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1.  Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies 
PLoS ONE  2013;8(12):e83208.
Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding.
PMCID: PMC3871612  PMID: 24376664
2.  Reproducibility of Linear Array for Human Papillomavirus Genotyping 
Journal of Clinical Microbiology  2013;51(2):625-628.
We conducted a Linear Array test/retest analysis using cytologic specimens from 198 women. A total of 67.2% of samples had the same human papillomavirus (HPV) types detected in both tests (type-specific positive agreement was 83.3% overall [Kappa = 0.9] and 86.8% for carcinogenic types [Kappa = 0.92]). Discordance was highest with a low hybridization signal strength. Overall, Linear Array was highly reproducible.
PMCID: PMC3553882  PMID: 23196360
3.  Can tissue-based immune markers be used for studying the natural history of cancer? 
Annals of epidemiology  2012;22(7):520-530.
Increasing evidence suggests that altered immunity and chronic inflammation play a key role in the etiology of many malignancies, but the underlying biological mechanisms involved remain unclear. Systemic markers of immunity may not represent the clinically relevant, site-specific immune response, whereas tissue-based markers may more accurately reflect the local immunologic mechanisms by which precursor lesions develop into cancer. Tissues are often only available in individuals with disease. Previous studies have measured tumor-infiltrating lymphocytes to predict prognosis and survival, but it can be challenging to use tissue-based markers to study the natural history of cancer due to limitations with regard to temporality, the availability of appropriate comparison groups, and other epidemiologic issues. In this commentary, we discuss several epidemiologic study design and study population considerations to address these issues, including the strengths and limitations of using tissue-based markers to study immune response and cancer development. We also discuss how the use of tissue-based immune markers fits into the greater context of molecular epidemiology, which encompasses multiple technologies and techniques, and how implementation of tissue-based immune markers will provide an increased understanding of site-specific biological mechanisms involved in carcinogenesis.
PMCID: PMC3596808  PMID: 22481034
4.  Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China 
BMC Cancer  2012;12:468.
Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.
To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.
Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).
These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.
PMCID: PMC3524039  PMID: 23057767
Biliary tract cancer; Biliary stones; Inflammation; Genetic susceptibility
5.  Knowledge and Intention to Participate in Cervical Cancer Screening after the Human Papillomavirus Vaccine 
Vaccine  2011;29(25):4238-4243.
If women who receive the human papillomavirus (HPV) vaccine are unduly reassured about the cancer prevention benefits of vaccination, they may choose not to participate in screening, thereby increasing their risk for cervical cancer. This study assesses adult women’s knowledge of the need to continue cervical cancer screening after HPV vaccination, describes Pap test intentions of vaccinated young adult women, and evaluates whether knowledge and intentions differ across groups at greatest risk for cervical cancer.
Data were from the 2008 Health Information National Trends Survey (HINTS) and the 2008 National Health Interview Survey (NHIS), which initiated data collection approximately 18 months after the first FDA approval of an HPV vaccine. We calculated associations between independent variables and the outcomes using chi-square tests.
Of 1,586 female HINTS respondents ages 18 through 74, 95.6% knew that HPV-vaccinated women should continue to receive Pap tests. This knowledge did not vary significantly by race/ethnicity, education, income, or healthcare access. Among 1,101 female NHIS respondents ages 18 to 26 who had ever received a Pap test, the proportion (12.7%; n = 139) who reported receipt of the HPV vaccine were more likely than those not vaccinated to plan to receive a Pap test within three years (98.1% vs. 92.5%, p<0.001).
US adult women possess high knowledge and intention to participate in Pap testing after HPV vaccination. The vast majority of young adult women who received the HPV vaccine within its first two years on the market intend to participate in cervical cancer screening in the near future. Future studies are needed to examine whether those vaccinated in adolescence will become aware of, and adhere to, screening guidelines as they become eligible.
PMCID: PMC3105777  PMID: 21473953
human papillomavirus (HPV); cervical cancer; cancer screening; disparities
6.  Helicobacter pylori Seropositivity and Risk of Lung Cancer 
PLoS ONE  2012;7(2):e32106.
