Damali N. Martin

Increased NOS2 predicts poor survival in estrogen receptor–negative breast cancer patients

Inducible nitric oxide synthase (NOS2) is involved in wound healing, angiogenesis, and carcinogenesis. NOS2 upregulation and increased nitric oxide (NO) production affect the redox state of cells and can induce protein, lipid, and DNA modifications. To investigate whether NOS2 levels influence survival of breast cancer patients, we examined NOS2 expression and its association with tumor markers and survival in 248 breast tumors. In multivariable survival analysis, increased NOS2 predicted inferior survival in women with estrogen receptor α-negative (ER-negative) tumors. Microdissected tumor epithelium from ER-negative tumors with high NOS2 had increased IL-8 and a gene expression signature characteristic of basal-like breast cancer with poor prognosis. In cell culture, NO only induced selected signature genes in ER-negative breast cancer cells. ER transgene expression in ER-negative cells inhibited NO-induced upregulation of the stem cell marker CD44 and other proteins encoded by signature genes, but not of IL-8. Exposure to NO also enhanced cell motility and invasion of ER-negative cells. Last, pathway analysis linked the tumor NOS2 gene signature to c-Myc activation. Thus, NOS2 is associated with a basal-like transcription pattern and poor survival of ER-negative patients.

Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients

Background African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. Methods and Results Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-Americans was further investigated by examining the extent of vascularization and macrophage infiltration in an expanded set of 248 breast tumors. Immunohistochemistry revealed that microvessel density and macrophage infiltration is higher in tumors of African-Americans than in tumors of European-Americans. Lastly, using an in silico approach, we explored the potential of tailored treatment options for African-American patients based on their gene expression profile. This exploratory approach generated lists of therapeutics that may have specific antagonistic activity against tumors of African-American patients, e.g., sirolimus, resveratrol, and chlorpromazine in estrogen receptor-negative tumors. Conclusions The gene expression profiles of breast tumors indicate that differences in tumor biology may exist between African-American and European-American patients beyond the knowledge of current markers. Notably, pathways related to tumor angiogenesis and chemotaxis could be functionally different in these two patient groups.

Interactions among genes, tumor biology and the environment in cancer health disparities: examining the evidence on a national and global scale

Cancer incidence and mortality rates show great variations across nations and between population groups. These variations are largely explained by differences in age distribution, diet and lifestyle, access to health care, cultural barriers and exposure to carcinogens and pathogens. Cancers caused by infections are significantly more common in developing than developed countries, and they overproportionally affect immigrant populations in the USA and other countries. The global pattern of cancer is not stagnant. Instead, it is dynamic because of fluctuations in the age distribution of populations, improvements in cancer prevention and early detection in affluent countries and rapid changes in diet and lifestyle in parts of the world. For example, increased smoking rates have caused tobacco-induced cancers to rise in various Asian countries, whereas reduced smoking rates have caused these cancers to plateau or even begin to decline in Western Europe and North America. Some population groups experience a disproportionally high cancer burden. In the USA and the Caribbean, cancer incidence and mortality rates are excessively high in populations of African ancestry when compared with other population groups. The causes of this disparity are multifaceted and may include tumor biological and genetic factors and their interaction with the environment. In this review, we will discuss the magnitude and causes of global cancer health disparities and will, with a focus on African-Americans and selected cancer sites, evaluate the evidence that genetic and tumor biological factors contribute to existing cancer incidence and outcome differences among population groups in the USA.

Association of MTHFR gene polymorphisms with breast cancer survival

BackgroundTwo functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women.MethodsAfrican-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival.ResultsWe observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05–4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31–1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17–6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12–1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, pinteraction= 0.088; C677T, pinteraction= 0.026).ConclusionWe found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival.

Building capacity for sustainable research programmes for cancer in Africa.

Cancer research in Africa will have a pivotal role in cancer control planning in this continent. However, environments (such as those in academic or clinical settings) with limited research infrastructure (laboratories, biorespositories, databases) coupled with inadequate funding and other resources have hampered African scientists from carrying out rigorous research. In September 2012, over 100 scientists with expertise in cancer research in Africa met in London to discuss the challenges in performing high-quality research, and to formulate the next steps for building sustainable, comprehensive and multi-disciplinary programmes relevant to Africa. This was the first meeting among five major organizations: the African Organisation for Research and Training in Africa (AORTIC), the Africa Oxford Cancer Foundation (AfrOx), and the National Cancer Institutes (NCI) of Brazil, France and the USA. This article summarizes the discussions and recommendations of this meeting, including the next steps required to create sustainable and impactful research programmes that will enable evidenced-based cancer control approaches and planning at the local, regional and national levels.

Biological determinants of health disparities in prostate cancer.

Purpose of review Prostate cancer mortality rates are highest among men of African ancestry in the United States and globally. Environmental exposures and ancestry-related factors may influence tumor biology and induce a more aggressive disease in this population. Here, we summarize the most recent advances in our understanding of race/ethnic differences in the tumor biology of prostate cancer with an emphasis on the excess disease burden among African–Americans. Recent findings Results from several DNA methylation studies showed an increased prevalence in DNA hypermethylation at disease-related loci in tumors from African–American patients compared with tumors from European–American patients. Analyses of genome-wide gene expression in prostate tumors revealed frequent alterations in the expression of genes related to immunobiology among the African–American patients, consistent with immune response differences between them and their European–American counterparts. Lastly, population differences in the frequency of oncogenic erythroblast transformation-specific family of transcription factors (ETS)-related gene rearrangements were evaluated in three studies that showed that these alterations manifest themselves most commonly in tumors from men of European ancestry, but are significantly less frequent in men of African ancestry, whereas least common in men of Asian ancestry. Summary Analysis of tumor markers indicates that tumor biological differences may exist between prostate cancer patients of African ancestry and those of European or Asian ancestry. These differences could affect disease aggressiveness and response to therapy.

An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.

Recommendations for Cancer Epidemiologic Research in Understudied Populations and Implications for Future Needs

Medically underserved populations in the United States continue to experience higher cancer burdens of incidence, mortality, and other cancer-related outcomes. It is imperative to understand how health inequities experienced by diverse population groups may contribute to our increasing unequal cancer burdens and disparate outcomes. The National Cancer Institute convened a diverse group of scientists to discuss research challenges and opportunities for cancer epidemiology in medically underserved and understudied populations. This report summarizes salient issues and discusses five recommendations from the group, including the next steps required to better examine and address cancer burden in the United States among our rapidly increasing diverse and understudied populations. Cancer Epidemiol Biomarkers Prev; 25(4); 573–80. ©2016 AACR. See all articles in this CEBP Focus section, “Multilevel Approaches to Addressing Cancer Health Disparities.”

Household Income Is Associated with the p53 Mutation Frequency in Human Breast Tumors

Background A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation. Methods We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI) among 173 breast cancer patients from the greater Baltimore area, United States. Results p53 mutational frequency was significantly associated with HI. Patients with <

Abstract B46: Cancer incidence and mortality rates and trends in Trinidad and Tobago

15,000 HI had the highest p53 mutation frequency (21%), followed by the income group between