Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from heathy women.

Single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and BMI, was used to identify differentially-methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR, and TYMS (P <5.0 x 10-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r=-0.25, P=0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR, and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome-wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as cis-methylation quantitative trait loci.

Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues.

p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.

Plasma IGF-1 and IGFBP-3 may be imprecise surrogates for breast concentrations: an analysis of healthy women.

We investigated insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations in histologically normal breast tissues and assessed their association with plasma concentrations, and breast cancer risk factors. IGF-1 and IGFBP-3 were assessed in plasma and breast tissues of 90 women with no history of any cancer and undergoing reduction mammoplasty. Pearson correlations and ANOVAs were used to describe plasma-breast associations and biomarker differences by breast cancer risk factors, respectively. Multivariable regression models were used to determine associations between risk factors, and breast IGF-1 and IGFBP-3. The mean age of the study sample was 37.3 years, 58 % were white, and generally these women were obese (mean BMI = 30.8 kg/m(2)). We observed no plasma-breast correlation for IGF-1, IGFBP-3, or IGF-1/IGFBP-3 (r = -0.08, r = 0.14, and r = 0.03, respectively; p-values >0.05). Through age- and BMI-adjusted analysis, BMI and years of oral contraceptive (OC) use were inversely associated with breast IGF-1 (p-values = 0.02 and 0.003, respectively) and age was associated with breast IGFBP-3 (p = 0.01), while breast IGF-1/IGFBP-3 was higher in blacks than whites (1.08 vs. 0.68, p = 0.04) and associated with age and BMI (p-values = 0.03 and 0.002, respectively). In multivariable-adjusted models, some breast cancer risk factors studied herein explained 24, 10, and 15 % of the variation in breast IGF-1, IGFBP-3, and IGF-1/IGFBP-3, respectively. While reasons for the lack of plasma-breast hormone correlations in these cancer-free women are unknown, several factors were shown to be associated with breast concentrations. The lack of correlation between blood and tissue IGF-1 and IGFBP-3 suggests that studies of breast cancer risk assessing blood IGF-1 and IGFBP-3 may have important limitations in understanding their role in breast carcinogenesis.

Association of Rad51 polymorphism with DNA repair in BRCA1 mutation carriers and sporadic breast cancer risk.

BACKGROUND: Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) than women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer. METHODS: Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls). RESULTS: Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study. CONCLUSIONS: Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.

Epigenetic targets in cancer epidemiology.

Recently, it has been shown that epigenetic changes are involved in early stages of tumorigenesis, and they may trigger the genetic events leading to tumor development. In cancer epidemiology, there are several epigenetic alterations involved, such as DNA hypermethylation, DNA hypomethylation, and chromatin modifications with critical roles in the initiation and progression of human neoplasms. This chapter discusses the hypermethylation profiles of several tumor types, including bladder, brain, breast, colorectal, ovarian, prostate, and other cancers as well as DNA hypomethylation phenomena together with the chromatin modifications and their role in the complex mechanism of epigenetic silencing. Moreover, the involvement of environmental exposures in cancer susceptibility is addressed. In conclusion, these epigenetic changes are important characteristics of human neoplasia, and a better understanding of these modifications and the link between these changes for each tumor type will be important in early diagnosis of cancer and cancer prevention.

Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells.

DNA alterations in mitochondria are believed to play a role in carcinogenesis and are found in smoking-related cancers. We sought to replicate earlier findings for the association of smoking with increased mitochondrial DNA (mtDNA) content in buccal cells and further hypothesized that there would be an increased number of somatic mtDNA mutations in smokers. Buccal cells and blood lymphocytes were studied from 42 healthy smokers and 30 non-smokers. Temporal temperature gradient electrophoresis screening and sequencing was used to identify mtDNA mutations. The relative mtDNA content was determined by real-time polymerase chain reaction. Assuming that mtDNA in lymphocytes represents the inherited sequence, it was found that 31% of smokers harbored at least one somatic mtDNA mutation in buccal cells with a total of 39 point mutations and 8 short deletions/insertions. In contrast, only 23% of non-smokers possessed mutations with a total of 10 point mutations and no insertions/deletions detected. mtDNA somatic mutation density was higher in smokers (0.68/10 000 bp per person) than in non-smokers (0.2/10 000 bp per person). There was a statistically significant difference in the pattern of homoplasmy and heteroplasmy mutation changes between smokers and non-smokers. Whereas non-smokers had the most mutations in D-loop region (70%), smokers had mutations in both messenger RNA encoding gene (36%) and D-loop region (49%). The mean ratio of buccal cells to lymphocytes of mtDNA content in smokers was increased (2.81) when compared with non-smokers (0.46). These results indicate that cigarette smoke exposure affects mtDNA in buccal cells of smokers. Additional studies are needed to determine if mitochondrial mutation assays provide new or complementary information for estimating cigarette smoke exposure at the cellular level or as a cancer risk biomarker.

Early Epigenetic Markers for Precision Medicine.

Over the last years, epigenetic changes, including DNA methylation and histone modifications detected in early tumorigenesis and cancer progression, have been proposed as biomarkers for cancer detection, tumor prognosis, and prediction to treatment response. Importantly for the clinical use of DNA methylation biomarkers, specific methylation signatures can be detected in many body fluids including serum/plasma samples. Several of these potential epigenetic biomarkers detected in women's cancers, colorectal cancers, prostate, pancreatic, gastric, and lung cancers are discussed. Studies conducted in breast cancer, for example, found that aberrant methylation detection of several genes in serum DNA and genome-wide epigenetic change could be used for early breast cancer diagnosis and prediction of breast cancer risk. In colorectal cancers, numerous studies have been conducted to identify specific methylation markers important for CRC detection and in fact clinical assays evaluating the methylation status of SEPT19 gene and vimentin, became commercially available. Furthermore, some epigenetic changes detected in gastric washes have been suggested as potential circulating noninvasive biomarkers for the early detection of gastric cancers. For the early detection of prostate cancer, few epigenetic markers have shown a better sensitivity and specificity than serum PSA, indicating that the inclusion of these markers together with current screening tools, could improve early diagnosis and may reduce unnecessary repeat biopsies. Similarly, in pancreatic cancers, abnormal DNA methylation of several genes including NPTX2, have been suggested as a diagnostic biomarker. Epigenetic dysregulation was also observed in several tumor suppressor genes and miRNAs in lung cancer patients, suggesting the important role of these changes in cancer initiation and progression. In conclusion, epigenetic changes detected in biological fluids could play an essential role in the early detection of several cancer types and this may have a great impact for the cancer precision medicine field.

Interplay Between Genetic and Epigenetic Changes in Breast Cancer Subtypes.

Breast cancer is the most common cancer among women and represents one of the top five leading causes of cancer-related mortality. Inherited and acquired genetic mutations as well as epigenetic aberrations are known to be important contributors to the development and progression of breast cancer. Recent developments in high-throughput technologies have increased our understanding of the molecular changes in breast cancer, leading to the identification of distinctive genetic and epigenetic modifications in different breast cancer molecular subtypes. These genetic and epigenetic changes in luminal A, luminal B, ERBB2/HER2-enriched, basal-like, and normal-like breast cancer subtypes are discussed in this chapter. Furthermore, recent epigenome studies provided more information about further stratification of breast cancer subtypes, with essential role in the appropriate diagnosis and treatment of breast cancer. Thus, the inclusion of both genetic and epigenetic information in breast cancer clinical care could provide critical scientific base for precision medicine in breast cancer.

Alcohol-Induced Epigenetic Changes in Cancer.