Lung cancer is the leading cause of cancer mortality worldwide. Helicobacter pylori (H. pylori) is a risk factor for distal stomach cancer, and a few small studies have suggested that H. pylori may be a potential risk factor for lung cancer. To test this hypothesis, we conducted a study of 350 lung adenocarcinoma cases, 350 squamous cell carcinoma cases, and 700 controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) cohort of male Finnish smokers. Controls were one-to-one matched by age and date of baseline serum draw. Using enzyme-linked immunosorbent assays to detect immunoglobulin G antibodies against H. pylori whole-cell and cytotoxin-associated gene (CagA) antigens, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between H. pylori seropositivity and lung cancer risk using conditional logistic regression. H. pylori seropositivity was detected in 79.7% of cases and 78.5% of controls. After adjusting for pack-years and cigarettes smoked per day, H. pylori seropositivity was not associated with either adenocarcinoma (OR: 1.1, 95% CI: 0.75–1.6) or squamous cell carcinoma (OR: 1.1, 95% CI: 0.77–1.7). Results were similar for CagA-negative and CagA-positive H. pylori seropositivity. Despite earlier small studies suggesting that H. pylori may contribute to lung carcinogenesis, H. pylori seropositivity does not appear to be associated with lung cancer.
PMCID: PMC3286451  PMID: 22384154
7.  Racial Differences in Chronic Immune Stimulatory Conditions and Risk of Non-Hodgkin's Lymphoma in Veterans From the United States 
Journal of Clinical Oncology  2010;29(4):378-385.
To examine underlying etiologic factors that may explain the racial disparity in non-Hodgkin's lymphoma (NHL) incidence patterns.
Patients and Methods
We assessed immune-related conditions and risk of developing NHL among more than 4 million hospitalized US veterans including 9,496 patients with NHL (7,999 white patients and 1,497 black patients) with up to 26 years of follow-up. We used time-dependent Poisson regression to estimate rate ratios (RRs) and 95% CIs for NHL risk among patients with a history of specific autoimmune diseases, infections, and allergies compared with patients without such history, adjusting for attained age, calendar year, race, number of hospital visits, and time between study entry and exit.
Patients with infectious conditions had an increased risk of developing NHL (RR, 1.2; 95% CI, 1.1 to 1.2), particularly for gastrohepatic, genital, and systemic infectious conditions. Patients with autoimmune disease were generally more likely to develop NHL than patients without autoimmune disease, especially for conditions that typically present with detectable autoantibodies with systemic involvement (RR, 2.0; 95% CI, 1.8 to 2.2). Allergies were also associated with increased risk (RR, 1.4; 95% CI, 1.3 to 1.5). Although the risk of NHL was lower for blacks than whites (RR, 0.87; 95% CI, 0.82 to 0.92), blacks had a slightly higher risk of NHL associated with infections than whites (likelihood ratio test, P = .002) and a tendency toward higher risk associated with allergies (likelihood ratio test, P = .05). Risks associated with autoimmune conditions were similar by race (likelihood ratio test, P = .5).
The observed difference in NHL risk by race supports a role for race-related differences in genes regulating immune/inflammatory response.
PMCID: PMC3058284  PMID: 21172877
8.  MicroRNA expression differentiates histology and predicts survival of lung cancer 
The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histological subtypes and predict survival for non-small cell lung cancer.
Experimental design
We analyzed miR expression in 165 adenocarcinoma (AD) and 125 squamous cell carcinoma (SQ) tissue samples from the Environmental And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t-tests and F-tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards and survival risk prediction models, accounting for demographic and tumor characteristics.
MiR expression profiles strongly differed between AD and SQ (global p<0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were down-regulated in SQ. Major findings were confirmed by QRT-PCR in EAGLE samples and in an independent set of lung cancer cases. In SQ, low expression of miRs down-regulated in the histology comparison was associated with 1.2 to 3.6-fold increased mortality risk. A 5-miR signature significantly predicted survival for SQ.
We identified a miR expression profile that strongly differentiated AD from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.
