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1.  Declining Second Primary Ovarian Cancer After First Primary Breast Cancer 
Journal of Clinical Oncology  2013;31(6):738-743.
Purpose
Although ovarian cancer incidence rates have declined in the United States, less is known of ovarian cancer trends among survivors of breast cancer. Therefore, we examined second primary ovarian cancers after first primary breast cancer.
Methods
Data were obtained from the Surveillance, Epidemiology, and End Results program (1973 to 2008). Standardized incidence ratios (SIRs) were calculated as the observed numbers of ovarian cancers among survivors of breast cancer compared with the expected numbers in the general population. Absolute rates were measured as the incidence rates for second primary ovarian cancer by year of diagnosis of the first primary breast cancer adjusted for age of breast cancer diagnosis and years since diagnosis.
Results
SIRs for second primary ovarian cancer were elevated over the entire study period (SIR, 1.24; 95% CI, 1.2 to 1.3), whereas the absolute rates declined with an estimated annual percentage change near 1% (−1.34% to −0.09% per year). Secular trends for second ovarian cancers were similar after estrogen receptor (ER) –positive and ER-negative breast cancers, whereas the age-specific patterns varied significantly by ER expression (P for interaction < .001). The largest SIR was among women age less than 50 years with ER-negative breast cancer (SIR, 4.35; 95% CI, 3.5 to 5.4).
Conclusion
Persistently elevated SIRs along with decreasing absolute rates over the entire study period suggest that ovarian cancers in both the general population and survivors of breast cancer are declining in parallel, possibly because of common risk factor exposures. Analytic studies are needed to further assess the parallel overall trends and the age-specific interaction by ER expression.
doi:10.1200/JCO.2012.43.2757
PMCID: PMC3574269  PMID: 23284037
2.  Extensions of criteria for evaluating risk prediction models for public health applications 
Biostatistics (Oxford, England)  2012;14(2):366-381.
We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057–1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case–control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data.
doi:10.1093/biostatistics/kxs037
PMCID: PMC3695651  PMID: 23087412
Area under the receiver operator characteristics curve (ROC); AUC; Discrimination; Discriminatory accuracy; Risk models; Study design
3.  An Aggregated Analysis of Hormonal Factors and Endometrial Cancer Risk by Parity 
Cancer  2012;119(7):1393-1401.
Background
Nulliparity is associated with an increased risk of endometrial cancer. Less clear is whether nulliparity modifies the association between other established hormone-related risk factors. The proportion of nulliparous women has increased since the mid-1970s, but most individual studies are too small to test the hypothesis that endometrial cancer risk factors may be more strongly associated with risk among nulliparous women compared with parous women.
Methods
We aggregated data on 26,936 postmenopausal, Caucasian nulliparous women (360 endometrial cancers) and 146,583 postmenopausal Caucasian parous women (1,378 endometrial cancers) from four U.S. prospective studies (1979–2006). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) in stratified analyses.
Results
As expected, endometrial cancer risk was higher among nulliparous women than among parous women (HR, nulliparous vs. parous = 1.42, 95% CI 1.26 to 1.60). Stratified associations between endometrial cancer and hormone-related risk factors did not differ among nulliparous vs. parous women: among both groups, oral contraceptives and earlier menopause were associated with reduced risk. The highest HRs were for obesity; body mass index ≥30 kg/m2 (vs. <25 kg/m2) increased endometrial cancer risk three-fold among nulliparous (HR= 3.04, 95% CI 2.34 to 3.94) and parous (HR= 2.88, 95% CI 2.52 to 3.29) women.
Conclusions
The results from this large, pooled analysis of data from four large prospective studies suggest that nulliparity does not modify endometrial cancer risks associated with established hormone-related risk factors.
doi:10.1002/cncr.27909
PMCID: PMC3744666  PMID: 23280123
endometrial cancer; nulliparity; reproductive history; oral contraceptives; hormonal; obesity
4.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
5.  Prediagnosis Body Mass Index, Physical Activity, and Mortality in Endometrial Cancer Patients 
Background
Higher body mass index (BMI) and inactivity have been associated with a higher risk of developing endometrial cancer, but the impact on endometrial cancer survival is unclear.
Methods
Among incident endometrial cancer case subjects in the National Institutes of Health–AARP Diet and Health Study, we examined associations of prediagnosis BMI (n = 1400) and physical activity (n = 875) with overall and disease-specific 5- and 10-year mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for tumor characteristics, treatment, and other risk factors. All statistical tests were two-sided.
Results
Compared with women with a BMI in the range of 18.5 to less than 25kg/m2, the hazard ratios for 5-year all-cause mortality were 1.74 (95% CI = 1.13 to 2.66) for BMI in the range of 25 to less than 30kg/m2, 1.84 (95% CI = 1.17 to 2.88) for BMI in the range of 30 to less than 35kg/m2, and 2.35 (95% CI = 1.48 to 3.73) for BMI greater than or equal to 35kg/m2 (P trend < .001). Higher BMI was also statistically significantly associated with poorer endometrial cancer–specific but not cardiovascular disease 5-year mortality. Hazard ratio estimates for 10-year all-cause and endometrial cancer–specific mortality as related to BMI were similar to 5-year hazard ratio estimates, whereas 10-year cardiovascular disease mortality became statistically significant (HR = 4.08; 95% CI = 1.56 to 10.71 comparing extreme BMI groups). More physical activity was related to lower all-cause 5-year mortality (HR = 0.57, 95% CI = 0.33 to 0.98 for >7 hours/week vs never/rarely), but the association was attenuated after adjustment for BMI (HR = 0.64, 95% CI = 0.37 to 1.12). No association was observed between physical activity and disease-specific mortality.
Conclusions
Our findings suggest that higher prediagnosis BMI increases risk of overall and disease-specific mortality among women diagnosed with endometrial cancer, whereas physical activity lowers risk. Intervention studies of the effect of these modifiable lifestyle factors on mortality are needed.
doi:10.1093/jnci/djs530
PMCID: PMC3589256  PMID: 23297041
6.  Characterization of ELISA Detection of Broad-spectrum Anti- Epstein-Barr Virus Antibodies Associated with Nasopharyngeal Carcinoma 
Journal of medical virology  2012;85(3):524-529.
Epstein-Barr virus (EBV) infection is associated with undifferentiated nasopharyngeal carcinomas (NPC). A distinct seroreactivity pattern to EBV is predictive of subsequent risk of sporadic and familial nasopharyngeal carcinomas. There are currently no accepted screening tools for guiding the clinical management of individuals at high-risk for nasopharyngeal carcinomas, particularly unaffected relatives from nasopharyngeal carcinoma multiplex families. Therefore, the reproducibility of a panel of largely synthetic peptide-based anti-EBV antibody ELISAs was evaluated and their ability to distinguish nasopharyngeal carcinoma cases from controls was explored. IgG and IgA antibodies against 6 different EBV antigens (10 assays, total) were tested on sera from 97 individuals representing the full spectrum of anti-EBV seroprevalence (i.e., healthy individuals with no known EBV seroreactivity, healthy individuals with known EBV seroreactivity, and nasopharyngeal carcinoma cases). Each specimen was tested in triplicate to assess within-batch and across-batch variation, and the triplicate testing was repeated on two separate days. Reproducibility was assessed by the coefficients of variation (CV) and intraclass correlation coefficients (ICC). All markers were detectable in 17% or more of samples. For all but one marker, the overall, within-batch, and across-batch CVs were below 15%, and the ICCs were above 70% for all but three markers. Sensitivity of these markers to detect prevalent nasopharyngeal carcinomas ranged from 22–100%, and among unaffected controls, most distinguished those with and without known seropositivity. In conclusion, a large number of EBV markers can be measured reliably in serum samples using peptide-based anti-EBV ELISAs.
doi:10.1002/jmv.23498
PMCID: PMC3553325  PMID: 23280934
Epstein-Barr virus; EBNA1; VCA; IgA; nasopharyngeal carcinoma; screening
7.  Plasma markers of B-cell activation and clonality in pediatric liver and hematopoietic stem cell transplant recipients 
Transplantation  2013;95(3):519-526.
Introduction
Transplant recipients are at risk of post-transplant lymphoproliferative disease (PTLD). Methods: Thirty-six pediatric transplant recipients were evaluated (18 hematopoietic stem cell and 18 liver recipients; 12 had PTLD). We studied 207 longitudinal plasma samples from these recipients for three markers of B-cell activation or clonality: immunoglobulin free light chains (FLCs), soluble CD30 (sCD30), and monoclonal immunoglobulins (M-proteins).
Results
Kappa FLCs, lambda FLCs, and sCD30 were elevated in 20.8%, 28.0%, and 94.2% of plasma specimens, respectively. FLC and sCD30 levels increased significantly 1.18–1.82 fold per log10 Epstein Barr virus (EBV) load in peripheral blood. Five PTLD cases manifested elevated FLCs with an abnormal kappa/lambda ratio, suggesting monoclonal FLC production. M-proteins were present in 91% of PTLD cases, vs. 50–67% of other recipients with high or low EBV loads (p=0.13). Concordance of FLCs, M-proteins, and PTLD tumor light chain restriction was imperfect. For example, one PTLD case with an IgG lambda M-protein had a tumor that was kappa restricted, and another case with an M-protein had a T-cell PTLD. In an additional case, an IgM kappa M-protein and excess kappa FLCs were both detected in plasma at PTLD diagnosis; while the tumor was not restricted at diagnosis, kappa restriction was present 5 years later when the PTLD relapsed.
Discussion
Plasma markers of B-cell dysfunction are frequent following transplantation and associated with poor EBV control. These abnormal markers may be produced by oligoclonal B-cell populations or PTLD tumor cells, and could potentially help identify recipients at high risk of PTLD.
doi:10.1097/TP.0b013e318274ab63
PMCID: PMC3566275  PMID: 23222884
post transplant lymphoproliferative disease; Epstein-Barr virus (EBV); B cell; immune monitoring; immunoglobulins; cytokines
8.  Proportions of Kaposi Sarcoma, Selected Non-Hodgkin Lymphomas, and Cervical Cancer in the United States Occurring in Persons With AIDS, 1980–2007 
Context
Given the higher risk of AIDS-defining malignancies that include Kaposi sarcoma (KS), certain non-Hodgkin lymphomas (NHLs), and cervical cancer in persons with human immunodeficiency virus (HIV) infection, the HIV epidemic has likely contributed to the overall numbers of these cancers in the United States.
Objective
To quantify the proportions of KS, AIDS-defining NHLs, and cervical cancer in the United States that occurred among persons with AIDS from 1980 to 2007.
Design, Setting, and Participants
The HIV/AIDS Cancer Match Study (1980–2007) linked data from 16 US HIV/AIDS and cancer registries to identify cases with and without AIDS for KS, AIDS-defining NHLs (ie, diffuse large B-cell lymphoma [DLBCL], Burkitt lymphoma [BL], and central nervous system [CNS] lymphoma), and cervical cancer. Using linked data, we derived cancer rates for persons with and without AIDS. To estimate national counts, the rates were applied to national AIDS surveillance and US Census data.
Main Outcome Measure
Proportion of AIDS-defining malignancies in the United States occurring in persons with AIDS.
Results
In the United States, an estimated 79.0% (95% confidence interval [CI], 78.6%–79.4%) of 85 922 KS cases, 5.5% (95% CI, 5.3%–5.6%) of 383 095 DLBCL cases, 19.4% (95% CI, 17.8%–21.1%) of 17 780 BL cases, 26.2% (95% CI, 25.2%–27.1%) of 28 259 CNS lymphoma cases, and 0.41% (95% CI, 0.36%–0.46%) of 386 166 cervical cancer cases occurred among persons with AIDS during 1980–2007. The proportion of KS and AIDS-defining NHLs in persons with AIDS peaked in the early 1990s (1990–1995: KS, 89.0% [95%CI, 88.6%–89.3%]; DLBCL, 9.5% [95%CI, 9.2%–9.8%]; BL, 27.4% [95% CI, 25.0%–29.7%]; and CNS lymphoma, 47.2% [95% CI, 45.7%–48.7%]; all P<.001 [compared with 1980–1989]) and then declined (2001–2007: KS, 67.0% [95% CI, 64.5%–69.4%]; DLBCL, 4.3% [95% CI, 3.9%–4.6%]; BL, 20.8% [95% CI, 17.2%–24.3%]; and CNS lymphoma, 12.3% [95% CI, 10.1%–14.4%]; all P<.001 [compared with 1990–1995]). The proportion of cervical cancers in persons with AIDS increased overtime (1980–1989: 0.11% [95% CI, 0.08%–0.13%]; 2001–2007: 0.69% [95% CI, 0.49%–0.89%]; P<.001).
Conclusions
In the United States, the estimated proportions of AIDS-defining malignancies that occurred among persons with AIDS were substantial, particularly for KS and some NHLs. Except for cervical cancer, the proportions of AIDS-defining malignancies occurring among persons with AIDS peaked in the mid-1990s and then declined.
doi:10.1001/jama.2011.396
PMCID: PMC3909038  PMID: 21486978
9.  Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States 
Journal of Clinical Oncology  2011;29(32):4294-4301.
Purpose
Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.
Patients and Methods
HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses.
Results
HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020.
Conclusion
Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.
doi:10.1200/JCO.2011.36.4596
PMCID: PMC3221528  PMID: 21969503
10.  Common obesity-related genetic variants and papillary thyroid cancer risk 
Background
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
Methods
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Results
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Conclusions
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Impact
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
doi:10.1158/1055-9965.EPI-12-0790
PMCID: PMC3518668  PMID: 23064004
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
11.  Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis 
PLoS ONE  2013;8(11):e79851.
Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.
doi:10.1371/journal.pone.0079851
PMCID: PMC3827449  PMID: 24236163
12.  Impact of the HIV Epidemic on the Incidence Rates of Anal Cancer in the United States 
Background
The risk of anal cancer is substantially increased in HIV-infected individuals. Thus, the HIV epidemic may have influenced the increasing anal cancer trends in the United States. We estimated the impact of the HIV epidemic on trends in anal cancer incidence in the United States during 1980–2005.
Methods
Data on anal cancer cases with and without AIDS were obtained from the HIV/AIDS Cancer Match Study. The number of HIV-infected anal cancer cases without AIDS was estimated from the number of anal cancers occurring before diagnosis of AIDS. The proportion of anal cancer cases with HIV infection in the general population was calculated. We estimated temporal trends in the incidence rates of anal cancer in the general population overall and after exclusion of HIV-infected cancer cases by calculating annual percent changes and 95% confidence intervals (CIs) using a Joinpoint log-linear model. All incidence rates were standardized to the 2000 US population by age, sex, and race.
Results
During 1980–2005, of the 20 533 estimated anal cancer cases, 1665 (8.1%) were HIV-infected. During 2001–2005, the proportion of anal cancer cases with HIV infection was the highest—1.2% (95% CI = 0.93 to 1.4%) among females and 28.4% (95% CI = 26.6 to 29.4%) among males. During 1980–2005, HIV infection did not have an impact on the trends in anal cancer among females (incidence rates increased by 3.3% [95% CI = 3.0 to 3.7%] annually overall, and by 3.3% [95% CI = 2.9 to 3.6%] annually without HIV-infected anal cancer cases) but had a strong impact on the trends in anal cancer among males (incidence rates increased by 3.4% [95% CI = 2.9 to 3.9%] annually overall, and by 1.7% [95% CI = 1.2 to 2.3%] annually without HIV infection).
Conclusion
During 1980–2005, the increasing anal cancer incidence rates in the United States were strongly influenced by the HIV epidemic in males but were independent of HIV infection in females.
doi:10.1093/jnci/djs371
PMCID: PMC3611819  PMID: 23042932
13.  A variant upstream of IFNL3 (IL28B) creating a novel interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus 
Nature genetics  2013;45(2):164-171.