Chronic, heavy alcohol consumption is associated with serious negative health effects, including the development of several cancer types. One of the pathways affected by alcohol toxicity is the one-carbon metabolism. The alcohol-induced impairment of this metabolic pathway results in epigenetic changes associated with cancer development. These epigenetic changes are induced by folate deficiency and by products of the ethanol metabolism. The changes induced by long-term heavy ethanol consumption result in elevations of homocysteine and S-adenosyl-homocysteine (SAH) and reductions in S-adenosylmethionine (SAM) and antioxidant glutathione (GSH) levels, leading to abnormal promoter gene hypermethylation, global hypomethylation, and metabolic insufficiency of antioxidant defense mechanisms. In addition, reactive oxygen species (ROS) generated during the ethanol metabolism induce alterations in DNA methylation patterns that play a critical role in cancer development. Specific epigenetic changes in esophageal, hepatic, and colorectal cancers have been detected in blood samples and proposed to be used clinically as epigenetic biomarkers for diagnosis and prognosis of these cancers. Also, genetic variants of genes involved in one-carbon metabolism and ethanol metabolism were found to modulate the relationship between alcohol-induced epigenetic changes and cancer risk. Furthermore, alcohol metabolism products have been associated with an increase in NADH levels, which lead to histone modifications and changes in gene expression that in turn influence cancer susceptibility. Chronic excessive use of alcohol also affects selected members of the family of microRNAs, and as miRNAs could act as epigenetic regulators, this may play an important role in carcinogenesis. In conclusion, targeting alcohol-induced epigenetic changes in several cancer types could make available clinical tools for the diagnosis, prognosis, and treatment of these cancers, with an important role in precision medicine.

MicroRNAs Role in Prostate Cancer.

Prostate cancer still represents a major health problem for men worldwide. Due to the specific limitation of the currently used clinical biomarkers for prostate cancer, there is a need to identify new and more accurate prostate-specific biomarkers, both for diagnosis and prediction. Small noncoding species of RNAs called microRNAs (miRNAs) have emerged as possible biomarkers in cancer tissues as well as biological fluids, including for prostate cancer. Moreover, it has been shown that miRNAs could be used as therapeutic targets in different cancer types, including prostate cancer, playing an important role in improving diagnosis and prognosis; and miRNAs have the potential to be clinically useful as predictors of response to personalized cancer therapy and as predictors of prognosis. The analysis of miRNAs in prostate tissue is rather straightforward and has been routinely done on fresh tissue. In addition, due to the more stable nature of miRNAs, they are amenable to be analyzed in archived formalin fixed paraffin embedded tissue as well, and also in serum, plasma and urine, using various analytical platforms including microarrays, next generation sequencing and real time PCR. Moreover, although the existence or prostasomes (microvesicles secreted by prostate cells including prostate cancer cells) has been known for years and they were studied as a source of biomarkers for prostate cancer, only recently it has been described that these vesicles also contain miRNAs that could be used as biomarkers in prostate cancer. This chapter underscores the feasibility of current technologies for miRNA analysis and their importance in prostate cancer biology. Moreover, elucidating the specific alteration of miRNA expression and how to modulate it in prostate tissue will open new avenues for developing therapeutic strategies for prostate cancer treatment.

Discovery and replication of microRNAs for breast cancer risk using genome-wide profiling.

