time could be saved for both doctor and patient in taking the history from patients with breast disorders. Only the patient''s age and the history of the mother and sisters with regard to breast cancer will help identify the "high-risk" patient. Other historical findings are either valueless or should be used to reassure these usually anxious women.     

Reproductive events and family history as risk factors for breast cancer in northern Alberta.

Reproductive events and family history as risk factors for breast cancer in northern Alberta were investigated with the use of data from a computerized population-based registry. Women aged 30 to 79 years attending diagnostic breast clinics at the Cross Cancer Institute from 1971 through 1975 constituted the two study groups; 1232 women had diagnosed breast cancer (malignant disease group) and 602 women were clinically free of all types of breast disease (control group). An increased relative risk of breast cancer was found in women with a family history of breast cancer, those who gave birth to their first term infant at age 30 years or older, those in whom more than 15 years elapsed between menarche and that birth, and those with a late natural menopause. There was a decreased risk, relative to nulliparity, in the postmenopausal women who first gave birth to a term infant 5 years or less after menarche. Artificial menopause (bilateral oophorectomy), parity and age at menarche had no apparent effect on the risk. The pattern of risk factors in northern Alberta differed from that reported for other geographic areas, including other provinces of Canada, thus emphasizing the need for local studies in the planning of screening programs.     

Circulating High-Molecular-Weight (HMW) Adiponectin Level Is Related with Breast Cancer Risk Better than Total Adiponectin: A Case-Control Study

The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer (P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk (P=0.020, 0.014, 0.035) in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk (P=0.034, 0.0116). This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed.     

What Is the Optimal Threshold at Which to Recommend Breast Biopsy?

Background

A 2% threshold, traditionally used as a level above which breast biopsy recommended, has been generalized to all patients from several specific situations analyzed in the literature. We use a sequential decision analytic model considering clinical and mammography features to determine the optimal general threshold for image guided breast biopsy and the sensitivity of this threshold to variation of these features.

Methodology/Principal Findings

We built a decision analytical model called a Markov Decision Process (MDP) model, which determines the optimal threshold of breast cancer risk to perform breast biopsy in order to maximize a patient’s total quality-adjusted life years (QALYs). The optimal biopsy threshold is determined based on a patient’s probability of breast cancer estimated by a logistic regression model (LRM) which uses demographic risk factors (age, family history, and hormone use) and mammographic findings (described using the established lexicon–BI-RADS). We estimate the MDP model''s parameters using SEER data (prevalence of invasive vs. in situ disease, stage at diagnosis, and survival), US life tables (all cause mortality), and the medical literature (biopsy disutility and treatment efficacy) to determine the optimal “base case” risk threshold for breast biopsy and perform sensitivity analysis. The base case MDP model reveals that 2% is the optimal threshold for breast biopsy for patients between 42 and 75 however the thresholds below age 42 is lower (1%) and above age 75 is higher (range of 3–5%). Our sensitivity analysis reveals that the optimal biopsy threshold varies most notably with changes in age and disutility of biopsy.

Conclusions/Significance

Our MDP model validates the 2% threshold currently used for biopsy but shows this optimal threshold varies substantially with patient age and biopsy disutility.     

The Effect of Breast‐Feeding with and without Formula Use on the Risk of Obesity at 4 Years of Age

Objective: To determine the minimal duration of breast‐feeding required to protect against later obesity, whether the concurrent use of formula lessened any protective effect of breast‐feeding, and what maternal or child characteristics might modify the association between breast‐feeding and child obesity. Research Methods and Procedures: This was a retrospective cohort study. Participants were 73, 458 white and black low‐income children followed from birth through 4 years of age. Obesity at age 4 years was defined as measured BMI ≥ 95th percentile. Feeding exposure was based on breast‐feeding duration and the age of formula initiation. Covariates were obtained from the children's birth certificates. Results: At age 4 years, the prevalence of obesity was 11.5%. Only 16% of children were breast‐fed 8 weeks or longer. Breast‐feeding was associated with a reduced risk of obesity only in white children whose mothers had not smoked in pregnancy. In this subgroup, the reduction in obesity risk (adjusted odds ratio, 95% confidence interval), compared with those never breast‐fed, occurred only for children who were breast‐fed at least 16 weeks without formula (0.71, 0.56 to 0.92) or at least 26 weeks with concurrent formula (0.70, 0.61 to 0.81). Among whites whose mothers smoked in pregnancy and among blacks, breast‐feeding was not associated with a reduced risk of obesity at age 4 years. Discussion: In a population of low‐income children, breast‐feeding was associated with a reduced risk of obesity at age 4 years only among whites whose mothers did not smoke in pregnancy and only when breast‐feeding continued for at least 16 weeks without formula or at least 26 weeks with formula.     

Oral Contraceptives and Breast Neoplasia: A Retrospective Study

Between 1 December 1968 and 31 December 1971 345 women aged 16-39 years with a lump in the breast (90 malignant and 255 benign) were interviewed at five London teaching hospitals together with 347 matched controls suffering from acute medical or surgical conditions or admitted to hospital for routine elective surgery. Questions were asked about each patient''s medical, obstetric, menstrual, contraceptive, and social histories.The data do not suggest that the use of oral contraceptives is related in any way to the risk of breast cancer but provide some evidence that the preparations may actually protect against benign breast disease. This protective effect is largely confined to women who continue to use oral contraceptives and have used them altogether for more than two years. Such women appear to have only about 25% as great a risk of being admitted to hospital for a breast biopsy as women who have never used oral contraceptives at all.     

