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1.  Progesterone receptor isoform-specific promoter methylation — Association of PRA promoter methylation with worse outcome in breast cancer patients 
ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
Experimental Design
We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n=500), and in patients who underwent surgery only (n=500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this study shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.
PMCID: PMC3955277  PMID: 21459801
2.  Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping 
Journal of hypertension  2012;30(10):1970-1976.
Genetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure, BMI, and HDL-C.
This study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, where ancestry association evidence for hypertension, BMI or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1,733 unrelated African-Americans from the National Heart, Lung and Blood Institute’s (NHLBI) Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age2, sex, local marker ancestry, and BMI, as applicable. An individual’s African ancestry estimated from 2,507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.
CXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (p < 0.0006). F2RL1 (rs631465) on chromosome 5 was associated with BMI (p = 0.0005). Local ancestry in these regions was associated with the respective traits as well.
This study suggests that CXADR and F2RL1 likely play important roles in blood pressure and obesity variation, respectively; and these findings are consistent with other studies, so replication and functional analyses are necessary.
PMCID: PMC3575678  PMID: 22914544
Blood pressure; Obesity; African Americans; Genetic Association Studies
3.  Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome 
BMC Cancer  2012;12:243.
Aberrant promoter CpG island hypermethylation is associated with transcriptional silencing. Tumor suppressor genes are the key targets of hypermethylation in breast cancer and therefore may lead to malignancy by deregulation of cell growth and division. Our previous pilot study with pairs of malignant and normal breast tissues identified correlated methylation of two pairs of genes - HIN-1/RASSFIA and RIL/CDH13 - with expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 (HER2). To determine the impact of methylation on clinical outcome, we have conducted a larger study with breast cancers for which time to first recurrence and overall survival are known.
Tumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival.
In this study, we found that ER was associated with RASSF1A methylation (p < 0.001) and HIN-1 methylation (p = 0.002). PR was associated with RIL methylation (p = 0.012), HIN-1 (p = 0.002), and RASSF1A methylation (p = 0.019). Tumor size was associated with RIL and CDH13 methylation (both p = 0.002), and S-phase was associated with RIL methylation (p = 0.036). Only RASSF1A was associated with worse time to first recurrence (p = 0.045) and worse overall survival (p = 0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor.
Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.
PMCID: PMC3476972  PMID: 22695491
4.  Estimating heritability using family and unrelated individuals data 
BMC Proceedings  2011;5(Suppl 9):S34.
For the family data from Genetic Analysis Workshop 17, we obtained heritability estimates of quantitative traits Q1 and Q4 using the ASSOC program in the S.A.G.E. software package. ASSOC is a family-based method that estimates heritability through the estimation of variance components. The covariate-adjusted mean heritability was 0.650 for Q1 and 0.745 for Q4. For the unrelated individuals data, we estimated the heritability of Q1 as the proportion of total variance that can be accounted for by all single-nucleotide polymorphisms under an additive model. We examined a novel ordinary least-squares method, a naïve restricted maximum-likelihood method, and a calibrated restricted maximum-likelihood method. We applied the different methods to all 200 replicates for Q1. We observed that the ordinary least-squares method yielded many estimates outside the interval [0, 1]. The restricted maximum-likelihood estimates were more stable than the ordinary least-squares estimates. The naïve restricted maximum-likelihood method yielded an average estimate of 0.462 ± 0.1, and the calibrated restricted maximum-likelihood method yielded an average of 0.535 ± 0.121. Our results demonstrate discrepancies in heritability estimates using the family data and the unrelated individuals data.
PMCID: PMC3287870  PMID: 22373039
5.  FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women 
Carcinogenesis  2010;31(8):1417-1423.
Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry [odds ratios (OR) range 1.17–1.81]. Associations were observed for SNPs in FGFR2, LSP1, H19, TLR1/TLR6 and RELN for AA; FGFR2, TNRC9, H19 and MAP3K1 for Whites; FGFR2, TNRC9, Msc5A1 and chromosome 8q for women ≥50 years old and FGFR2 and TNRC9 for women <50 years old. FGFR2 haplotypes based upon rs11200014, rs2981579, rs1219648 and rs2420946 were associated with increased risk of breast cancer, including the GTGT haplotype in AAs [OR = 1.27, 95% confidence interval (CI) 1.04–1.56] and younger women of either race [OR = 1.35, 95% CI 1.02–1.78) and the ATGT haplotype in Whites (OR = 1.30, 95% CI 1.15–1.46). Recent GWAS hits for breast cancer in Europeans and Whites (i.e. women of European descent) thus showed evidence of replication among AAs and Whites in the CBCS. Several new haplotypes were associated with breast cancer in AA and younger women, particularly the FGFR2 GTGT haplotype. These results highlight the need to conduct GWAS among younger women and in a variety of racial–ethnic populations.
PMCID: PMC2950798  PMID: 20554749
6.  EGFR Expression in Breast Cancer Association with biologic phenotype and clinical outcomes 
Cancer  2010;116(5):1234-1242.
EGFR expression is associated with aggressive phenotypes in preclinical breast cancer models, but in clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression in human breast tumors, when centrally and uniformly assessed, is associated with an aggressive phenotype and resistance to systemic therapy.
In a database of 47,286 patients with breast cancer, EGFR status was known on 2,567. EGFR levels were measured centrally by ligand binding assay, and tumors with ≥10 fmol/mg were prospectively deemed positive. Clinical and biological features of EGFR positive and negative tumors were compared. Clinical outcomes were assessed by systemic therapy status.
475 out of 2,567 tumors (18%) were EGFR positive. EGFR-positive tumors were more common in younger and in black women, were larger, had a higher S-phase fraction, and were more likely to be aneuploid. EGFR positive tumors were more likely to be HER2-positive (26% vs. 16%, p<0.0001), but less likely to be ER-positive (60% vs. 88%, p<0.0001), or PR-positive (26% vs. 65%, p<0.0001).
In multivariate analyses, EGFR expression independently correlated with worse DFS (HR=1.66, 95% CI=1.4–2.41, p=0.007) and OS (HR=1.98, 95% CI=1.36–2.88, p=0.0004) in treated patients, but not in untreated patients.
EGFR expression is more common in breast tumors in younger and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, and HER2 over-expression. It is correlated with higher risk of relapse in patients receiving adjuvant treatment. Blocking EGFR may improve outcome in selected patients.
PMCID: PMC2829330  PMID: 20082448
Breast cancer; EGFR; resistance to endocrine therapy; chemotherapy resistance

Results 1-6 (6)