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Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor. We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods. No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association. Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR = 1.90, 95 % CI: 1.12–3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR = 1.45, 95 % CI: 1.06–1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR = 0.57, 95 % CI: 0.39–0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR = 1.48, 95 % CI: 1.00–2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose–response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33G-allele, POT1-18T-allele, TERF2-03GG, TERT-14CC, and TERT-67TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.

The association between promoter methylation status and survival was investigated in a large cohort of women with breast cancer, participants in the Long Island Breast Cancer Study Project. Archived tumor tissues (n = 839) were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. Vital status was followed through the end of 2005 with a mean follow-up time of 8 years. Promoter methylation of eight breast cancer-related genes was assessed by Methy- Light. The frequencies of methylation for HIN1, RASSF1A, DAPK1, GSTP1, CyclinD2, TWIST, CDH1 and RARb were 62.9, 85.2, 14.1, 27.8, 19.6, 15.3, 5.8 and 27.6%, respec- tively. Since survival rates of in situ and invasive breast cancers are substantially different, survival analyses were conducted within 670 invasive cases with complete data on all genes. Age-adjusted Cox proportional hazards models revealed that GSTP1, TWIST and RARb methylation was significantly associated with higher breast cancer-specific mortality. Methylation of GSTP1 and RARb was signifi- cantly associated with higher all-cause mortality. To investigate the relationship between the number of meth- ylated genes and breast cancer-specific mortality, we included previously published MethyLight data on p16 and APC methylation status. Breast cancer-specific mortality increased in a dose-dependent manner with increasing number of methylated genes (Ptrend = 0.002), although confidence intervals were wide. Our results suggest that promoter methylation, particularly for a panel of genes, has the potential to be used as a biomarker for predicting prognosis in breast cancer.

Differences in incidence, prognosis, and treatment response suggest gene expression patterns may discern breast cancer subtypes with unique risk factor profiles; however, previous results were based predominantly on older women. In this study, we examined similar relationships in women ≤ 56 years, classified by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 for 890 breast cancer cases and 3,432 frequency-matched population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) for tumor subtypes were calculated using multivariate polytomous regression models. A total of 455 (51.1%) tumors were considered luminal A, 72 (8.1%) luminal B, 117 (13.1%) non-luminal HER-2/neu+, and 246 (27.6%) triple negative. Triple negative tumors were associated with breast feeding duration (per 6 months: OR = 0.76, 95% CI 0.64-0.90). Among premenopausal women, increasing body size was more strongly associated with luminal B (OR = 1.73, 95% CI 1.07-2.77) and triple negative tumors (OR = 1.67, 95% CI 1.22-2.28). A history of benign breast disease was associated only with increased risk of luminal A tumors (OR = 1.89, 95% CI 1.43-2.50). A family history of breast cancer was a risk factor for luminal A tumors (OR = 1.93, 95% CI 1.38-2.70) regardless of age, and triple negative tumors with higher risks for women

To better understand breast cancer etiology and progression, we explored the association between promoter methylation status of three breast cancer-related genes (BRCA1, APC, and p16) and survival in a large cohort of women with breast cancer. About 800 archived tumor tissues were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. The vital status of the participants was followed through the end of year 2005 with a mean follow-up time of 8.0 years. Promoter methylation was assessed by methylation-specific PCR (for BRCA1) and MethyLight (for APC and p16). The association of promoter methylation and breast cancer mortality was evaluated by Cox-proportional hazards models. Methylated promoters were found in 59.0, 48.4, and 3.6% of the tumor samples for BRCA1, APC, and p16, respectively. Breast cancer-specific mortality was strongly associated with promoter methylation of p16 [HR and 95% CI: 3.53 (1.83-6.78)], whereas the associations with of BRCA1 and APC were less pronounced [HR and 95% CI: 1.81 (1.18-2.78) and 1.46 (0.98-2.17), respectively]. Similar associations were observed with all-cause mortality. As the number of methylated genes increased, the risk of breast cancer-specific mortality also increased in a dose-dependent manner (P, trend = 0.01). Importantly, even with our results stratified by hormone receptor status, promoter methylation of the three genes remained predictive of mortality. Our results suggest that promoter methylation could be promising epigenetic markers to be considered for breast cancer survival.

