In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10−8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17–1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10−14) and rs12617313 (P = 7.48 × 10−12), both highly correlated with rs9679290 (r2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10−9, per-allele OR = 1.28, 95% CI: 1.18–1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.

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.

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.

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.

The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.

Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and χ2 tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28B-genotype with HCV clearance may improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association.

Context

Myotonic muscular dystrophy (MMD) is an autosomal dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks which have never been quantified.

Objective

To quantitatively evaluate cancer risk in patients with MMD, overall, and by sex and age.

Design, Setting, and Participants

We identified 1,658 patients with an MMD discharge diagnosis in the Swedish Inpatient Hospital or Danish Patient Discharge Registries between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed from date of first MMD-related inpatient or outpatient contact, to first cancer diagnosis, death, emigration, or completion of cancer registration.

Main Outcome Measures

Risks of all cancers combined, and by anatomic site, stratified by sex and age.

Results

104 patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during post-discharge follow-up. This corresponds to an observed cancer rate of 73.4/10,000 person-years in MMD versus an expected rate of 36.9/10,000 in the general Swedish and Danish populations combined (SIR =2.0, 95% CI =1.6–2.4). Specifically, we observed significant excess risks of cancers of the endometrium (observed rate=16.1/10,000 person-years: SIR=7.6, 95%CI=4.0–13.2), brain (observed rate=4.9/10,000 person-years: SIR=5.3, 95%CI=2.3–10.4), ovary (observed rate=10.3/10,000 person-years: SIR=5.2, 95% CI=2.3–10.2), and colon (observed rate=7.1/10,000 person-years: SIR=2.9, 95%CI=1.5–5.1). Cancer risks were similar in females and males after excluding genital organ tumors (SIR=1.9, 95% CI=1.4–2.5 vs. 1.8, 95% CI=1.3–2.5, respectively, p-heterogeneity=0.81; observed rates=64.5 and 47.7/10,000 person-years in women and men, respectively), The same pattern of cancer excess was observed first in the Swedish, and then in the Danish cohorts, which were studied sequentially and initially analyzed independently.

Conclusions

MMD patients identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.

Background & Aims

Epstein-Barr virus (EBV) has been causally associated with cancer; some gastric carcinomas have a monoclonal EBV genome in every cancer cell, indicating that they arose from a single infected progenitor cell. However, the proportion of EBV-positive gastric carcinomas is uncertain and the etiological significance is unknown.

Methods

We conducted a meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA.

Results

The pooled prevalence estimate of EBV-positivity was 8.7% (95% CI: 7.5, 10.0) overall, with a two-fold difference by sex: 11.1% (95% CI: 8.7, 14.1) of gastric cancer cases in males vs. 5.2% (95% CI: 3.6, 7.4) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV-positive as those in the antrum (5.2%; p<0.01 for both comparisons). EBV-prevalence was four times higher (35.1%) for tumors in post-surgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV-positive but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (7.6%) and intestinal (9.5%) histologies. EBV-prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%).

Conclusions

EBV-positive gastric cancers greatly differ from other gastric carcinomas based on sex, anatomic subsite, and surgically disrupted anatomy, indicating that it is a distinct etiologic entity. Epidemiologic studies comparing EBV-positive and -negative gastric cancers are warranted to investigate EBV’s role in gastric carcinogenesis.

Several case–control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (>2 times/wk) of aspirin and risk of glioma (HR=1.16; 95% CI, 0.87–1.56) or glioblastoma (HR=1.17; 95% CI, 0.83–1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma = 0.90; 95% CI, 0.65–1.25 and HR for glioblastoma=0.83; 95% CI, 0.56–1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma.

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.

OBJECTIVES

Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma.

METHODS

Patient data from 7 studies of height, and 3 of birth-weight were obtained, resulting in 1067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1000 age and gender matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis.

RESULTS

Compared to average birth-weight subjects (2665–4045g), individuals with high birth-weight (≥4046g) had an increased osteosarcoma risk (OR 1.35, 95%CI 1.01–1.79). Taller than average (51st–89th percentile) and very tall individuals (≥90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95%CI 1.18–1.54, and OR 2.60, 95%CI 2.19–3.07, respectively; Ptrend <0.0001).

CONCLUSIONS

This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology.

Background

Cell-cycle proteins are important predictive markers in urothelial carcinoma but may also exhibit exposure-specific heterogeneity.

Methods

Tumor tissue from 491 bladder cancer cases enrolled in the Maine and Vermont component of the New England Bladder Cancer Study was assembled as tissue microarrays and examined for aberrant expression of p53, p63, p16, cyclin D1, Rb, and Ki-67. The association between expression and histopathology, demographics, and cigarette smoking was examined using χ2 tests, multivariable Poisson, and multinomial regression models.

Results

We found that overexpression of p53 and Ki-67 was associated with high-stage/grade tumors [relative risk (RR), 1.26; Ptrend = 0.003; and RR, 3.21; Ptrend < 0.0001, respectively], whereas expression of p63 and p16 was decreased in high-stage/grade tumors (RR, 0.52; Ptrend < 0.0001; and RR, 0.88; Ptrend = 0.04, respectively). No significant aberrations of cell-cycle proteins were identified using various smoking variables and multiple statistical models.

Conclusion

The results of this population-based study of histologically confirmed urothelial carcinomas show significant aberration of cell-cycle proteins p53, p63, p16, and Ki-67, but not Rb or cyclin D1. p53 showed the most significant heterogeneity with respect to tumor stage and grade, especially when stratified for different staining intensities using novel digital image analysis techniques. Our findings do not support that smoking modifies expression of cell-cycle proteins.

Impact

Our study shows significant heterogeneity in the expression of key cell-cycle proteins that are associated with disease progression in bladder cancer. Further studies may lead to the identification of biomarkers and their multiplexed interactions as useful prognostic and therapeutic targets.

We present a Bayesian variable selection method for the setting in which the number of independent variables or predictors in a particular dataset is much larger than the available sample size. While most existing methods allow some degree of correlations among predictors but do not consider these correlations for variable selection, our method accounts for correlations among the predictors in variable selection. Our correlation-based stochastic search (CBS) method, the hybrid-CBS algorithm, extends a popular search algorithm for high-dimensional data, the stochastic search variable selection (SSVS) method. Similar to SSVS, we search the space of all possible models using variable addition, deletion or swap moves. However, our moves through the model space are designed to accommodate correlations among the variables. We describe our approach for continuous, binary, ordinal, and count outcome data. The impact of choices of prior distributions and hyper-parameters is assessed in simulation studies. We also examined performance of variable selection and prediction as the correlation structure of the predictors varies. We found that the hybrid-CBS resulted in lower prediction errors and better identified the true outcome associated predictors than SSVS when predictors were moderately to highly correlated. We illustrate the method on data from a proteomic profiling study of melanoma, a skin cancer.

Cancer is an important cause of morbidity in the elderly, and many medical conditions and treatments influence cancer risk. The Surveillance, Epidemiology, and End Results (SEER)-Medicare database can be used to conduct population-based case-control studies that elucidate the etiology of cancer among the US elderly. SEER-Medicare links data on malignancies ascertained through SEER cancer registries to claims from Medicare, the US government insurance program for people over age 65 years. Under one approach described herein, elderly cancer cases are ascertained from SEER data (1987–2005). Matched controls are selected from a 5% random sample of Medicare beneficiaries. Risk factors of interest, including medical conditions and procedures, are identified by using linked Medicare claims. Strengths of this design include the ready availability of data, representative sampling from the US elderly population, and large sample size (e.g., under one scenario: 1,176,950 cases, including 221,389 prostate cancers, 185,853 lung cancers, 138,041 breast cancers, and 124,442 colorectal cancers; and 100,000 control subjects). Limitations reflect challenges in exposure assessment related to Medicare claims: restricted range of evaluable risk factors, short time before diagnosis/selection for ascertainment, and inaccuracies in claims. With awareness of limitations, investigators have in SEER-Medicare data a valuable resource for epidemiologic research on cancer etiology.

