Associations of Prostate-Specific Antigen (PSA) Testing in the US Population: Results from a National Cross-Sectional Survey.

Prostate-specific antigen (PSA) testing is one of the standard screening methods for prostate cancer (PC); however, a high proportion of men with abnormal PSA findings lack evidence for PC and may undergo unnecessary treatment. Furthermore, little is known about the prevalence of PSA testing for US men, after the US Preventive Services Task Force (USPSTF) recommended against routine PSA screening in 2012. Our objectives were to: (1) examine the self-reported patterns of PSA testing following a change in the USPSTF prostate cancer screening recommendations and (2) to determine the associated socio-demographic factors. Data were from the 2010 and 2015 National Health Interview Surveys. Men were ages ≥ 40 years and responded to the question "Ever had a PSA test?". Multivariable logistic regression was used to examine PSA testing prevalence in 2010 and 2015, and their associated socio-demographic factors. The analytic sample contained 15,372 men. A majority (75.2%) identified as non-Hispanic (NHW) and 14.2% were foreign-born. Those surveyed in 2015 were less likely to report ever having had a PSA test when compared to those in 2010. Compared to US-born and older NHW men, PSA testing was statistically significantly lower among foreign-born men and men belonging to all other racial categories. Fewer men reported PSA testing following the USPSTF 2012 recommendations. Associated socio-demographic factors included nativity, age, race/ethnicity, educational attainment and type of health insurance. Further studies are required to elucidate our findings and their health implications for the US native and foreign-born population.

10-year trends in noncommunicable disease mortality in the Caribbean region.

OBJECTIVE: Between 2006 and 2016, 70% of all deaths worldwide were due to noncommunicable diseases (NCDs). NCDs kill nearly 40 million people a year globally, with almost three-quarters of NCD deaths occurring in low- and middle-income countries. The objective of this study was to assess mortality rates and trends due to deaths from NCDs in the Caribbean region. METHODS: The study examines age-standardized mortality rates and 10-year trends due to death from cancer, heart disease, cerebrovascular disease, and diabetes in two territories of the United States of America (Puerto Rico and the U.S. Virgin Islands) and in 20 other English- or Dutch-speaking Caribbean countries or territories, for the most recent, available 10 years of data ranging from 1999 to 2014. For the analysis, the SEER*Stat and Joinpoint software packages were used. RESULTS: These four NCDs accounted for 39% to 67% of all deaths in these 22 countries and territories, and more than half of the deaths in 17 of them. Heart disease accounted for higher percentages of deaths in most of the Caribbean countries and territories (13%-25%), followed by cancer (8%-25%), diabetes (4%-21%), and cerebrovascular disease (1%-13%). Age-standardized mortality rates due to cancer and heart disease were higher for males than for females, but there were no significant mortality trends in the region for any of the NCDs. CONCLUSIONS: The reasons for the high mortality of NCDs in these Caribbean countries and territories remain a critical public health issue that warrants further investigation.

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.

Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila.

Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 (ddlc1) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration.

Cancer Epidemiology in Hispanic Populations: An Analysis of Funded Observational Research at the National Cancer Institute.

BACKGROUND: More than 62 million people self-identified as Hispanic/Latino (H/L) in the 2020 United States census. The U.S. H/L population has higher burden of certain cancers compared with their non-Hispanic White counterparts. METHODS: Key term search using the NIH Query/View/Report (QVR) system, along with Research, Condition, and Disease Categorization codes identified cancer epidemiology research grants in H/L populations funded by the NCI as a primary or secondary funder from fiscal years 2016 through 2021. Three reviewers identified eligible grants based on specified inclusion/exclusion criteria and a codebook for consistency extracting key characteristics. RESULTS: A total of 450 grants were identified through the QVR system using key words related to H/Ls; 41 cancer epidemiology grants remained after applying exclusion criteria. These grants contained specific aims focused on H/Ls (32%) or included H/Ls as part of a racial/ethnic comparison (68%). NCI was the primary funder of the majority of the grants (85%), and most of the research grants focused on cancer etiology (44%) and/or survivorship (49%). Few grants (10%) investigated environmental exposures. CONCLUSIONS: This article provides an overview of NCI-funded cancer epidemiology research in H/L populations from 2016 to 2021. Future cancer epidemiology research should reflect the changing dynamics of the U.S. demography with diverse, representative populations and well-characterized ethnicity. IMPACT: Research that carefully measures the relevant biological, environmental, behavioral, psychologic, sociocultural, and clinical risk factors will be critical to better understanding the nuanced patterns influencing cancer-related outcomes in the heterogenous H/L population.

Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry.

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies >10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

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.

Epidemiologic Research of Rare Cancers: Trends, Resources, and Challenges.

BACKGROUND: The goals of this project were to assess the status of NCI's rare cancer-focused population science research managed by the Division of Cancer Control and Population Sciences (DCCPS), to develop a framework for evaluation of rare cancer research activities, and to review available resources to study rare cancers. METHODS: Cancer types with an overall age-adjusted incidence rate of less than 20 cases per 100,000 individuals were identified using NCI Surveillance, Epidemiology and End Results (SEER) Program data. SEER data were utilized to develop a framework based on statistical commonalities. A portfolio analysis of DCCPS-supported active grants and a review of three genomic databases were conducted. RESULTS: For the 45 rare cancer types included in the analysis, 123 active DCCPS-supported rare cancer-focused grants were identified, of which the highest percentage (18.7%) focused on ovarian cancer. The developed framework revealed five clusters of rare cancer types. The cluster with the highest number of grants (n = 43) and grants per cancer type (10.8) was the cluster that included cancer types of higher incidence, average to better survival, and high prevalence (in comparison with other rare cancers). Resource review revealed rare cancers are represented in available genomic resources, but to a lesser extent compared with more common cancers. CONCLUSIONS: This article provides an overview of the rare cancer-focused population sciences research landscape as well as information on gaps and opportunities. IMPACT: The findings of this article can be used to develop efficient and comprehensive strategies to accelerate rare cancer research.See related commentary by James V. Lacey Jr, p. 1300.

Cancer Registration in the Caribbean.

The Caribbean region faces a growing burden due to cancer. Urgent action needs to be taken to monitor this disease and inform measures required for prevention and control. Cancer surveillance, supported by the implementation of population-based cancer registries (PBCRs), is an important component of cancer prevention and control strategies. Yet, the ability of some Caribbean countries to implement infrastructure needed for sustainable, high-quality PBCRs remains a challenge given limitations in resources and competing health priorities. While some Caribbean cancer registries have been successful in contributing high-quality cancer data in support of national cancer control and prevention efforts, this represents coverage of only a small percentage of the Caribbean population, and these data have limited generalizability to other countries in the region. The International Agency for Research on Cancer (IARC) Caribbean Cancer Registry Hub (http:// caribbeancrh.carpha.org) is performing an important role in providing technical support, capacity building, advocacy, and research needed for strengthening cancer registration in the region. The Caribbean Hub engages high-level political and technical stakeholders, and shares appropriate and relevant resources and expertise to help health care and public health professionals and policymakers understand the importance of data generated from PBCRs for cancer control planning and monitoring. Through the provision of technical support for the implementation or strengthening of PBCRs in the region, the Caribbean Hub will support efforts being made by Caribbean countries to establish high-quality PBCRs. The Hub will continue to facilitate capacity building through training workshops and other similar activities as well as support training opportunities for cancer registries throughout the region. Research initiatives will continue to be conducted and supported by the Caribbean Hub to identify priorities and to monitor and evaluate cancer control strategies in the region. Through the work of the IARC Caribbean Cancer Registry Hub, Caribbean countries are better equipped to overcome challenges faced and strengthen cancer surveillance nationally and regionally. This is an important step towards mitigating the cancer burden and improving cancer prevention and control measures in the Caribbean.

Association of MTHFR gene polymorphisms with breast cancer survival.

BACKGROUND: Two 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. METHODS: African-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. RESULTS: We 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). CONCLUSION: We 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.

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".

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.

10-year trends in noncommunicable disease mortality in the Caribbean region

[ABSTRACT]. Objective. Between 2006 and 2016, 70% of all deaths worldwide were due to noncommunicable diseases (NCDs). NCDs kill nearly 40 million people a year globally, with almost three-quarters of NCD deaths occurring in low- and middle-income countries. The objective of this study was to assess mortality rates and trends due to deaths from NCDs in the Caribbean region. Methods. The study examines age-standardized mortality rates and 10-year trends due to death from cancer, heart disease, cerebrovascular disease, and diabetes in two territories of the United States of America (Puerto Rico and the U.S. Virgin Islands) and in 20 other English- or Dutch-speaking Caribbean countries or territories, for the most recent, available 10 years of data ranging from 1999 to 2014. For the analysis, the SEER*Stat and Joinpoint software packages were used. Results. These four NCDs accounted for 39% to 67% of all deaths in these 22 countries and territories, and more than half of the deaths in 17 of them. Heart disease accounted for higher percentages of deaths in most of the Caribbean countries and territories (13%-25%), followed by cancer (8%-25%), diabetes (4%-21%), and cerebrovascular disease (1%-13%). Age-standardized mortality rates due to cancer and heart disease were higher for males than for females, but there were no significant mortality trends in the region for any of the NCDs. Conclusions. The reasons for the high mortality of NCDs in these Caribbean countries and territories remain a critical public health issue that warrants further investigation.

[RESUMEN]. Objetivo. Entre los años 2006 y 2016, las enfermedades no transmisibles (ENT) ocasionaron un 70 % de todas las muertes mundiales. Las ENT son responsables de la muerte de aproximadamente 40 millones de personas al año a nivel mundial, de las cuales casi tres cuartas partes tienen lugar en países de ingresos medianos y bajos. El objetivo de este estudio es evaluar las tasas de mortalidad y las tendencias relacionadas con las defunciones por ENT en el Caribe. Métodos. En el estudio se examinan las tasas de mortalidad ajustadas por edad y las tendencias a lo largo de diez años relacionadas con la muerte por cáncer, cardiopatías, enfermedades cerebrovasculares y diabetes en dos territorios de Estados Unidos (Puerto Rico e Islas Vírgenes), así como en otros veinte países o territorios de habla inglesa o neerlandesa, empleando la información disponible más reciente que corresponde a los diez años comprendidos entre 1999 y el 2014. Para el análisis, se utilizaron los programas informáticos JointPoint y SEER*Stat. Resultados. Estas cuatro ENT representan entre el 39 % y el 67 % del total de muertes en estos 22 países y territorios, y más de la mitad de las muertes en 17 de ellos. Las cardiopatías representan porcentajes mayores de muertes en la mayor parte de los países y territorios del Caribe (13 %-25 %), seguidos por el cáncer (8 %-25 %), la diabetes (4 %-21 %) y las enfermedades cerebrovasculares (1 %-13 %). Las tasas de mortalidad ajustadas por edad relacionadas con el cáncer y las cardiopatías son mayores en hombres que en mujeres, si bien no hubo en la región tendencias significativas relacionadas con la mortalidad en lo que concierne a ninguna ENT. Conclusiones. Las causas de la elevada mortalidad por ENT en estos países y territorios del Caribe siguen siendo un grave problema de salud pública que justifica una investigación en profundidad.

[RESUMO]. Objetivo. No período de 2006 a 2016, 70% das mortes na população mundial foram decorrentes de doenças não transmissíveis (DNTs). Cerca de 40 milhões de pessoas morrem por DNTs por ano em todo o mundo, com quase 75% das mortes ocorrendo nos países de baixa e média renda. O objetivo deste estudo foi avaliar as taxas e as tendências de mortalidade por DNTs no Caribe. Métodos. Foram examinadas as taxas de mortalidade padronizadas por idade e as tendências ao longo de 10 anos da mortalidade por câncer, doença cardíaca, doença cerebrovascular e diabetes em dois territórios dos Estados Unidos (Porto Rico e Ilhas Virgens Americanas) e em 20 países ou territórios do Caribe de língua inglesa ou holandesa, com base nos últimos dados de 10 anos para o período de 1999 a 2014. Os softwares SEER*Stat e Joinpoint foram usados na análise. Resultados. As quatro DNTs estudadas representaram 39% a 67% das causas de mortes nos 22 países e territórios, e foram responsáveis por mais da metade das mortes em 17 deles. A mortalidade na maioria dos países e territórios do Caribe foi maior por doença cardíaca (13% a 25%), seguida do câncer (8% a 25%), diabetes (4% a 21%) e doença cerebrovascular (1% a 13%). As taxas de mortalidade padronizadas pela idade por câncer e doença cardíaca foram maiores nos homens que nas mulheres, mas não se verificaram, na região, tendências de mortalidade significativas para qualquer uma das DNTs. Conclusões. A elevada mortalidade por DNTs nos países e territórios do Caribe é ainda um sério problema de saúde pública e os motivos devem ser investigados mais a fundo.

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.

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 < $15,000 HI had the highest p53 mutation frequency (21%), followed by the income group between $15,000 and $60,000 (18%), while those above $60,000 HI had the fewest mutations (5%). When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05). In the adjusted logistic regression analysis with 3 income categories (trend test), the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER)-negative disease. Within this group, 42% of the low income patients (< $15,000 HI) carried a mutation, followed by the middle income group (21%), while those above $60,000 HI did not carry mutations (Ptrend < 0.05). CONCLUSIONS: HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.

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.

Autoimmunity and hematologic malignancies: associations and mechanisms.

Although the true prevalence of autoimmune diseases remains to be better defined, in Western countries the current estimates indicate that at least 5% of the population is affected by an autoimmune disorder. Over the last few decades, autoimmune diseases have been associated with an elevated risk of developing lymphoproliferative malignancies, particularly non-Hodgkin lymphomas. Some studies have found the relationship between autoimmunity and lymphoproliferative tumors to be bi-directional. Although substantial work has been carried out to characterise the associations between autoimmunity and lymphoproliferation, current insights regarding underlying biological mechanisms remain limited and hence present a gap in the literature. In this article, we review reported main associations between selected common autoimmune diseases and lymphoproliferative neoplasms. We also discuss potential underlying mechanisms that have been proposed to connect these two disorders. Finally, we provide future directions for new research studies aimed to improve our understanding of inflammation and the dysregulated immune system in the development of autoimmunity and hematologic malignancies.

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.

Caspases function in autophagic programmed cell death in Drosophila.

Self-digestion of cytoplasmic components is the hallmark of autophagic programmed cell death. This auto-degradation appears to be distinct from what occurs in apoptotic cells that are engulfed and digested by phagocytes. Although much is known about apoptosis, far less is known about the mechanisms that regulate autophagic cell death. Here we show that autophagic cell death is regulated by steroid activation of caspases in Drosophila salivary glands. Salivary glands exhibit some morphological changes that are similar to apoptotic cells, including fragmentation of the cytoplasm, but do not appear to use phagocytes in their degradation. Changes in the levels and localization of filamentous Actin, alpha-Tubulin, alpha-Spectrin and nuclear Lamins precede salivary gland destruction, and coincide with increased levels of active Caspase 3 and a cleaved form of nuclear Lamin. Mutations in the steroid-regulated genes beta FTZ-F1, E93, BR-C and E74A that prevent salivary gland cell death possess altered levels and localization of filamentous Actin, alpha-Tubulin, alpha-Spectrin, nuclear Lamins and active Caspase 3. Inhibition of caspases, by expression of either the caspase inhibitor p35 or a dominant-negative form of the initiator caspase Dronc, is sufficient to inhibit salivary gland cell death, and prevent changes in nuclear Lamins and alpha-Tubulin, but not to prevent the reorganization of filamentous Actin. These studies suggest that aspects of the cytoskeleton may be required for changes in dying salivary glands. Furthermore, caspases are not only used during apoptosis, but also function in the regulation of autophagic cell death.