Promoter-CpG island hypermethylation is a common molecular defect in cancer cells. It has been proposed as an alternative mechanism to inactivate BRCA1in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. We also examined whether dietary methyl content and functional polymorphisms of genes involved in one-carbon metabolism influenced the methylation pattern. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996–1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (p=0.02) and among premenopausal cases (p=0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05–2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02–2.18). Among dietary methyl intakes in the year prior to the baseline interview examined, cases with lowest quintile of choline intake (

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20-2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74-8.70] and OR = 2.52 [1.26-5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82-1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.

p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function. We evaluated whether three well-characterized TP53 variants—Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362)—were associated with breast cancer risk in a population-based case-control study. Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls. For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH–DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27–0.90; OR = 0.42, 95% CI 0.22–0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk. These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.

The gene encoding catechol-O-methyltransferase (COMT), critical to the inactivation of reactive catechol estrogens, has several single nucleotide polymorphisms (SNPs) that influence enzyme activity. A 3-SNP haplotype (IVS1+255 C>T; Ex4-12 G>A; 3′UTR-521 A>G), which has been shown to reduce COMT expression in the human brain, has been identified. To evaluate the influence of genetic variation of COMT on breast cancer risk, these 3-SNPs were genotyped in 1052 cases and 1098 controls. We estimated the associations between breast cancer and individual SNPs, as well as, multilocus haplotypes. We also examined surrogates of hormone exposure as potential modifiers of the putatively functional Ex4-12 SNP-breast cancer association. Odds ratios (OR) and 95% confidence intervals (CI) were based on age-adjusted unconditional logistic regression models. We found no association between the individual SNPs alone and breast cancer. When examining the association between breast cancer and the 3-SNP haplotypes, we observed a 19% increase in risk associated with each copy of the TGG haplotype (OR=1.19, 95% CI 0.96–1.49), relative to the common TAA haplotype, which was statistically significant when assuming a dominant model (OR=1.32, 95% CI 1.05–1.67, p-value=0.02). In this report of COMT haplotypes and breast cancer, we found some evidence that additional genetic variability beyond the Ex4-12 G>A SNP contributes to risk of breast cancer among a small subgroup of women; however, these results need to be replicated in additional studies.

This analysis investigated whether reproductive factors such as age at menarche, parity, and timing and outcomes of pregnancies were associated with survival among women with breast cancer younger than 55 years. Female residents of Atlanta, Georgia, and central New Jersey who were diagnosed with a primary, incident invasive breast cancer between 1990 and 1992 and enrolled in a population-based study (n = 1,264) were followed for 8-10 years. Detailed exposure and covariate information was collected via in-person interviews administered shortly after diagnosis. Vital status as of January 1, 2000 was ascertained through the National Death Index via the state cancer registries (n = 292 deaths). Cox regression methods were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for confounders. Parity of 4 or more births, as compared with nulliparity, was positively associated with all-cause mortality, [HR (95% CI) = 1.71 (1.09-2.67)]. Increased mortality was associated with having given birth within 5 years prior to diagnosis (or=5 vs.5 years) [1.78 (1.28-2.47)], and was more pronounced among women with a pre-diagnostic body mass index of25 kg/m2 [2.54 (1.61-4.00)]. Early age at menarche and early age at first birth also modestly increased mortality; history of miscarriage, induced abortion, and ever breastfeeding were not related to survival. These results may help elucidate breast cancer progression mechanisms and enable a better understanding of how reproductive characteristics influence breast cancer survival.

Reproductive factors have been shown to affect pre- and postmenopausal breast cancer risk differently, but whether there are additional age-specific differences among menopausal women as they age has not been clarified. We analyzed data from a large population-based case-control study that included 1,508 breast cancer cases and 1,556 controls, aged 20-98 years, who completed an in-home interviewer-administered questionnaire. The following subgroups were created to examine if the associations between reproductive factors and breast cancer risk varied by age- and menopausal-status: premenopausal (n=968), postmenopausal65 years (n=1,045), postmenopausalor=65 years (n=958). Among postmenopausal womenor=65 years, ever having breastfed decreased risk (odds ratio (OR)=0.67, 95% confidence interval (CI)=0.48, 0.92), and a strong dose-response relationship was observed for longer durations of breastfeeding (P trend=0.02), with the most pronounced protective effect observed foror=14 months of breastfeeding (OR=0.40, 95% CI=0.21,0.76). Late age at first birth (AFB) and older age at last birth (ALB) were associated with non-statistically significant increases in breast cancer risk in this older group, while late age at menarche and surgical menopause decreased risk. ORs for multiparity were close to the null. Among premenopausal women and postmenopausal women65 years, multiparity significantly decreased risk, and older AFB nonsignificantly increased risk. Our findings suggest that the well-known protective effect of multiparity attenuates with older age. Moreover, breastfeeding, one of the few potentially modifiable risk factors for breast cancer, was an important factor in decreasing risk among older parous postmenopausal women.