BACKGROUND: Genome-wide miRNA expression may be useful for predicting breast cancer risk and/or for the early detection of breast cancer. RESULTS: A 41-miRNA model distinguished breast cancer risk in the discovery study (accuracy of 83.3%), which was replicated in the independent study (accuracy = 63.4%, P=0.09). Among the 41 miRNA, 20 miRNAs were detectable in serum, and predicted breast cancer occurrence within 18 months of blood draw (accuracy 53%, P=0.06). These risk-related miRNAs were enriched for HER-2 and estrogen-dependent breast cancer signaling. MATERIALS AND METHODS: MiRNAs were assessed in two cross-sectional studies of women without breast cancer and a nested case-control study of breast cancer. Using breast tissues, a multivariate analysis was used to model women with high and low breast cancer risk (based upon Gail risk model) in a discovery study of women without breast cancer (n=90), and applied to an independent replication study (n=71). The model was then assessed using serum samples from the nested case-control study (n=410). CONCLUSIONS: Studying breast tissues of women without breast cancer revealed miRNAs correlated with breast cancer risk, which were then found to be altered in the serum of women who later developed breast cancer. These results serve as proof-of-principle that miRNAs in women without breast cancer may be useful for predicting breast cancer risk and/or as an adjunct for breast cancer early detection. The miRNAs identified herein may be involved in breast carcinogenic pathways because they were first identified in the breast tissues of healthy women.

The etiology of alcohol-induced breast cancer.

Breast cancer is the most common cancer in women in the United States, and it is second among cancer deaths in women. Results of most epidemiologic studies, as well as of most experimental studies in animals, have shown that alcohol intake is associated with increased breast cancer risk. Alcohol consumption may cause breast cancer through different mechanisms, including through mutagenesis by acetaldehyde, through perturbation of estrogen metabolism and response, and by inducing oxidative damage and/or by affecting folate and one-carbon metabolism pathways. Alcohol-metabolizing enzymes are present in human breast tissue. Acetaldehyde is a known, although weak, mutagen. However, results of some studies with human subjects implicate this agent in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species, resulting from ethanol metabolism, may be involved in breast carcinogenesis by causing damage, as well as by generating DNA and protein adducts. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. With regard to one-carbon metabolism, alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some study results indicate that genetic variants of one-carbon metabolism genes might increase alcohol-related breast cancer risk. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation.

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women.

Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) and AAs (n = 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer.

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues.

Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

Genetic variation in adipokine genes and associations with adiponectin and leptin concentrations in plasma and breast tissue.

BACKGROUND: Circulating adipokines may be associated with breast cancer risk. Genetic variants governing adipokines and adipokine receptors may also predict risk, but their effect on breast adipokine concentrations is unknown. METHODS: We conducted a cross-sectional analysis of functional SNPs in 5 adipokine genes [adiponectin, leptin (LEP), and their receptors] among 85 cancer-free women who were undergoing reduction mammoplasty. RESULTS: In multivariable-adjusted regression models, compared with the common GG genotype, the AA genotype of the LEP A19G SNP was associated with 27% lower plasma adiponectin [ratio, 0.73; 95% confidence interval (CI), 0.54-0.98] and leptin (ratio, 0.73; 95% CI, 0.55-0.96). Women with the AG genotype of LEP A19G had 39% lower breast leptin (ratio, 0.61; 95% CI, 0.39-0.97) compared with those with the GG genotype. No associations were observed for SNPs in the remaining genes. CONCLUSIONS: Genetic variation in LEP may alter endogenous adipokine concentrations in circulation and in breast tissues. IMPACT: These preliminary findings may support the hypothesis that genetic variation in adipokine genes modifies circulating adipokine concentrations and possibly leptin concentrations in local breast tissues, which may be associated with breast cancer risk.

Epigenetic markers of early tumor development.

Cancer patients' outcome and survival depends on the early diagnosis of malignant lesions. Several investigation methods used for the prevention and early detection strategies have specific limitations. More recently, epigenetic changes have been considered one of the most promising tools for the early diagnosis of cancer. Some of these epigenetic alterations including promoter hypermethylation of genes like P16INK4a, BRCA1, BRCA2, ERα and RARß2, APC, and RASSF1A have been associated with early stages of mammary gland tumorigenesis and have been suggested to be included in the models that evaluate individual breast cancer risk. In lung cancer, P16INK4a and MGMT gene hypermethylation was observed in sputum years before clinical manifestation of the squamous cell carcinoma among smokers. Loss of GSTP1 function by DNA hypermethylation together with changes in the methylation levels of repetitive elements like LINE-1 and Sat2 was reported in prostatic preneoplastic lesions. Also, DNA hypermethylation for hMLH1 and MGMT DNA repair genes was reported in precursor lesions to colorectal cancer. These epigenetic alterations may be influenced by factors such as xenoestrogens, folate, and multivitamins. Detection of these changes may help determining cancer susceptibility and early diagnosis.

