A smoking-associated 7-gene signature for lung cancer diagnosis and prognosis.

Smoking is responsible for 90% of lung cancer cases. There is currently no clinically available gene test for early detection of lung cancer in smokers, or an effective patient selection strategy for adjuvant chemotherapy in lung cancer treatment. In this study, concurrent coexpression with multiple signaling pathways was modeled among a set of genes associated with smoking and lung cancer survival. This approach identified and validated a 7-gene signature for lung cancer diagnosis and prognosis in smokers using patient transcriptional profiles (n=847). The smoking-associated gene coexpression networks in lung adenocarcinoma tumors (n=442) were highly significant in terms of biological relevance (network precision = 0.91, FDR<0.01) when evaluated with numerous databases containing multi-level molecular associations. The gene coexpression network in smoking lung adenocarcinoma patients was confirmed in qRT-PCR assays of the identified biomarkers and involved signaling pathway genes in human lung adenocarcinoma cells (H23) treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Furthermore, the western blotting results of p53, phospho­p53, Rb and EGFR in NNK-treated H23 and transformed normal human lung epithelial cells (BEAS-2B) support their functional involvement in smoking-induced lung cancer carcinogenesis and progression.

The rates of HIV superinfection and primary HIV incidence in a general population in Rakai, Uganda.

BACKGROUND: Human immunodeficiency virus (HIV) superinfection has been documented in high-risk individuals; however, the rate of superinfection among HIV-infected individuals within a general population remains unknown. METHODS: A novel next-generation ultra-deep sequencing technique was utilized to determine the rate of HIV superinfection in a heterosexual population by examining two regions of the viral genome in longitudinal samples from recent HIV seroconverters (n=149) in Rakai District, Uganda. RESULTS: The rate of superinfection was 1.44 per 100 person years (PYs) (95% confidence interval [CI], .4-2.5) and consisted of both inter- and intrasubtype superinfections. This was compared to primary HIV incidence in 20 220 initially HIV-negative individuals in the general population in Rakai (1.15 per 100 PYs; 95% CI, 1.1-1.2; P= .26). Propensity score matching (PS) was used to control for differences in sociodemographic and behavioral characteristics between the HIV-positive individuals at risk for superinfection and the HIV-negative population at baseline and follow-up. After PS matching, the estimated rate of primary incidence was 3.28 per 100 PYs (95% CI, 2.0-5.3; P = .07) controlling for baseline differences and 2.51 per 100 PYs (95% CI, 1.5-4.3; P = .24) controlling for follow-up differences. CONCLUSIONS: This suggests that the rate of HIV superinfection in a general population is substantial, which could have a significant impact on future public health and HIV vaccine strategies.

Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in sub-Saharan Africa.

OBJECTIVES: High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men. DESIGN: HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15-49 years who participated in male circumcision trials in Rakai, Uganda. METHODS: Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRRs) and clearance risk ratios (adjRRs). RESULTS: HR-HPV incidence was 66.5/100 person-years in HIV-positive men and 32.9/100 person-years among HIV-negative men [IRR=2.02, 95% confidence interval (CI) 1.67-2.44]. Incidence was higher in the unmarried men (adjIRR=1.73, 95% CI 1.19-2.52), and decreased with age (adjIRR for men >35 years=0.64, 95% CI 0.43-0.94) and male circumcision (adjIRR=0.70, 95% CI 0.55-0.89). HR-HPV clearance was 114.7/100 person-years for HIV-positive men and 170.2/100 person-years for HIV-negative men (risk ratio=0.67, 95% CI 0.59-0.77). HR-HPV clearance in HIV-negative men increased with circumcision (adjRR=1.48, 95% CI 1.26-1.74), HSV-2 infection (adjRR=1.20, 95% CI 1.01-1.44), and symptoms of urethral discharge (adjRR=1.35, 95% CI 1.06-1.73). Clearance of HR-HPV was significantly lower for unmarried men (adjRR 0.76, 95% CI 0.59-0.98). CONCLUSION: HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and additional prevention measures, such as HPV vaccination, is critical in sub-Saharan Africa.

Network-Based Identification of Smoking-Associated Gene Signature for Lung Cancer.

This study presents a novel computational approach to identifying a smoking-associated gene signature. The methodology contains the following steps: 1) identifying genes significantly associated with lung cancer survival, 2) selecting genes which are differentially expressed in smoker versus non-smoker groups from the survival genes, 3) from these candidate genes, constructing gene co-expression networks based on prediction logic for smokers and non-smokers, 4) identifying smoking-mediated differential components, i.e., the unique gene co-expression patterns specific to each group, and 5) from the differential components, identifying genes directly co-expressed with major lung cancer hallmarks. The identified 7-gene signature could separate lung cancer patients into two risk groups with distinct post-operative survival (log-rank P < 0.05, Kaplan-Meier analysis) in four independent cohorts (n=427). It also has implications in the diagnosis of lung cancer (accuracy = 74%) in a cohort of smokers (n=164). Computationally derived co-expression patterns were validated with Pathway Studio and STRING 8.