PMCID: PMC3163170  PMID: 20068076
10.  No role for human papillomavirus in esophageal squamous cell carcinoma in China 
Certain regions of China have high rates of esophageal squamous cell carcinoma (ESCC). Previous studies of human papillomavirus (HPV), a proposed causal factor, have produced highly variable results. We attempted to evaluate HPV and ESCC more definitively using extreme care to prevent DNA contamination. We collected tissue and serum in China from 272 histopathologically-confirmed ESCC cases with rigorous attention to good molecular biology technique. We tested for HPV DNA in fresh-frozen tumor tissue using PCR with PGMY L1 consensus primers and HPV16 and 18 type-specific E6 and E7 primers, and in formalin-fixed paraffin-embedded tumor tissue using SPF10 L1 primers. In HPV-positive cases, we evaluated p16INK4a overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity. β-globin, and thus DNA, was adequate in 98.2% of the frozen tumor tissues (267/272). Of these, 99.6% (95% confidence interval (CI) = 97.9–100.0%) were negative for HPV DNA by PGMY, and 100% (95% CI = 98.6–100%) were negative by HPV16/18 E6/E7 PCR. In the corresponding formalin-fixed paraffin-embedded tumor specimens, 99.3% (95% CI = 97.3–99.9%) were HPV negative by SPF10. By PGMY, 1 case tested weakly positive for HPV89, a noncancer causing HPV type. By SPF10, 2 cases tested weakly positive: 1 for HPV16 and 1 for HPV31. No HPV DNA-positive case had evidence of HPV oncogene activity as measured by p16INK4a overexpression or E6/E7 seropositivity. This study provides the most definitive evidence to date that HPV is not involved in ESCC carcinogenesis in China. HPV DNA contamination cannot be ruled out as an explanation for high HPV prevalence in ESCC tissue studies with less stringent tissue procurement and processing protocols.
PMCID: PMC3069961  PMID: 19918949
human papillomavirus; esophageal squamous cell carcinoma
11.  Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenström Macroglobulinemia 
Chronic immune stimulation appears to be associated with lymphoplasmacytic lymphoma (LPL)-Waldenström macroglobulinemia (WM); however, available information is sparse. We conducted, to our knowledge, the most comprehensive study to date to evaluate associations between a personal or family history of many immune-related and/or inflammatory disorders and the subsequent risk of LPL-WM.
We used Swedish population-based registries to identify 2470 case patients with LPL-WM, 9698 matched control subjects, and almost 30 000 first-degree relatives of either case patients or control subjects. We evaluated a wide range of autoimmune, infectious, allergic, and inflammatory conditions. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each condition by use of logistic regression.
An increased risk of LPL-WM was associated with a personal history of the following autoimmune diseases: systemic sclerosis (OR = 4.7, 95% CI = 1.4 to 15.3), Sjögren syndrome (OR = 12.1, 95% CI = 3.3 to 45.0), autoimmune hemolytic anemia (OR = 24.2, 95% CI = 5.4 to 108.2), polymyalgia rheumatica (OR = 2.9, 95% CI = 1.6 to 5.2), and giant cell arteritis (OR = 8.3, 95% CI = 2.1 to 33.1). An increased risk of LPL-WM was associated with a personal history of the following infectious diseases: pneumonia (OR = 1.4, 95% CI = 1.1 to 1.7), septicemia (OR = 2.4, 95% CI = 1.2 to 4.3), pyelonephritis (OR = 1.7, 95% CI = 1.1 to 2.5), sinusitis (OR = 2.7, 95% CI = 1.4 to 4.9), herpes zoster (OR = 3.4, 95% CI = 2.0 to 5.6), and influenza (OR = 2.9, 95% CI = 1.7 to 5.0). An increased risk of LPL-WM was associated with a family history of the following autoimmune or infectious diseases: Sjögren syndrome (OR = 5.0, 95% CI = 2.1 to 12.0), autoimmune hemolytic anemia (OR = 3.8, 95% CI = 1.1 to 13.2), Guillain–Barré syndrome (OR = 4.1, 95% CI = 1.8 to 9.4), cytomegalovirus (OR = 2.7, 95% CI = 1.4 to 5.3), gingivitis and periodontitis (OR = 1.9, 95% CI = 1.3 to 2.7), and chronic prostatitis (OR = 4.3, 95% CI = 1.7 to 11.1).
Personal history of certain immune-related and/or infectious conditions was strongly associated with increased risk of LPL-WM. The association of both personal and family history of Sjögren syndrome and autoimmune hemolytic anemia with risk of LPL-WM indicates the potential for shared susceptibility for these conditions.
PMCID: PMC2857799  PMID: 20181958
12.  The Gastric Cardia is not a Target for Human Papillomavirus-induced Carcinogenesis 
Thousands of people in central Asia die every year from gastric cardia adenocarcinoma (GCA). GCA arises in the transformation zone between the esophagus and the stomach, similar to cervical and oropharyngeal carcinoma, which arise in areas with transformation zone characteristics. The analogous biology of the gastric cardia to the cervix and oropharynx, where human papillomavirus (HPV) is known to cause cancer, raises the possibility that GCA could be an HPV-associated cancer. Given the availability of an effective HPV vaccine and its potential to prevent HPV-associated cancer, we decided to evaluate the prevalence of HPV DNA in GCA.
We collected tumor tissue from 144 histopathologically-confirmed GCA patients at Yaocun Commune Hospital, Linxian, China, with rigorous attention to prevent DNA contamination. We tested for the presence of HPV DNA in fresh-frozen tumor specimens using PCR with sensitive L1, E6, and E7-based primers.
DNA was adequate, as indicated by β-globin positivity, in 108 cases. Of these, all (100%, 95% confidence interval: 97%–100%) were negative for HPV DNA
These results suggest that HPV does not contribute to gastric cardia carcinogenesis in north central China.
Since GCA does not appear to be an HPV-associated cancer, prophylactic HPV vaccination is unlikely to affect rates of GCA in China.
PMCID: PMC2852466  PMID: 20332262
13.  Strengths and limitations of laboratory procedures for microRNA detection 
MicroRNAs (miRs) are endogenous, non-coding RNAs involved in many cellular processes and have been associated with the development and progression of cancer. There are many different ways to evaluate miRs.
We described some of the most commonly used and promising miR detection methods.
Each miR detection method has benefits and limitations. Microarray profiling and quantitative real-time reverse transcription PCR (qRT-PCR) are the two most common methods to evaluate miR expression. However, the results from microarray and qRT-PCR do not always agree. High-throughput, high-resolution next generation sequencing of small RNAs may offer the opportunity to quickly and accurately discover new miRs and confirm the presence of known miRs in the near future.
All of the current and new technologies have benefits and limitations to consider when designing miR studies. Results can vary across platforms, requiring careful and critical evaluation when interpreting findings.
Although miR detection and expression analyses are rapidly improving, there are still many technical challenges to overcome. The old molecular epidemiology tenet of rigorous biomarker validation and confirmation in independent studies remains essential.
PMCID: PMC2852469  PMID: 20332265
14.  Lower Risk of Lung Cancer after Multiple Pneumonia Diagnoses 
Although pneumonia has been suggested as a risk factor for lung cancer, previous studies have not evaluated the influence of number of pneumonia diagnoses in relation to lung cancer risk.
The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based study of 2,100 cases and 2,120 controls collected information on pneumonia more than one year before enrollment from 1,890 cases and 2,078 controls.
After adjusting for study design variables, smoking, and chronic bronchitis, pneumonia was associated with decreased risk of lung cancer (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.64–0.97), especially among individuals with ≥3 diagnoses versus none (OR, 0.35; 95% CI, 0.16–0.75). Adjustment for chronic bronchitis contributed to this inverse association. In comparison, pulmonary tuberculosis was not associated with lung cancer (OR, 0.96; 95% CI, 0.62–1.48).
The apparent protective effect of pneumonia among individuals with multiple pneumonia diagnoses may reflect an underlying difference in immune response and requires further investigation and confirmation.
Careful evaluation of number of pneumonia episodes may shed light on lung cancer etiology.
PMCID: PMC2837523  PMID: 20200440
pneumonia; epidemiology; lung cancer; multiple infections; tuberculosis
15.  Assessment of Human Papillomavirus in Lung Tumor Tissue 
Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)–associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial.
We selected 450 lung cancer patients from an Italian population–based case–control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated.
Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type–specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type.
When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.
