Genetic polymorphisms of PGF and TNFAIP2 genes related to cervical cancer risk among Uygur females from China.

BACKGROUND: PGF and TNFAIP2 are important angiogenic factors, which were abnormal expression in cervical cancer (CC). However, there is currently no report investigating the relationship of PGF and TNFAIP2 gene polymorphisms to CC risk. METHODS: We conducted a case-control study of 342 CC patients and 498 cancer-free controls in a Chinese Uygur female population. Three SNPs (PGF rs8019391, PGF rs2268615, and TNFAIP2 rs710100) were selected and genotyped to assess the possible association of PGF and TNFAIP2 polymorphisms with CC susceptibility. Logistic regression analysis adjusted by age was used. RESULTS: PGF rs2268615 (OR = 1.39, 95% CI = 1.04-1.86, p = 0.024) and TNFAIP2 rs710100 (OR = 1.44, 95% CI =1.07-1.95, p = 0.018) polymorphisms were associated with the increased risk of CC. Moreover, T allele of PGF rs8019391 was highly represented in patients with stage III-IV compared with stage I-II (OR = 2.17, p = 4.58 × 10- 4). MDR analysis revealed a positive interaction between the SNPs. CONCLUSION: Our data indicated that PGF rs2268615, and TNFAIP2 rs710100 polymorphisms might be risk factors for CC susceptibility, which contributed to the increased risk of CC. TRIAL REGISTRATION: Not applicable.

Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.

Ethnic/racial differences in circulating markers of angiogenesis and their association with cardiovascular risk factors and cardiovascular disease.

OBJECTIVE: To determine (a) whether ethnic/racial differences exist in circulating markers of angiogenesis (Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), soluble Tie-2 receptor (sTie-2) and Angiogenin) between South Asian (SA; from India, Pakistan and Bangladesh); Black African-Caribbean and White (W) ethnic groups, and (b) associations between these markers in stable cardiovascular disease (CVD) and its risk factors. PATIENTS AND METHODS: We recruited 243 subjects (82 SA, 84 Black and 77 W) with symptomatic and clinically confirmed CVD (n=108), risk factor controls (with ≥ 1 cardiovascular risk factor, e.g. smoking, diabetes mellitus, dyslipidaemia, hypertension) and with ankle brachial pressure index >1) (n=64) and healthy controls free of CVD and risk factors (n=56). Angiogenic markers were measured by enzyme linked immunoassay. RESULTS: In healthy controls, angiogenin was higher in SA and Black subjects, compared to Whites (p<0.05). sTie-2 correlated inversely with angiogenin (p=0.001), was higher in women (p=0.029) and was lower in smokers (p=0.007). Overall, age (p=0.001) was the only independent factor associated with angiopoietin-1. Angiogenin (p=0.01) and SBP (p=0.014) were both independently higher in the Black group compared to the White group. CONCLUSIONS: Ethnic, racial, and demographic differences are evident in certain circulating markers of angiogenesis. With the exception of an effect of smoking on sTie-2, these differences are not influenced by the presence of other risk factors, nor the presence of stable cardiovascular disease.

A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. RESULTS: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. CONCLUSION: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile.

Association of interferon-gamma, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms with occurrence and severity of Eales' disease.

PURPOSE: Eales' disease (ED) is an idiopathic retinal vasculitis characterized by capillary nonperfusion and neovascularization. Previous reports on ED demonstrated that T-cell-mediated immunoresponse and differential cytokine production in inflammatory and angiogenic stage seem to influence the extent and severity of this disease. Therefore, the purpose of this study is to investigate the influence of cytokine gene polymorphisms on occurrence and severity of ED. METHODS: One hundred twenty-one patients with ED were recruited from an Eastern Indian population and compared with 223 matched healthy control subjects. Genotyping of IFN-γ, IL-10, and TNF-α were performed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). RESULTS: A statistically significant association was found between the IL-10 -1082AA (P = 0.002), TNF-α -308AA (P = 0.0017) genotypes and the IL-10 ATA haplotype (P = 0.0123) and the occurrence of ED. In addition IL-10 -1082GG (P = 0.0005), TNF-α -308GG (P < 0.0001) genotype were found to be protective against disease occurrence. A synergistically low IL-10/high TNF-α genotype increased the risk of development (P < 0.0001) and the severity (P = 0.019) of ED. CONCLUSIONS: These data suggest that a low IL-10-expressing and high TNF-α-expressing genotype of the host can influence the occurrence and severity of outcome of ED.