Additive Interactions of Maternal Prepregnancy BMI and Breast‐feeding on Childhood Overweight

Objective: To examine the interactions of maternal prepregnancy BMI and breast‐feeding on the risk of overweight among children 2 to 14 years of age. Research Methods and Procedures: The 1996 National Longitudinal Survey of Youth, Child and Young Adult data in the United States were analyzed (n = 2636). The weighted sample represented 51.3% boys, 78.0% whites, 15.0% blacks, and 7.0% Hispanics. Childhood overweight was defined as BMI ≥95th percentile for age and sex. Maternal prepregnancy obesity was determined as BMI ≥30 kg/m². The duration of breast‐feeding was measured as the weeks of age from birth when breast‐feeding ended. Results: After adjusting for potential confounders, children whose mothers were obese before pregnancy were at a greater risk of becoming overweight [adjusted odds ratio (OR), 4.1; 95% confidence interval (CI), 2.6, 6.4] than children whose mothers had normal BMI (<25 kg/m²; p < 0.001 for linear trend). Breast‐feeding for ≥4 months was associated with a lower risk of childhood overweight (OR, 0.6; 95% CI, 0.4, 1.0; p = 0.06 for linear trend). The additive interaction between maternal prepregnancy obesity and lack of breast‐feeding was detected (p < 0.05), such that children whose mothers were obese and who were never breast‐fed had the greatest risk of becoming overweight (OR, 6.1; 95% CI, 2.9, 13.1). Discussion: The combination of maternal prepregnancy obesity and lack of breast‐feeding may be associated with a greater risk of childhood overweight. Special attention may be needed for children with obese mothers and lack of breast‐feeding in developing childhood obesity intervention programs.     

O‐6RESPECTIVE ROLES OF FINE NEEDLE ASPIRATION CYTOLOGY AND CORE BIOPSY IN DIAGNOSIS OF SYMPTOMATIC BREAST LESIONS

Introduction: To evaluate and compare the respective roles of fine needle aspiration cytology and core biopsy for diagnosis of symptomatic breast lesions. Methods: Retrospective study on 589 breast fine needle aspiration cytology (FNAC) cases and 88 core biopsies (CB) with no associated FNAC, performed between January and December 2004. A computer database was searched for initial results, subsequent investigations and outcomes. Results: Of the cases that had FNAC performed as an initial investigation, the final diagnosis was reached by FNAC alone in 81.8% of cases. Of these, 59.2% were benign, 6.1% malignant and 2.4% remaining suspicious with 14.1% inadequate samples. There were 31 cases reported as suspicious (C3/C4) on FNAC, of these 14% of C3 and all of C4 were malignant on CB. Of the 86 cases that had both FNAC and CB, CB improved on the FNAC diagnosis of malignancy in 19.8% of cases, half of which were considered inadequate on FNAC. The positive predictive value of malignant cases was 100%, and the negative predictive value 98%. The absolute sensitivity of FNAC in this study was 65% and complete sensitivity 72%. The false negative rate was 8% and false positive rate 0%. The diagnosis of 88 CB without FNAC showed 37.5% to be malignant and 60.2% as benign, with 2.3% as inadequate biopsies. Discussion: FNAC remains the first line investigation in symptomatic breast lesions. Its best use is in the diagnosis of benign disease which constitutes over two thirds of patients in our practice. In suspicious and clinically malignant lesions, it is complemented by CB which may provide additional information relevant to management. In conclusion, the majority benign findings in our patients who had CB without prior FNAC, does not justify the use of CB as a first line investigation. CB is indicated in cases of inadequate or suboptimal FNAC. The continuous use of suspicious categories (C3/C4) in breast cytology is justified by the subsequent outcomes, both benign and malignant.     

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.     

DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil

Several studies have reported that the genes involved in DNA repair and in the maintenance of genome integrity play a crucial role in protecting against mutations that lead to cancer. Epidemiologic evidence has shown that the inheritance of genetic variants at one or more loci results in a reduced DNA repair capacity and in an increased risk of cancer. Polymorphisms have been identified in several DNA repair genes, such as XRCC1, XPD, XRCC3, and RAD51, but the influence of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. This was a case-control study design with three case groups: 53 women with breast cancer and family history; 33 women with sporadic breast cancer; 175 women with no breast cancer but with family history. The control group included 120 women with no breast cancer and no family history. The PCR-RFLP method was used to analyze the XRCC1-Arg399Gln, XPD-Lys751Gln, XRCC3-Thr241Met, and RAD51-G135C polymorphisms. No statistically significant differences were found between the case groups and the control group for any of the polymorphisms analyzed, and also between the breast cancer and family history group and the sporadic breast cancer group. Sample sizes of women with breast cancer, whether familial or sporadic, were insufficient to show any small true differences between the groups, but we have to consider that currently there is no clear consensus with respect to the association of these polymorphisms with breast cancer risk. Considering the data available, it can be conjectured that if there is any risk association between these single-nucleotide polymorphisms and breast cancer, this risk will probably be minimal. The greater the risk associated with cancer, the smaller the sample size required to demonstrate this association, and the data of different studies are usually, therefore, more concordant.     

Differences in DNA methylation by extent of breast cancer family history in unaffected women

Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = ?46.8%, 0.1%), 17.9% (95%CI = ?39.5%, 3.7%) and 11.4% (95% CI = ?20.3%, ?2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = ?28.8%, ?7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors.