Luisel Ricks-Santi

Influence of provider discussion and specific recommendation on colorectal cancer screening uptake among U.S. adults

OBJECTIVES It is unclear if provider recommendations regarding colorectal cancer (CRC) screening modalities affect patient compliance. We evaluated provider-patient communications about CRC screening with and without a specific screening modality recommendation on patient compliance with screening guidelines. METHODS We used the 2007 Health Information National Trends Survey (HINTS) and identified 4283 respondents who were at least 50 years of age and answered questions about their communication with their care providers and CRC screening uptake. We defined being compliant with CRC screening as the use of fecal occult blood testing (FOBT) within 1 year, sigmoidoscopy within 5 years, or colonoscopy within 10 years. We used survey weights in all analyses. RESULTS CRC screening discussions occurred with 3320 (76.2%) respondents. Approximately 95% of these discussions were with physicians. Overall, 2793 (62.6%) respondents were current with CRC screening regardless of the screening modality. Discussion about screening (odds ratio (OR)=8.83; 95% confidence interval (CI): 7.20-10.84) and providers making a specific recommendation about screening modality rather than leaving it to the patient to decide (OR=2.04; 95% CI: 1.54-2.68) were associated with patient compliance with CRC screening guidelines. CONCLUSION Compliance with CRC screening guidelines is improved when providers discuss options and make specific screening test recommendations.

p53 Pro72Arg polymorphism and prostate cancer in men of African descent

p53 is a transcription factor that regulates the cell cycle, DNA repair, and apoptosis. A variant at codon 72, rs1042522, results in altered activities for p53 and is, notably, differentially distributed among different ethnic populations. However, associations of this variant with cancer in men of African descent have not been explored. Herein, we tested the hypothesis that rs1042522 was associated with prostate cancer (PCa) risk.

Association of CD14 variant with prostate cancer in African American men

African American men have the highest rates of prostate cancer worldwide, and immunogenetic studies suggest that people of African descent have increased susceptibility to diseases of inflammation. Since genetic susceptibility is an etiological factor in prostate cancer, we hypothesize that sequence variants in the promoter region of the CD14 gene that regulate inflammation may modify individual susceptibility to this disease.

Demographic Differences in Willingness to Provide Broad and Narrow Consent for Biobank Research

PURPOSE This study examined acceptability of two biobank consent models and evaluated the impact of beliefs about privacy and genetic safeguards on acceptance. METHODS U.S. adults surveyed online in English and Spanish were randomly assigned to one of two scenarios examining acceptance of broad consent (n=1528), or narrow consent (n=1533). RESULTS Overall, willingness to provide broad (76%) and narrow (74%) consents were similar. African Americans were as likely as white non-Hispanics to accept narrow consent (72% vs. 77%, p=0.35) but significantly less likely to accept broad consent (69% vs. 81%, p=0.004). Education, insurance, and blood donation history were also related to acceptance. Adjusting for beliefs about privacy and policy protections (Genetic Information Nondiscrimination Act, GINA), the effects of the variables were reduced. Respondents who drew comfort from GINA were more likely to support both consent (both p<0.001); those who believed it is impossible to maintain privacy were less likely to find both broad (p=0.04) and narrow models acceptable (p=0.02). CONCLUSIONS Choice of consent model matters when engaging diverse populations in biobank research. Beliefs underlying concerns about privacy and genetic protections should be considered when constructing biobank protocols.

Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women

Background Fascin, an actin bundling protein, plays a critical role in cell motility due to formation of actin rich protrusions called filopodia, important in cell migration, invasion and metastatic spread. Fascin overexpression has been associated with epithelial to mesenchymal transition and correlates with progression and unfavourable prognosis in breast carcinoma. Objective To evaluate fascin expression by immunohistochemistry and correlate the expression pattern with clinicopathological parameters in breast cancer in African-American (AA) women, in whom triple negative breast cancer (TNBC), an aggressive subtype, is more prevalent. Methods Tissue microarrays were constructed from formalin-fixed, paraffin-embedded blocks of tumour tissue from primary breast carcinomas in 202 AA women. Immunohistochemical detection of fascin was correlated with four major subtypes of breast carcinoma (luminal A, luminal B, human epidermal growth factor receptor 2 and triple negative (TN)) and other clinicopathological factors, including age, grade, tumour size, stage, regional lymph node status and survival. Results We observed a significant association between fascin expression and TN subtype, oestrogen receptor (ER) negativity, progesterone receptor (PR) negativity, Elston–Nottingham (EN) grade 3 and decreased overall survival. There was also a significant association between expression of CK 5/6, a marker of basal-like phenotype, and fascin expression. Conclusion These results suggest that fascin is a marker for TN subtype having a basal-like phenotype and decreased overall survival. Fascin may represent a target for therapy in TNBC in AA women.

Identification of genetic risk associated with prostate cancer using ancestry informative markers

Background:Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.Methods:A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.Results:Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P=0.002). SNPs rs1561131 (genotypic, P=0.007), rs1963562 (dominant, P=0.01) and rs615382 (recessive, P=0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P=0.04) and rs1963562 (P=0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113–, rs1963562–rs615382l and rs1993973–rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P=0.032 and 0.0017, respectively).Conclusions:The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

A new biophysical metric for interrogating the information content in human genome sequence variation: Proof of concept.

The 21st century emergence of genomic medicine is shifting the paradigm in biomedical science from the population phenotype to the individual genotype. In characterizing the biology of disease and health disparities in population genetics, human populations are often defined by the most common alleles in the group. This definition poses difficulties when categorizing individuals in the population who do not have the most common allele(s). Various epidemiological studies have shown an association between common genomic variation, such as single nucleotide polymorphisms (SNPs), and common diseases. We hypothesize that information encoded in the structure of SNP haploblock variation in the human leukocyte antigen-disease related (HLA-DR) region of the genome illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. In this paper we describe the development and application of the normalized information content (NIC) as a novel metric based on SNP haploblock variation. The NIC facilitates translation of biochemical DNA sequence variation into a biophysical quantity derived from Boltzmanns canonical ensemble in statistical physics and used widely in information theory. Our normalization of this information metric allows for comparisons of unlike, or even unrelated, regions of the genome. We report here NIC values calculated for HLA-DR SNP haploblocks constructed by Haploview, a product of the International Haplotype Map Project. These haploblocks were scanned for potential regulatory elements using ConSite and miRBase, publicly available bioinformatics tools. We found that all of the haploblocks with statistically low NIC values contained putative transcription factor binding sites and microRNA motifs, suggesting correlation with genomic regulation. Thus, we were able to relate a mathematical measure of information content in HLA-DR SNP haploblocks to biologically relevant functional knowledge embedded in the structure of DNA sequence variation. We submit that NIC may be useful in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens and in decoding the functional significance of common variation in the human genome.

BRCA1 Polymorphisms and Breast Cancer Epidemiology in the Western New York Exposures and Breast Cancer (WEB) Study

Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case‐control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case‐control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional, polytomous logistic regression and χ2‐tests were used to examine the associations of breast cancer with genotypes and haplotypes. In addition, interactions between genotype and smoking, benign breast disease, family history of breast cancer, body mass index (BMI), alcohol consumption, and hormonal risk factors, hormone receptor status, and breast cancer pathology were calculated also using logistic regression and χ2. Although sporadic breast cancer was not associated with BRCA1 genotypes or haplotypes overall or by menopausal status, there was evidence of an interaction between the E1038G BRCA1 genotype, smoking, and BMI among premenopausal women (P for interaction = 0.01 and 0.045, respectively) and between E1038G and D693N BRCA1 genotypes and hormone therapy use among postmenopausal women (P for interaction = 0.01 and 0.02, respectively). There were no other associations found between BRCA1 genotypes and stage, histological grade, or nuclear grade. However, the D693N SNP was associated with the risk of triple negative breast cancer (odds ratio = 2.31 95% confidence interval 1.08–4.93). The BRCA1 variants studied may play a role in the etiology of triple negative breast cancer and may interact with environmental factors such as hormone therapy or smoking and increase sporadic breast cancer risk.

Association of Cumulative Ultraviolet Radiation Exposure with Prostate Cancer Risk in a Case-control Study of African-American Men

It is well established that exposure to ultraviolet (UV) radiation has beneficial effects in reducing prostate cancer risk. To determine if there is a correlation between UV exposure and prostate cancer risk, we assessed sun exposure in a case-control study of 182 African-American men aged 40 years and older residing in the Metropolitan Washington, DC area. Using data on cumulative exposure per year and adult sunbathing scores derived from a validated questionnaire, analysis revealed significant difference in cumulative sun exposure between cases and controls (p=0.003). Additionally, the outdoor and recreation UV exposures were significantly higher in controls when compared to cases (p=0.003; p=0.03 in age-matched cases and controls). Although the results of conditional logistic regression analysis indicate that there was no association between total UV exposure and risk of prostate cancer after adjusting for age (OR=2.04, 95% CI 0.54-7.70, p=0.29), outdoor UV exposure was associated with decreased prostate cancer risk (OR= 0.31, 95% CI 0.14-0.65, p=0.002). Furthermore, a trend for reduced prostate cancer risk was found among men with early life high sun exposure during childhood ages 0-5 years (OR=0.17, 95% CI 0.03-0.74, p=0.02) and 6-11 years (OR= 0.28, 95% CI 0.07-1.05, p=0.06). Interestingly, this inverse association between prostate cancer risk and early life high sun exposure intensity was also observed among young men at ages 12-17 years although not statistically significant (OR=0.41, 95% CI 0.09-1.95, p=0.26). These findings indicate that UV exposure earlier in life may affect susceptibility to prostate cancer.

Loss of PTEN in High Grade Advanced Stage Triple Negative Breast Ductal Cancers in African American Women

INTRODUCTION PTEN is a tumor suppressor gene that inhibits cell proliferation by inhibiting the phosphoinositide 3-kinase (PI3 K) signaling pathway. The significance of PTEN mutations resulting in variable PTEN expression and their impact on prognosis of breast cancer is not well established. The objective of our study was to correlate the immunohistochemical expression of PTEN in the four major subtypes of breast carcinoma (Luminal A, Luminal B, HER2 positive, and Triple Negative) in a population of 202 African-American (AA) females with other clinicopathological factors. MATERIALS AND METHODS Tissue microarrays (TMAs) were constructed from FFPE tumor blocks from primary ductal breast carcinomas in 202 African-American females. Five micrometer sections were stained with a mouse monoclonal antibody against PTEN. The sections were evaluated for the intensity of cytoplasmic and nuclear reactivity. Bivariate analysis was done via χ2 analysis and survivability data was calculated via the generation of Kaplan-Meier curves (SPSS v19). RESULTS Loss of PTEN expression was associated with ER negative (p = 0.021), PR negative (p = 0.024) and triple negative (p = 0.0024) breast ductal cancers. It was marginally associated with distant metastasis (p = 0.074). There was no association between PTEN loss and recurrence-free survival or overall survival. CONCLUSION In our study, a statistically significant association between PTEN loss and the triple negative breast cancers (TNBC) was found in AA women. PTEN inhibits PI3 K resulting in decreased activation of downstream effector, mammalian target of rapamycin (mTOR). Loss of PTEN results in cell proliferation through activation of mTOR. Targeted therapy with mTOR inhibitors might be useful in the treatment of TNBC.