Laboratory and bioinformatics studies have suggested that immunoglobulin μ-binding protein 2 (IGHMBP2) is involved in DNA repair, replication and recombination. Using 1067 cases and 1110 controls from a population-based case-control study, we sought to clarify the potential role of the IGHMBP2 Thr671Ala polymorphism (A to G substitution) alone and as a modifier of the effects for cigarette smoking and PAH–DNA adducts on breast cancer risk. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Overall, there was no significant association between the IGHMBP2 variant-G allele and breast cancer risk (OR = 1.1, 95% CI = 0.9–1.3). Increased risk was found among women who had detectable PAH–DNA adducts and carried at least one variant-G allele (OR = 1.4, 95% CI = 1.0–1.8, p for trend = 0.01) compared to women carrying the wild-type AA genotype and with non-detectable adducts. Smokers carrying the IGHMBP2 variant-G allele had no significant increased breast cancer risk compared with non-smoking women with the AA genotype. Heavy smokers (>31 pack years) had a statistically significant association with breast cancer risk (OR=2.0, 95% CI=1.2–3.3) relative to nonsmokers with the AA genotype though the magnitude of association was not different than heavy smokers (> 31 pack years) with the AA genotype (OR=1.6, 95% CI=0.9–2.6). Overall our study observes only modestly higher effect estimates for PAH-DNA adduct exposure and cigarette smoking among those with the high-risk genotype, but these differences are not statistically significant. Additional studies focused on the biological function of the variant-G allele and interactions with other genetic polymorphisms are necessary to confirm our findings.

To determine whether fruit, vegetable, and micronutrient intake 1 year prior to breast cancer diagnosis is associated with a reduction in the subsequent risk of all-cause or breast cancer-specific mortality.Follow-up data from 1,235 invasive breast cancer cases age 25-98 years from the Long Island Breast Cancer Study Project were analyzed. At the 1996-1997 case-control interview, respondents completed a food frequency questionnaire, which assessed dietary intake of fruits, vegetables, and vitamin supplement use in the previous 12 months. All-cause mortality (n=186 deaths) and breast cancer-specific mortality status (n=125 deaths, 67.2%) were determined through December 31, 2002.Hazard ratios (HRs) for all-cause mortality were insignificantly reduced for intake of any fruits, fruit juices, and vegetables (HR=0.68, 95% CI: 0.42-1.09) and leafy vegetables (HR=0.72, 95% CI: 0.41-1.24) among post-menopausal women only. Both of these associations were more pronounced among those with ER+PR+ tumors (HR=0.54, 95% CI: 0.27-1.10, and HR=0.66, 95% CI: 0.33-1.31, respectively). Similar associations were observed for breast cancer-specific mortality.In a cohort of women diagnosed with breast cancer, higher intake of fruits, vegetables, and micronutrients was associated with a non-significant survival advantage in post-menopausal women only.

The Long Island Breast Cancer Study Project is a federally mandated, population-based case-control study to determine whether breast cancer risk among women in the counties of Nassau and Suffolk, NY, is associated with selected environmental exposures, assessed by blood samples, self-reports, and environmental home samples. This report describes the collaborative project's background, rationale, methods, participation rates, and distributions of known risk factors for breast cancer by case-control status, by blood donation, and by availability of environmental home samples. Interview response rates among eligible cases and controls were 82.1% (n = 1,508) and 62.8% (n = 1,556), respectively. Among case and control respondents who completed the interviewer-administered questionnaire, 98.2 and 97.6% self-completed the food frequency questionnaire; 73.0 and 73.3% donated a blood sample; and 93.0 and 83.3% donated a urine sample. Among a random sample of case and control respondents who are long-term residents, samples of dust (83.6 and 83.0%); soil (93.5 and 89.7%); and water (94.3 and 93.9%) were collected. Established risk factors for breast cancer that were found to increase risk among Long Island women include lower parity, late age at first birth, little or no breast feeding, and family history of breast cancer. Factors that were found to be associated with a decreased likelihood that a respondent would donate blood include increasing age and past smoking; factors associated with an increased probability include white or other race, alcohol use, ever breastfed, ever use of hormone replacement therapy, ever use of oral contraceptives, and ever had a mammogram. Long-term residents (defined as 15+ years in the interview home) with environmental home samples did not differ from other long-term residents, although there were a number of differences in risk factor distributions between long-term residents and other participants, as anticipated.