PMCID: PMC3057981  PMID: 21293027
16.  Evaluation of normalization methods for two-channel microRNA microarrays 
MiR arrays distinguish themselves from gene expression arrays by their more limited number of probes, and the shorter and less flexible sequence in probe design. Robust data processing and analysis methods tailored to the unique characteristics of miR arrays are greatly needed. Assumptions underlying commonly used normalization methods for gene expression microarrays containing tens of thousands or more probes may not hold for miR microarrays. Findings from previous studies have sometimes been inconclusive or contradictory. Further studies to determine optimal normalization methods for miR microarrays are needed.
We evaluated many different normalization methods for data generated with a custom-made two channel miR microarray using two data sets that have technical replicates from several different cell lines. The impact of each normalization method was examined on both within miR error variance (between replicate arrays) and between miR variance to determine which normalization methods minimized differences between replicate samples while preserving differences between biologically distinct miRs.
Lowess normalization generally did not perform as well as the other methods, and quantile normalization based on an invariant set showed the best performance in many cases unless restricted to a very small invariant set. Global median and global mean methods performed reasonably well in both data sets and have the advantage of computational simplicity.
Researchers need to consider carefully which assumptions underlying the different normalization methods appear most reasonable for their experimental setting and possibly consider more than one normalization approach to determine the sensitivity of their results to normalization method used.
PMCID: PMC2917409  PMID: 20663154
17.  Knowledge of Human Papillomavirus 
Journal of health communication  2009;14(4):331-345.
The aim of this study was to evaluate knowledge about human papillomavirus (HPV) in individuals with genital warts compared to women from the general population without genital warts. HPV knowledge among women reporting treatment for genital warts was compared to HPV knowledge in women reporting no treatment was assessed using data from the population-based 2005 Health Information National Trends Survey. Three percent (N=97) of women answered “yes” and 97% (N=3450) “no” to “Have you ever been treated for venereal warts or condyloma?” Women who reported treatment for genital warts were more likely to have heard of HPV (Odds ratio (OR): 2.4, 95% confidence interval (CI): 1.4-4.2 vs. no or don’t know), to have been told they had HPV (OR: 24.5, 95% CI: 11.4-52.8), and to have accurate information about HPV, such as HPV causes cancer (OR: 2.7, 95% CI: 1.8-4.3). However, a large proportion (41%) of women who reported treatment for genital warts had not heard of HPV. These women tended to be older, poorer, less educated, non-Hispanic black, less likely to have had a recent Pap test, and divorced, widowed, or separated. Women with genital warts are learning about HPV, but socioeconomically disadvantaged groups may need to be targeted.
PMCID: PMC2768561  PMID: 19466646
Human papillomavirus; knowledge; genital warts
18.  Common genetic variation in TP53 and risk of human papillomavirus persistence and progression to CIN3/cancer revisited 
Driven by findings that human papillomavirus (HPV)-induced degradation of p53 differs by a TP53 polymorphism at codon 72 (Pro72Arg), past studies of TP53 genetic variants and cervical cancer have focused on this nonsynonymous polymorphism, with mixed results. We analyzed common single nucleotide polymorphisms (SNPs) across the TP53 locus in a population-based nested case-control study in Guanacaste, Costa Rica. We evaluated 11 SNPs, including Pro72Arg (rs1042522), among 1,281 women: 465 with cervical intraepithelial neoplasia grade 3/cancer (CIN3+), 380 with HPV persistence (median: 25 months), and 436 random population controls. We combined HPV persistence and CIN3+ into one case group because they did not differ in TP53 genotypic frequencies and calculated odds ratios (OR) and 95%confidence intervals (CI) for individual SNPs and inferred haplotypes. We observed that proline at codon 72 was associated with increased risk of CIN3+/persistence compared to population controls. Relative to GG (Arg), the CG (Pro/Arg) and CC (Pro) genotypes had a 1.3-fold (95% CI, 0.99–1.6) and 1.8-fold (95% CI, 1.2–2.7) increased risk, respectively (p-trend<0.01). rs12951053 and rs1642785 were also associated with CIN3+/persistence (p-trend, 0.05 and 0.04, respectively), as was a haplotype containing the codon 72 variant (rs1042522), rs12951053, rs1642785, and rs12947788 (OR, 1.6; 95% CI, 1.1–2.3 versus the most common haplotype, which comprised the major alleles for all 11 SNPs). Although genetic variation in TP53 might affect the natural history of HPV and cervical cancer, further work is needed to elucidate the possible mechanism.
PMCID: PMC2764239  PMID: 19423538
TP53; polymorphisms; human papillomavirus; persistence; cervical neoplasia
19.  Genetic and immune-related factors in the pathogenesis of lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia 
Clinical lymphoma & myeloma  2009;9(1):23-26.
There are emerging data to support a role for genetic and immune-related factors in the pathogenesis of lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. In this paper, we review our recently published large population-based studies using data from Sweden and from U.S. Veterans and proposed mechanisms and pathways underlying our observations. We also talk about future directions for new studies designed to increase our current knowledge and to define underlying biological mechanisms of our findings. Finally, based on novel insights on this topic, we discuss clinical implications and provide perspective on the relevance of these data for patient counseling and clinical follow-up.
PMCID: PMC2796606  PMID: 19362964
Lymphoplasmacytic lymphoma; Waldenström’s macroglobulinemia; lymphoproliferative malignancies; MGUS; familial aggregation; susceptibility; immune-related; hepatitis C virus; autoimmune disease; rheumatoid arthritis
20.  Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study 
PLoS ONE  2009;4(10):e7380.
Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.
Methodology/Principal Findings
The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).
These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.
PMCID: PMC2753644  PMID: 19812684
21.  Chronic immune stimulation and subsequent Waldenström’s macroglobulinemia 
Archives of internal medicine  2008;168(17):1903-1909.
Certain autoimmune and infectious conditions are associated with increased risks of subtypes of non-Hodgkin’s lymphomas (NHL). A few prior studies suggest that chronic inflammation may particularly elevate risk for the distinct NHL subtype Waldenström’s macroglobulinemia (WM). We assessed WM risk in relation to a wide range of chronic immune stimulatory conditions among 4 million U.S. veterans.
We identified 361 WM cases with up to 27 years of follow-up. Using time-dependent Poisson regression we estimated rate ratios (RR) and 95% confidence intervals (CI) for WM risk in relation to history of autoimmune diseases that typically have autoantibodies (with systematic or organ involvement) or do not have autoantibodies, infections, and allergies. All models were adjusted for attained age, calendar-year, race, number of hospital visits, and latency between study entry and exit.
The age-standardized incidence of WM was 0.34/100,000 person-years. WM risk was elevated among individuals with any prior autoimmune condition (RR, 2.2; 95% CI, 1.7–3.0), autoantibodies with systemic involvement (RR, 2.50; 95% CI, 1.55–4.02), autoantibodies with organ involvement (RR, 2.30; 95% CI, 1.57–3.37). Risks for WM were also increased with hepatitis (RR, 3.39; 95% CI, 1.38–8.30), human immunodeficiency virus (HIV) (RR, 12.05; 95% CI, 2.83–51.46), and rickettsiosis (RR, 3.35; 95% CI, 1.38–8.14)
In the largest investigation of WM risk factors to date, we found 2- to 3-fold elevated risk of WM among persons with a personal history of autoimmune diseases with autoantibodies and notably elevated risks for hepatitis, HIV, and rickettsiosis. Our findings provide novel insights into the as yet unknown etiology of WM.
PMCID: PMC2670401  PMID: 18809818
22.  Persistent Human Papillomavirus Infection and Cervical Neoplasia: A Systematic Review and Meta-Analysis 
American Journal of Epidemiology  2008;168(2):123-137.
Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as a marker for cervical cancer risk in clinical trials. The authors performed a systematic review and meta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelial neoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use. MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) were stratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in the meta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detection and cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95% confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus 12 months), wider testing intervals, CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higher RRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite wide variation in definitions and study methods. The magnitude of association varied by duration of persistence and testing interval. Precise definition and standardization of HPV testing, sampling procedure, and test interval are needed for reliable clinical testing. These findings validate HPV persistence as a clinical marker and endpoint.
PMCID: PMC2878094  PMID: 18483125
human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms

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