Jill A. Ohar

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk

Deletions on human chromosome 8p22–23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Chronic Obstructive Pulmonary Disease and Asthma–Patient Characteristics and Health Impairment

Abstract Background: Persons with chronic obstructive pulmonary disease (COPD) and/or asthma have great risk for morbidity. There has been sparse state-specific surveillance data to estimate the impact of COPD or COPD with concomitant asthma (overlap syndrome) on health-related impairment. Methods: The North Carolina (NC) Behavioral Risk Factor Surveillance System (BRFSS) was used to assess relationships between COPD and asthma with health impairment indicators. Five categories [COPD, current asthma, former asthma, overlap syndrome, and neither] were defined for 24,073 respondents. Associations of these categories with health impairments (physical or mental disability, use of special equipment, mental or physical distress) and with co-morbidities (diabetes, coronary heart disease, stroke, arthritis, and high blood pressure) were assessed. Results: Fifteen percent of NC adults reported a COPD and/or asthma history. The overall age-adjusted prevalence of any self-reported COPD and current asthma were 5.6% and 7.6%, respectively; 2.4% reported both. In multivariable analyses, adults with overlap syndrome, current asthma only, and COPD only were twice as likely as those with neither disease to report health impairments (p < 0.05). Compared to those with neither disease, adults with overlap syndrome and COPD were more likely to have co-morbidities (p < 0.05). The prevalence of the five co-morbid conditions was highest in overlap syndrome; comparisons with the other groups were significant (p < 0.05) only for diabetes, stroke, and arthritis. Conclusions: The BRFSS demonstrates different levels of health impairment among persons with COPD, asthma, overlap syndrome, and those with neither disease. Persons reporting overlap syndrome had the most impairment and highest prevalence of co-morbidities.

Do Symptoms Predict COPD in Smokers

BACKGROUND The US Preventive Services Task Force recommends against spirometry in the absence of symptoms. However, as much as 50% of COPD cases in the United States remain undiagnosed. METHODS Report of symptoms, smoking history, and spirometric data were collected from subjects screened for a work-related medical evaluation (N = 3,955). Prevalence of airflow obstruction and respiratory symptoms were assessed. Sensitivity, specificity, positive and negative predictive values, and relative risks of predicting symptoms and smoking history for COPD were calculated. RESULTS Forty-four percent of smokers in our sample had airways obstruction (AO). Of these, 36% reported a diagnosis of or treatment for COPD. Odds ratio (95% CI) for AO with smoking (> or = 20 pack-years) was 3.73 (3.12- 4.45), 1.98 (1.73-2.27) for cough, 1.79 (1.55-2.08) for dyspnea, 1.95 (1.70-2.34) for sputum, and 2.59 (2.26-2.97) for wheeze. Respiratory symptoms were reported by 92% of smokers with AO, 86% smokers with restriction, 76% smokers with normal spirometry, and 73% of nonsmokers. Sensitivity (92% vs 90%), specificity (19% vs 22%), positive (47% vs 40%) and negative (75% vs 80%) predictive values for the presence of one or more symptoms were similar between smokers and all subjects. CONCLUSIONS COPD is underdiagnosed in the United States. Symptoms are frequent in subjects with AO and increase their risk for COPD, but add little beyond age and smoking history to the predictive value of spirometry. In view of the high prevalence of symptoms and their poor predictive value, a simpler and more effective approach would be to screen older smokers.

COPD Is Associated With a Macrophage Scavenger Receptor-1 Gene Sequence Variation

BACKGROUND Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene (MSR1) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis. METHODS Smokers (> or = 20 pack-years) who were > 40 years (n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293x_C/T), four missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G, and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, and IVS5-59_C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A_CG/GG and eight P275A_CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1). RESULTS The MSR1-coding SNP P275A was associated with susceptibility to COPD in smokers (P < .005) and a lower percent predicted (pp) FEV(1), FEV(1)/FVC, and pp forced expiratory flow (FEF)(25-75) (P = .03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vitro (P < .05). CONCLUSIONS The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.

Characteristics and Prevalence of Asthma/Chronic Obstructive Pulmonary Disease Overlap in the United States.

RATIONALE The asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) occurs in patients with fixed airway obstruction that defines COPD and with symptoms more typical of asthma. ACOS prevalence and the comorbidities associated with this syndrome have been inadequately characterized. OBJECTIVES Because this population is prone to more frequent exacerbations, we hypothesized that comorbidities associated with ACOS are higher than those with COPD, asthma, and control populations in the United States. METHODS We examined the self-reported demographics, smoking status, comorbidities, and hospitalization or emergency department (ED) visitation experience among study respondents older than 35 years of age (n = 90,851) in the Behavioral Risk Factor Surveillance System survey and compared participants with ACOS to COPD, asthma, and control groups. We used logistic regression to compare ACOS and COPD populations to model the impact of comorbid conditions and hospitalization/ED visits after adjusting for demographic factors and smoking status to generate odds ratios and confidence intervals. MEASUREMENTS AND MAIN RESULTS The U.S. prevalence of ACOS was 3.2%, COPD alone was 6.0%, and both increased with age. Respondents with ACOS were younger (64.0 ± 11.7 yr) than respondents with COPD (67.1 ± 11.8 yr) and older than respondents with asthma (59.0 ± 13.1 yr; P < 0.0001). The prevalence of comorbidities was higher in the group with ACOS and COPD than in asthma or control groups. The ACOS group had a higher body mass index, lower income, and lower education than other groups. The ACOS group was more likely to have at least one comorbidity (90.2 vs. 84%, P < 0.0001), more hospitalization or ED visits (22.0 vs. 13.2%, P < 0.0001), less exercise (50.0 vs. 58.6%, P = 0.0024), and more disability (70.8 vs. 58.6%, P < 0.0001) than the COPD group. CONCLUSIONS The patients with a dual diagnosis of asthma and COPD are younger and with more disparities than those diagnosed with COPD alone. ACOS has a higher burden of self-reported comorbidity, disability, and hospitalization or ED visitation than COPD alone.

Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.

Smoking duration, respiratory symptoms, and COPD in adults aged ≥45 years with a smoking history

Background The purpose of this study was to assess the relationship of smoking duration with respiratory symptoms and history of chronic obstructive pulmonary disease (COPD) in the South Carolina Behavioral Risk Factor Surveillance System survey in 2012. Methods Data from 4,135 adults aged ≥45 years with a smoking history were analyzed using multivariable logistic regression that accounted for sex, age, race/ethnicity, education, and current smoking status, as well as the complex sampling design. Results The distribution of smoking duration ranged from 19.2% (1–9 years) to 36.2% (≥30 years). Among 1,454 respondents who had smoked for ≥30 years, 58.3% were current smokers, 25.0% had frequent productive cough, 11.2% had frequent shortness of breath, 16.7% strongly agreed that shortness of breath affected physical activity, and 25.6% had been diagnosed with COPD. Prevalence of COPD and each respiratory symptom was lower among former smokers who quit ≥10 years earlier compared with current smokers. Smoking duration had a linear relationship with COPD (P<0.001) and all three respiratory symptoms (P<0.001) after adjusting for smoking status and other covariates. While COPD prevalence increased with prolonged smoking duration in both men and women, women had a higher age-adjusted prevalence of COPD in the 1–9 years, 20–29 years, and ≥30 years duration periods. Conclusion These state population data confirm that prolonged tobacco use is associated with respiratory symptoms and COPD after controlling for current smoking behavior.

Changing Pattern in Malignant Mesothelioma Survival

Survival for mesothelioma has been shown to be poor, with marginal improvement over time. Recent advances in the understanding of pathophysiology and treatment of mesothelioma may impact therapy to improve survival that may not be evident from available clinical trials that are often small and not randomized. Therapies may affect survival differently based on mesothelioma location (pleural vs peritoneal). Data are conflicting regarding the effect of asbestos exposure on mesothelioma location. OBJECTIVES: We examined survival in a large cohort of mesothelioma subjects analyzed by tumor location and presence and mode of asbestos exposure. METHODS: Data were analyzed from cases (n = 380) diagnosed with mesothelioma from 1992 to 2012. Cases were either drawn from treatment referrals, independent medical evaluation for medical legal purposes, or volunteers who were diagnosed with mesothelioma. Subjects completed an occupational medical questionnaire, personal interview with the examining physician, and physician review of the medical record. RESULTS: This study reports better survival for mesothelioma than historical reports. Survival for peritoneal mesothelioma was longer than that for pleural mesothelioma (hazard ratio = 0.36, 95% confidence interval = 0.24-0.54, P < .001) after adjusting for gender and age at diagnosis. Non-occupational cases were more likely to be 1) diagnosed with peritoneal mesothelioma, 2) female, 3) exposed, and 4) diagnosed at a younger age and to have a 5) shorter latency compared to occupational cases (P < .001). CONCLUSION: Peritoneal mesothelioma was more likely associated with non-occupational exposure, thus emphasizing the importance of exposure history in enhancing early diagnosis and treatment impact.

Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction.

We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively.

Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and health care expenditure worldwide. Relaxation of airway smooth muscle with inhaled bronchodilators is the cornerstone of treatment for stable COPD, with inhaled corticosteroids reserved for those with a history of exacerbations. Tiotropium has occupied center stage in COPD treatment for over 10 years and improves lung function, quality of life, exercise endurance, and reduces the risk of COPD exacerbation. Long-acting β2-agonists (LABAs) improve lung function, reduce dynamic hyperinflation, increase exercise tolerance, health-related quality of life, and reduce acute exacerbation of COPD. The combination of long-acting muscarinic antagonists (LAMAs) and LABAs is thought to leverage different pathways to induce bronchodilation using submaximal drug doses, increasing the benefits and minimizing receptor-specific side effects. Umeclidinium/vilanterol is the first combination of LAMA/LABA to be approved for use in stable COPD in USA and Europe. Additionally, indacaterol/glycopyrronium and aclidinium/formoterol have been approved in Europe and in numerous locations outside USA. Several other agents are in the late stages of development, most of which offer once-daily dosing. The benefits of new LAMA/LABA combinations include improved pulmonary function, dyspnea, and health-related quality of life, and in some cases, reduced exacerbations. These evolving treatments will provide new opportunities and challenges in the management of COPD.