Single nucleotide polymorphisms and the etiology of basal-like and luminal A breast cancer: a pathway-based approach

Genetic models suggest that there are breast cancer-associated genetic variants that remain uncharacterized. Heterogeneity among breast tumors may increase the difficulty of identifying these variants. The intrinsic molecular subtypes of breast cancer are associated with distinct risk factors and survival. Genetic risk factors may also differ by subtype. 312 potentially functional and tag SNPs in candidate genes related to hormone synthesis and signaling (CYP19A1, ESR1, HSD17B2, HSD3B1, PGR, SHBG) and central adiposity (ADIPOQ, LEP, LEPR, IL6, TNF) were genotyped in the Carolina Breast Cancer Study, a population-based study of African-American and white women. Genotype data was available for 1776 of 2022 controls and 1972 of 2311 cases (200 basal-like, 679 luminal A). Data from 144 ancestry informative markers was used to estimate ancestry and adjust for residual population stratification. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between genotypes and breast cancer were estimated using logistic regression. Haplotype ORs and 95% CIs were estimated using HAPSTAT. Genotypes in LEP, LEPR, TNF, CYP19A1, ESR1, HSD3B1, HSD17B2, and PGR were associated with breast cancer overall. Genotypes in ADIPOQ, IL6, LEP, LEPR, ESR1, HSD17B2, HSD3B1, PGR, and SHBG were associated with the luminal A or basal-like subtype. Many associations were stronger when cases were stratified by subtype compared to associations for breast cancer overall. In some cases, such as with the strongest associations in ESR1 and HSD17B2, associations were strong overall and by subtype. Haplotypes in IL6, LEP, LEPR, CYP19A1, ESR1, and PGR were associated with breast cancer overall and by subtype. Waist-hip ratio (WHR) and combined parity and lactation were evaluated as potential effect measure modifiers. Among genotypes and haplotypes displaying evidence of multiplicative or additive interaction, genotype/haplotype associations were weaker among women with higher WHR compared to those with lower WHR. There were no clear patterns of interaction between SNPs and parity and lactation. These results suggest that, for a subset of SNPs, SNP-breast cancer associations differ by intrinsic molecular subtype. Analyzing subtypes as distinct outcomes can increase the likelihood of identifying subtype-specific associations that may have been masked in analyses of breast cancer overall

RASSF1A and the rs2073498 Cancer Associated SNP

RASSF1A is one of the most frequently inactivated tumor suppressors yet identified in human cancer. It is pro-apoptotic and appears to function as a scaffolding protein that interacts with a variety of other tumor suppressors to modulate their function. It can also complex with the Ras oncoprotein and may serve to integrate pro-growth and pro-death signaling pathways. A SNP has been identified that is present in approximately 29% of European populations [rs2073498, A(133)S]. Several studies have now presented evidence that this SNP is associated with an enhanced risk of developing breast cancer. We have used a proteomics based approach to identify multiple differences in the pattern of protein/protein interactions mediated by the wild type compared to the SNP variant protein. We have also identified a significant difference in biological activity between wild type and SNP variant protein. However, we have found only a very modest association of the SNP with breast cancer predisposition

Epidemiologic Risk Factors for In Situ and Invasive Breast Cancers Among Postmenopausal Women in the National Institutes of Health-AARP Diet and Health Study

Comparing risk factor associations between invasive breast cancers and possible precursors may further our understanding of factors related to initiation versus progression. Accordingly, among 190,325 postmenopausal participants in the National Institutes of Health-AARP Diet and Health Study (1995-2011), we compared the association between risk factors and incident ductal carcinoma in situ (DCIS; n = 1,453) with that of risk factors and invasive ductal carcinomas (n = 7,525); in addition, we compared the association between risk factors and lobular carcinoma in situ (LCIS; n = 186) with that of risk factors and invasive lobular carcinomas (n = 1,191). Hazard ratios and 95% confidence intervals were estimated from multivariable Cox proportional hazards regression models. We used case-only multivariable logistic regression to test for heterogeneity in associations. Younger age at menopause was associated with a higher risk of DCIS but lower risks of LCIS and invasive ductal carcinomas (P for heterogeneity < 0.01). Prior breast biopsy was more strongly associated with the risk of LCIS than the risk of DCIS (P for heterogeneity = 0.04). Increased risks associated with use of menopausal hormone therapy were stronger for LCIS than DCIS (P for heterogeneity = 0.03) and invasive lobular carcinomas (P for heterogeneity < 0.01). Associations were similar for race, age at menarche, age at first birth, family history, alcohol consumption, and smoking status, which suggests that most risk factor associations are similar for in situ and invasive cancers and may influence early stages of tumorigenesis. The differential associations observed for various factors may provide important clues for understanding the etiology of certain breast cancers

Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study

Common germline variation in the 5′ region proximal to precursor (pre-) miRNA gene sequences is evaluated for association with breast cancer risk and survival among African Americans and Caucasians

Performance of digital screening mammography in a population-based cohort of black and white women

There is scarce information on whether digital screening mammography performance differs between black and white women

Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects

To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina

Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes

Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case–control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations

Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting

Within ten years after breast cancer diagnosis, 5% of patients develop contralateral primary breast cancer (CBC). Randomized trials have found that tamoxifen and aromatase inhibitors (AIs) reduce CBC risk. However, little is known about the magnitude and duration of protective effects within the context of “real world” clinical management settings, where varying durations and gaps in treatment are common

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P \u3c 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants