Role of adenosine deaminase in prostate cancer progression.

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

Race/Ethnic Variations in Predictors of Health Consciousness Within the Cancer Prevention Context.

PURPOSE: Although the literature establishes a link between health consciousness (HC) and prevention behavior, less explored are the individual, social, and health characteristics that are associated with increased HC. Similarly, underexamined is the influence of race and ethnicity on the relationship of these characteristics to higher levels of HC. DESIGN: This cross-sectional study aims to identify and assess the relative importance of factors associated with higher levels of HC, highlighting the role of race and ethnicity. PARTICIPANTS: Participants came from a national research panel survey (N = 1007). MEASURES: Participants completed a 4-item scale capturing key concepts of HC as well as questionnaires capturing demographic profiles, social support, social networking activities, and health status. ANALYSIS: A stepwise multiple regression was used to identify significant predictors of HC. RESULTS: Female and more educated participants report higher levels of HC. African American and Hispanic participants report higher levels of HC compared to white participants. Findings indicate social support, social network participation, education, cancer survivorship, and health status were positively associated with higher HC for the collective sample. However, results revealed variations in factors associated with higher HC when stratified by race/ethnicity. CONCLUSION: Findings suggest that interventions aiming to motivate cancer prevention behaviors within at-risk communities may find more success by incorporating factors that are aligned with increased HC among culturally diverse populations.

Methionine-Homocysteine Pathway in African-American Prostate Cancer.

African American (AA) men have a 60% higher incidence and two times greater risk of dying of prostate cancer (PCa) than European American men, yet there is limited insight into the molecular mechanisms driving this difference. To our knowledge, metabolic alterations, a cancer-associated hallmark, have not been reported in AA PCa, despite their importance in tumor biology. Therefore, we measured 190 metabolites across ancestry-verified AA PCa/benign adjacent tissue pairs (n = 33 each) and identified alterations in the methionine-homocysteine pathway utilizing two-sided statistical tests for all comparisons. Consistent with this finding, methionine and homocysteine were elevated in plasma from AA PCa patients using case-control (AA PCa vs AA control, methionine: P = .0007 and homocysteine: P < .0001), biopsy cohorts (AA biopsy positive vs AA biopsy negative, methionine: P = .0002 and homocysteine: P < .0001), and race assignments based on either self-report (AA PCa vs European American PCa, methionine: P = .001, homocysteine: P < .0001) or West African ancestry (upper tertile vs middle tertile, homocysteine: P < .0001; upper tertile vs low tertile, homocysteine: P = .002). These findings demonstrate reprogrammed metabolism in AA PCa patients and provide a potential biological basis for PCa disparities.

ERR1 and PGC1α associated mitochondrial alterations correlate with pan-cancer disparity in African Americans.

BACKGROUND: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting. METHODS: A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to Transcription Factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.

Metabolomic profiling of hormone-dependent cancers: a bird's eye view.

Hormone-dependent cancers present a significant public health challenge, because they are among the most common cancers in the world. One factor associated with cancer development and progression is metabolic reprogramming. By understanding these alterations, we can identify potential markers and novel biochemical therapeutic targets. Metabolic profiling is an advanced technology that allows investigators to assess low-molecular-weight compounds that reflect physiological alterations. Current research in metabolomics on prostate (PCa) and breast cancer (BCa) have made great strides in uncovering specific metabolic pathways that are associated with cancer development, progression, and resistance. In this review, we highlight some of the major findings and potential therapeutic advances that have been reported utilizing this technology.

Cytokinesis-blocked micronucleus cytome assay and spectral karyotyping as methods for identifying chromosome damage in a lung cancer case-control population.

Lung cancer is the leading cause of all cancer-related deaths in the US. The need to develop more accurate cancer risk assessment tools is imperative to improve the ability to identify individuals at greatest risk of developing disease. The Cytokinesis-Blocked Micronucleus Cytome Assay (CBMNcyt) presents a sensitive and specific method of assessing DNA damage. We have previously reported that this assay is sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and that binucleated cells with micronuclei, nucleoplasmic bridges and nuclear buds are strong predictors of lung cancer risk. The current study confirmed our previous findings and sought to identify the specific chromosomes involved in lung carcinogenesis. Spectral karyotyping was conducted on a subset of lung cancer cases [n = 116] and cancer-free controls [n = 126] with the highest CBMNcyt endpoints, on baseline and NNK-treated blood lymphocytes. After adjusting for age, gender, race/ethnicity, smoking status, and pack and smoke years, consistent significant associations between chromosome: 9, 19, 22, X, at baseline; chromosome: 3, 4, and 16 after NNK-induction; and chromosome: 1, 13, and 17 at both baseline and NNK-induction; and lung cancer risk (all P ≤ 0.05) were observed. Several of these chromosomes harbor critical genes involved in lung carcinogenesis, such as the FHIT gene, CDKN2A, PADPRP, and TP53. Our results indicate that the CBMNcyt assay when used in conjunction with other cytogenetic methodologies can increase our ability to identify specific chromosomal regions associated with DNA damage, thereby improving our understanding of the underlying mechanisms involved in individual cancer predisposition.

Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.

BACKGROUND: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. METHODS: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. RESULTS: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)). CONCLUSIONS: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. IMPACT: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.

Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans.

Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10-4). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10-5). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.