SUMMARY
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
doi:10.1038/ng.2521
PMCID: PMC3793390  PMID: 23291588
15.  Estrogen metabolism and mammographic density in postmenopausal women: a cross-sectional study 
Background
Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens and mammographic density (MD), an intermediate marker of breast cancer risk, have been inconsistent. We investigated the cross-sectional associations of urinary estrogens, and their 2-, 4-, and 16-hydroxylated metabolites with MD.
Methods
Postmenopausal women without breast cancer (n=194), ages 48-82 years, and reporting no current menopausal hormone therapy use were enrolled at a clinic in Western NY in 2005. Urinary estrogens and estrogen metabolites were measured using mass spectrometry. Percent MD and dense area (cm2) were measured using computer-assisted analyses of digitized films. Linear regression models were used to estimate associations of log-transformed estrogen measures with MD while adjusting for age, body mass index (BMI), parity, and past hormone therapy use.
Results
Urinary concentrations of most individual estrogens and metabolites were not associated with MD; however, across the interdecile range of the ratio of parent estrogens (estrone and estradiol) to their metabolites, MD increased by 6.8 percentage points (p=0.02) and dense area increased by 10.3 cm2 (p=0.03). Across the interdecile ranges of the ratios of 2-, 4-, and 16-hydroxylation pathways to the parent estrogens, MD declined by 6.2 (p=0.03), 6.4 (p=0.04), and 5.7 (p=0.05) percentage points, respectively. All associations remained apparent in models without adjustment for BMI.
Conclusions
In this study of postmenopausal women, less extensive hydroxylation of parent estrogens was associated with higher MD.
Impact
Hydroxylation of estrogens may modulate postmenopausal breast cancer risk through a pathway involving MD.
doi:10.1158/1055-9965.EPI-12-0247
PMCID: PMC3436977  PMID: 22736791
Estrogens; metabolism; mammography; breast neoplasms; risk factors; human; female; middle-aged
16.  Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations 
PLoS ONE  2013;8(8):e71121.
Introduction
Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.
Materials and Methods
We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.
Results
We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.
Discussion
Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
doi:10.1371/journal.pone.0071121
PMCID: PMC3747185  PMID: 23990928
17.  High prevalence of polyclonal hypergamma-globulinemia in adult males in Ghana, Africa 
American journal of hematology  2011;86(7):554-558.
Chronic antigenic stimulation is associated with hypergamma-globulinemia. Higher rates of hypergamma-globulinemia in tropical populations are maintained even with migration to temperate regions. We conducted a population-based screening study to assess the prevalence and risk factors for hypergamma-globulinemia in Ghana, Africa. 917 Ghanaian males (50–74 years) underwent in-person interviews and health examinations. Serum from all persons was analyzed by electrophoresis performed on agarose gel; serum with a discrete/localized band was subjected to immunofixation. 54 persons with monoclonal proteins were excluded and 17 samples were insufficient for analysis. Using logistic regression and Chi-square statistics we analyzed patterns of hypergamma-globulinemia. Among 846 study subjects, the median γ-globulin level was 1.86 g/dL. On the basis of a U.S. reference, 616 (73%) had hypergamma-globulinemia (>1.6 g/dL) and 178 (21%) had γ-globulin levels >2.17 gm/dl. On multivariate analyses, lower education status (P = 0.0013) and never smoking (P = 0.038) were associated with increased γ-globulin levels. Self-reported history of syphilis was associated with hypergamma-globulinemia. We conclude that three quarters of this population-based adult Ghanaian male sample had hypergamma-globulinemia with γ-globulin levels >1.6 g/dL. Future studies are needed to uncover genetic and environmental underpinnings of our finding, and to define the relationship between hypergamma-globulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.
doi:10.1002/ajh.22040
PMCID: PMC3736856  PMID: 21674575
18.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
19.  Mortality due to cancer among people with AIDS: a novel approach using registry-linkage data and population attributable risk methods 
AIDS (London, England)  2012;26(10):1311-1318.
Objective
Deaths related to HIV/AIDS have declined due to improved HIV therapies. However, people with AIDS remain at elevated risk for cancer and cancer deaths. Prior studies evaluated cancer deaths using death certificates, which may be inaccurate. We utilized population attributable risk methods (which do not rely on death certificates) to assess cancer mortality.
Design
Data from a U.S. population-based record linkage study were used to identify incident cancers and deaths in 372,364 people with AIDS (1980–2006) followed for up to 5-years after AIDS onset. We utilized Cox regression to compare mortality in subjects with and without cancer and to calculate cancer-attributable mortality across calendar periods (AIDS onset in 1980–1989, 1990–1995, and 1996–2006).
Results
Mortality declined across calendar periods for all people with AIDS but remained higher among those with cancer vs. those without. During 1996–2006, among individuals with an AIDS-defining cancer (ADC) who died, 88.3% of deaths were attributable to their ADC; likewise, among individuals with a non-AIDS-defining cancer (NADC), 87.1% of deaths were attributable to their NADC. The fraction of all deaths in people with AIDS attributable to ADC (i.e., population attributable risk) decreased significantly from 6.3% (1980–1990) to 3.9% (1996–2006), but NADC population attributable mortality increased significantly over time from 0.5% (1980–1989) to 2.3% (1996–2006).
Conclusions
Among those with AIDS and cancer who subsequently die, most deaths are attributable to their cancer. With declining overall mortality, the proportion of all deaths attributable to NADCs has increased. These results highlight the need for improved cancer prevention and treatment.
doi:10.1097/QAD.0b013e328353f38e
PMCID: PMC3377813  PMID: 22472857
AIDS; attributable risk; cancer; HIV
20.  Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer 
Endocrine-Related Cancer  2012;19(3):333-344.
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (Ptrend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (Pgene interaction) were evaluated by combining Ptrend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (Ptrend≤0.01) and seven genes/regions (Pregion<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (Pgene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (Pgene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.
doi:10.1530/ERC-11-0372
PMCID: PMC3394851  PMID: 22389382
21.  Validation of a Colorectal Cancer Risk Prediction Model Among White Patients Age 50 Years and Older 
Journal of Clinical Oncology  2008;27(5):694-698.
Purpose
Validation of an absolute risk prediction model for colorectal cancer (CRC) by using a large, population-based cohort.
Patients and Methods
The National Institutes of Health (NIH) –American Association of Retired Persons (AARP) diet and health study, a prospective cohort study, was used to validate the model. Men and women age 50 to 71 years at baseline answered self-administered questionnaires that asked about demographic characteristics, diet, lifestyle, and medical histories. We compared expected numbers of CRC patient cases predicted by the model to the observed numbers of CRC patient cases identified in the NIH-AARP study overall and in subgroups defined by risk factor combinations. The discriminatory power was measured by the area under the receiver-operating characteristic curve (AUC).
Results
During an average of 6.9 years of follow-up, we identified 2,092 and 832 incident CRC patient cases in men and women, respectively. The overall expected/observed ratio was 0.99 (95% CI, 0.95 to 1.04) in men and 1.05 (95% CI, 0.98 to 1.11) in women. Agreement between the expected and the observed number of cases was good in most risk factor categories, except for in subgroups defined by CRC screening and polyp history. This discrepancy may be caused by differences in the question on screening and polyp history between two studies. The AUC was 0.61 (95% CI, 0.60 to 0.62) for men and 0.61 (95% CI, 0.59 to 0.62) for women, which was similar to other risk prediction models.
Conclusion
The absolute risk model for CRC was well calibrated in a large prospective cohort study. This prediction model, which estimates an individual's risk of CRC given age and risk factors, may be a useful tool for physicians, researchers, and policy makers.
doi:10.1200/JCO.2008.17.4813
PMCID: PMC2645089  PMID: 19114700
22.  Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations 
Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors, and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families.