DNA methylation and histone modifications in breast cancer.

Breast cancer is caused by progressive genetic alterations and epigenetic changes that trigger tumor development. Among the epigenetic alterations descried in breast cancer, DNA promoter methylation has been extensively studied and observed in genes involved in several critical signaling pathways that initiate and promote breast tumorigenesis. In addition to DNA hypermethylation, global methylation levels have been observed to decrease with breast cancer progression. In close connection with DNA methylation changes, histone modifications, especially the acetylation and methylation of histone lysines, play an essential role in the nucleosomes remodeling and gene expression regulation in breast cancer.

Nutrigenomics: implications for breast and colon cancer prevention.

Nutrigenomics refers to the interaction between one's diet and his/her genes. These interactions can markedly influence digestion, absorption, and the elimination of bioactive food components, as well as influence their site of actions/molecular targets. Nutrigenomics comprises nutrigenetics, epigenetics, and transcriptomics, coupled with other "omic," such as proteomics and metabolomics, that apparently account for the wide variability in cancer risk among individuals with similar dietary habits. Multiple food components including essential nutrients, phytochemical, zoochemicals, fungochemical, and bacterochemicals have been implicated in cancer risk and tumor behavior, admittedly with mixed results. Such findings suggest that not all individuals respond identically to a diet. This chapter highlights the influence of single-nucleotide polymorphism, copy number, epigenetic events, and transcriptomic homeostasis as factors influencing the response to food components and ultimately health, including cancer risk. Both breast and colorectal cancers are reviewed as examples about how nutrigenomics may influence the response to dietary intakes. As the concept that "one size fits all" comes to an end and personalized approaches surface, additional research data will be required to identify those who will benefit most from dietary change and any who might be placed at risk because of an adjustment.

Adipokines in plasma and breast tissues: associations with breast cancer risk factors.

BACKGROUND: Blood adipokines are associated with breast cancer risk; however, blood-breast adipokine correlations and factors that explain variation in adipokines are unknown. METHODS: Plasma (n = 155) and breast (n = 85) leptin and adiponectin were assessed by immunoassays in women with no history of cancer. Multivariable-adjusted regression models were used to determine breast adipokine associations. RESULTS: Through body mass index (BMI)-adjusted analyses, we initially observed positive plasma-breast correlations for leptin (r = 0.41, P = 0.0002) and adiponectin (r = 0.23, P = 0.05). The positive plasma-breast correlation for leptin was strongest among normal weight women (r = 0.62), whereas the correlation for adiponectin was strongest among obese women (r = 0.31). In multivariable models, adjusting for BMI, demographic, reproductive, and lifestyle factors, plasma leptin was not associated with breast leptin, and only the highest quartile of plasma adiponectin was associated with tissue levels. Of the risk factors investigated, those that contributed most to the variation in breast tissue adipokines were BMI and race for leptin, oral contraceptive use and smoking status for adiponectin. CONCLUSIONS: Although we report positive plasma-breast adipokine correlations overall, plasma adipokine concentrations may not be good surrogates for breast concentrations among all women. Predictors of breast adipokines vary, depending on subject characteristics, possibly explaining inconsistent epidemiologic results and they implicate differing pathways toward carcinogenesis. IMPACT: A clearer understanding of the relationships between plasma adipokines and their levels within the target organ is necessary to better understand the impact of these hormones on breast cancer risk. Future studies are needed to identify additional factors associated with breast adipokines in target tissues.