Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.

Purpose To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado Cohort and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic Stage I lung cancer patients from New Mexico. Experimental Design Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. Results Seventeen genes with odds ratios of 1.4 – 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (odds ratios, 3.2 – 4.2) seen for the PAX5α, GATA5, and SULF2 genes. ROC curves generated from seven gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. Conclusions These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomography screening for early detection of lung cancer.

Purpose Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of transforming growth factor β type II receptor (TGFβRII) promotes lung AdC and SCC carcinogenesis. Experimental Design We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinico-pathologic parameters. To determine if sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic KrasG12D to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. Results Reduced TGFβRII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGFβRII deletion in mouse airway epithelia increases the size and number of KrasG12D-initiated AdC and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion. Conclusions Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is at least partially mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes AdC and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII demonstrates haploid insufficiency, suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.

Background Bronchial dysplasia (BD), a presumed precursor of pulmonary squamous cell carcinoma (SCC), rarely progresses to invasive cancer. A high risk cohort at the University of Colorado provided an opportunity to directly sample airway epithelium at mapped sites on successive bronchoscopies. We have hypothesized that persistent dysplastic lesions showing a similar or higher level of dysplasia on follow-up biopsy, are associated with increased risk for the development of SCC. Methods and Material Endoscopic biopsies from 188 high risk subjects were histologically classified according to the current WHO classification for BD utilizing a numeric histology score ranging from 1-8 representing normal bronchial mucosa through invasive lung cancer. Differences in follow-up histology scores were compared between sites classified by clinical, histologic and immunohistochemical variables. Results Subjects with a higher frequency of sites that persist or progress to high grade dysplasia (≥37.5% persist/progress, N=35 versus <37.5% persist/progress, N=114) show a significant association with development of incident invasive SCC (adjusted hazard ratio: 7.84; 95% confidence interval: 1.56, 39.39), and those with incident lung SCC have adjusted mean follow-up histology scores 1.55 units higher than in subjects without lung cancer. Current smoking, elevated Ki-67 growth fraction, histologic features of angiogenic squamous dysplasia (ASD) and higher histology score in baseline biopsies are significantly associated with increased follow up histology scores. Conclusions These results show that persistent BD is associated with the development of invasive SCC. Furthermore, increased expression of Ki-67, the presence of angiogenic change and degree of baseline atypia are associated with persistence of BD.

Lung cancer usually is disseminated (advanced) and has a poor prognosis at diagnosis. Current and former smokers are at a high risk for lung cancer and are candidates for prevention and early detection strategies. Sputum is a potential source of biomarkers that might determine either lung cancer risk or the presence of early lung cancer, but no current sputum test is sufficiently sensitive and specific for effective screening. We used fluorescence in situ hybridization (FISH) to measure chromosomal aneusomy (CA) in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls (matched on age, gender, and date of collection) nested within an ongoing high-risk cohort. The CA-FISH assay was aimed at four DNA targets: epidermal growth factor receptor, MYC, 5p15, and CEP 6. The sensitivity of a positive CA-FISH assay (abnormal for two or more of the four markers) for lung cancer was substantially higher for samples collected within 18 months (76% sensitivity) than for samples collected more than 18 months (31%) before lung cancer diagnosis. Sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). CA-FISH specificity based on samples collected within 18 months before diagnosis was 88%. The adjusted odds ratio (OR) of lung cancer for specimens collected within 18 months before a cancer diagnosis was higher for the CA-FISH assay [OR, 29.9; 95% confidence interval (95% CI), 9.5-94.1] than for previously studied ORs of cytologic atypia (OR, 1.8; 95% CI, 1.3-2.6) and gene promoter methylation (OR, 6.5; 95% CI, 1.2-35.5). Whether CA-FISH is an indicator of extreme risk for incident lung cancer or detects exfoliated cancer cells is unknown. The apparent promise of CA-FISH in sputum for assessing lung cancer risk and/or for lung cancer early detection now needs to be validated in a clinical screening trial. Cancer Prev Res; 3(4); 447-53. ©2010 AACR.

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Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10 À5 ) in a recently published meta-analysis. In a GWA dataset of 1,447lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genomewide significance (OR ¼ 1.15, P ¼ 1

Weight gain following breast cancer diagnosis is common, but limited data exists on whether this gain is in excess of that gained during normal aging. This study investigated weight patterns among women with and without breast cancer to determine the effects of the breast cancer experience on weight change. Using the SHINE 4-Corners Breast Cancer Study, 305 women with breast cancer and 345 women without were followed prospectively. Weight change of ≥5% was defined as the difference between the self-reported weight measurements obtained at breast cancer diagnosis (or referent date for women without breast cancer) and about 6 yr later. Multiple logistic regression analyses were used. Within this cohort, 60% of women were overweight or obese and 37% of women gained weight. No significant greater weight gain was observed between women with vs. without breast cancer [adjusted odds ratio (ORadj) = 1.15, 95% CI 0.79-1.68] or between Hispanic vs. non-Hispanic White women (ORadj = 1.09, 95% CI 0.72-1.66) after adjustment. Weight gain was associated with being younger and having a lower body mass index. Among breast cancer survivors, cancer treatment factors were not associated with weight gain. These results suggest that weight management approaches are needed, especially those targeted to at-risk populations such as breast cancer survivors.