Enhanced surgery-induced angiogenesis among premenopausal women might partially explain excess breast cancer mortality of blacks compared to whites: an hypothesis.

There is excess breast cancer mortality for African-Americans (AA) compared to European-Americans (EA) of 1.5-2.2 fold that first appeared in 1970s and has been worsening since. This disparity may not be explained solely by reduced access to medical care. We proposed that surgery to remove a primary tumor induces angiogenesis of distant dormant micrometastases in 20% of premenopausal node-positive patients. This hypothesis helps explain the reduced benefit of mammography for women aged 40-49. Interestingly, for AA the average age at diagnosis is 46 while for EA it is 57. The resultant increased proportion of AA premenopausal breast cancer suggests a possible explanation for the AA/EA excess mortality. Early detection, which began in the 1970s, is more effective in postmenopausal women than in premenopausal women. Since AA breast cancer is mostly premenopausal and EA breast cancer is mostly postmenopausal, it might be anticipated that starting in the 1970s because of surgery-induced early mortality, outcome would be superior for EA compared to AA.

Choroidal neovascularization in black patients.

OBJECTIVE: To characterize choroidal neovascularization (CNV) in black patients examined at a retinal disease referral center. DESIGN: Retrospective review of the medical records of all patients diagnosed as having CNV to identify black patients with CNV. SETTING: Single tertiary retinal referral center that included four ophthalmologists. PATIENTS: All patients diagnosed as having CNV between April 1990 and October 1992. MAIN OUTCOME MEASURES: Prevalence, demographic information, fundus photographic and fluorescein angiographic characteristics, natural history, and response to laser photocoagulation of CNV in black patients. RESULTS: Black patients comprise 15% of all patients seen at this center. Of 1725 patients identified as having CNV who were seen at the center during a 2.5-year period, only 25 were black (1.4%). In these patients, CNV was associated with a variety of retinal diseases, the most frequent being age-related macular degeneration. The average age of the study group was 54 years, women outnumbered men 2:1, and 13 of the patients developed bilateral lesions. Twelve of the 38 lesions were extrafoveal on presentation, and five of these were peripapillary. In the laser-treated eyes, recurrence of CNV was frequent and associated with visual loss. CONCLUSIONS: Choroidal neovascularization seems to be rare in blacks among a retinal disease referral center population. The overall presentation, natural history, and response to laser treatment seems to be similar to that of white patients. No feature of CNV in black patients was identified that would suggest that results of randomized clinical trials of laser photocoagulation for CNV are not valid for these patients.

Symptomatic choroidal neovascularization in blacks.

OBJECTIVE: To acquire descriptive clinical information regarding choroidal neovascularization (CNV) in black Americans. DESIGN: Retrospective review of 1308 fluorescein angiograms obtained during a 4-year interval. Color photographs and clinical records of all black patients with angiographically apparent CNV were subsequently reviewed. SETTING: Retina service of an inner-city county hospital in Atlanta, Ga, serving a predominantly black population. RESULTS: Thirty blacks with CNV (36 of 59 eyes) were identified, 26 (87%) of whom were female. Active, exudative neovascularization was present in at least one eye of 21 patients (70%). Patients were assigned to one of four diagnostic groups for analysis. Group 1 was made up of 13 patients (43%) with age-related macular degeneration with CNV. Women outnumbered men 5.5:1. Choroidal neovascularization was peripapillary in seven (54%) of these 13 patients. Group 2 was made up of six patients (20%) with idiopathic CNV, which was peripapillary in all eyes. Group 3 consisted of three women (10%) with idiopathic polypoidal choroidal vasculopathy. Group 4 was composed of eight patients (27%) with secondary CNV. The CNV was peripapillary in three (33%) of nine eyes, and women outnumbered men 7:1. CONCLUSIONS: The spectrum of neovascular maculopathy in blacks in the current study differed from that typically seen in whites, both clinically and demographically. Clinically, CNV was most commonly juxtapapillary (13 [68%] of 19 patients) and unilateral (12 [92%] of 13 patients) among the age-related macular degeneration and idiopathic groups, while six (20%) of 30 patients (all older than 50 years) had CNV in the absence of drusen or other known predisposing conditions. Disciform-stage CNV in both groups was associated with a greater degree of pigment proliferation than that typically noted in whites. Demographically, female predominance (87% overall) was dramatic compared with prior studies.