We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (−)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. P-values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p=0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p=0.0006). 28~56% of genotyped SNPs in these genes had single SNP p<0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (−) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
doi:10.1002/ijc.26231
PMCID: PMC3274649  PMID: 21671477
23.  Green tea intake is associated with urinary estrogen profiles in Japanese-American women 
Nutrition Journal  2013;12:25.
Scope
Intake of green tea may reduce the risk of breast cancer; polyphenols in this drink can influence enzymes that metabolize estrogens, known causal factors in breast cancer etiology.
Methods and results
We examined the associations of green tea intake (<1 time/week, 1-6 times weekly, or 7+ times weekly) with urinary estrogens and estrogen metabolites (jointly EM) in a cross-sectional sample of healthy Japanese American women, including 119 premenopausal women in luteal phase and 72 postmenopausal women. We fit robust regression models to each log-transformed EM concentration (picomoles per mg creatinine), adjusting for age and study center. In premenopausal women, intake of green tea was associated with lower luteal total EM (P trend = 0.01) and lower urinary 16-pathway EM (P trend = 0.01). In postmenopausal women, urinary estrone and estradiol were approximately 20% and 40% lower (P trend = 0.01 and 0.05, respectively) in women drinking green tea daily compared to those drinking <1 time/week. Adjustment for potential confounders (age at menarche, parity/age at first birth, body mass index, Asian birthplace, soy) did not change these associations.
Conclusions
Findings suggest that intake of green tea may modify estrogen metabolism or conjugation and in this way may influence breast cancer risk.
doi:10.1186/1475-2891-12-25
PMCID: PMC3584908  PMID: 23413779
Estrogens; Metabolism; Green tea; Camellia sinensis; Breast neoplasms; Risk factors; Human; Female; Middle-aged
24.  Common Genetic Variants in Sex Hormone Pathway Genes and Papillary Thyroid Cancer Risk 
Thyroid  2012;22(2):151-156.
Background
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.
Methods
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.
Results
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.
Conclusions
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
doi:10.1089/thy.2011.0309
PMCID: PMC3271376  PMID: 22224819
25.  A population-based study of Kaposi Sarcoma-associated herpesvirus seropositivity in Uganda using principal components analysis 
Background
Kaposi sarcoma-associated herpesvirus (KSHV) seropositivity is associated with sexual, environmental, and socioeconomic exposures. Whether these characteristics are independent risk factors is uncertain because of reliance on selected high-risk or hospital-based populations and incomplete adjustment for confounding. Therefore, we evaluated risk factors for KSHV seropositivity in a population-based study in Uganda using principal components analysis (PCA).
Methods
The study population comprised 2,681 individuals randomly selected from a nationally-representative population-based HIV/AIDS sero-behavioral survey conducted in 2004/05. Questionnaire and laboratory data (97 variables) were transformed into a smaller set of uncorrelated variables using PCA. Multivariable logistic regression models were fitted to estimate odds ratios and 95% confidence intervals for the association between components and KSHV seropositivity.
Results
Data were reduced to three principal components (PCs) labeled as Sexual behavioral, Socioeconomic, and Knowledge PCs. In crude analysis, KSHV seropositivity was associated with the Knowledge (ptrend = 0.012) and Socioeconomic components (ptrend = 0.0001), but not with the Sexual-behavioral component (ptrend = 0.066). KSHV seropositivity was associated with the Socioeconomic PC (ptrend = 0.037), but not with the Sexual-behavioral and Knowledge PCs, in the models including PCs, age, gender and geographic region.
Conclusions
Our results fit with the view that in Uganda socioeconomic characteristic may influence KSHV seropositivity. Conversely, the results fit with the interpretation that in Uganda sexual-behavioral characteristics, if relevant, contribute minimally.
doi:10.1186/1750-9378-8-3
PMCID: PMC3599442  PMID: 23324546
Kaposi sarcoma-associated herpesvirus; Uganda; Kaposi sarcoma; Socioeconomic; Principal Components Analysis; Human herpesvirus 8

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