Cytokine dysregulation and decontrol of Epstein-Barr virus (EBV) latency by human immunodeficiency virus (HIV) infection are potential mechanisms for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). We therefore assessed circulating blood levels in pre-diagnosis plasma or serum from 63 AIDS-related NHL cases 0.1 – 2.0 (median 1.0) years pre-NHL and 181 controls matched for CD4+ T-cell count. Cytokines were measured by Millipore 30-plex Luminex assays and cell-free EBV DNA detected by polymerase chain reaction (PCR). Correlations in multiplex cytokine levels were summarized by factor analysis. Individual cytokines and their principal factors were analyzed for associations with NHL by conditional logistic regression. Cases had higher levels for 25 of the 30 cytokines. In analyses of cytokine profiles, cases had significantly higher scores for a principal factor primarily reflecting levels of interleukin (IL)-4, IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (four gene products with coordinated transcription in vitro), as well as IL-1alpha. Epstein-Barr viremia was not significantly associated based on 113 evaluable samples without PCR inhibition. We found increases of T-helper type 2 interleukins and generalized elevations of other inflammatory cytokines and growth factors up to two years before AIDS-NHL. Cytokine-mediated hyperstimulation of B-cell proliferation may play a role in AIDS-related lymphomagenesis.

Background

The control of the host cytokine network is known to influence gastric cancer susceptibility; the specific inflammatory responses in gastric carcinogenesis remain unclear.

Methods

We prospectively examined the relationships of plasma levels of interleukin (IL)-1β, IL6, IL8 and tumor necrosis factor (TNF)-α to gastric cancer risk within The Shanghai Women’s Health Study. Two controls were matched to each case by age, menopausal status and sample collection parameters. The associations of gastric cancer risk and tertile of cytokine levels were estimated by odds ratios (ORs) and 95 per cent confidence intervals (% CIs) from conditional logistic regression, adjusting for education.

Results

During a median follow-up period of 4 years (range: 0.1–8), 141 women developed gastric cancer and were matched to 282 cancer-free study participants. Elevated levels of plasma IL6 were associated with an increased risk of gastric cancer (Ρtrend=0.04). Risk increased 70% (OR=1.7, 95% CI, 1.0, 3.0) for women in the highest tertile (> 4 pg/mL) of IL-6 compared to those in the lowest tertile (<1.8 pg/mL). The association with IL6 was stronger after 4 years of follow-up (OR=2.6, 95% CI, 1.0, 6.7 for highest vs. lowest tertile) compared to an OR of 1.4 (0.7, 2.9) for those diagnosed within 1–4 years of follow-up. No associations were observed with the other examined pro-inflammatory cytokines, IL1β, IL8 and TNFα.

Conclusions

Systemic plasma IL6 levels may inform long-term gastric cancer risk. This novel finding awaits confirmation in future studies with sequential plasma collection.

Background

Chronic inflammation is etiologically-related to several cancers. We evaluated the performance (ability to detect concentrations above the assay’s lower limit of detection, coefficients-of-variation [CVs], and intraclass correlation coefficients [ICCs]) of 116 inflammation, immune, and metabolic markers across two luminex bead-based commercial kits and three specimen types.

Methods

From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type.

Results

A majority of markers were detectable in >25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all 3 specimen types and across-batch CVs <20% on at least 2 of 3 specimen types). Median concentrations and ICCs differed to a small extent across specimen types and to a large extent between Bio-Rad and Millipore.

Conclusions

Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed luminex-based methods.

Impact

Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology.

DNA damage is an important mechanism in carcinogenesis, so genes related to maintaining genomic integrity may influence papillary thyroid cancer (PTC) risk. Candidate gene studies targeting some of these genes have identified only a few polymorphisms associated with risk of PTC. Here, we expanded the scope of previous candidate studies by increasing the number and coverage of genes related to maintenance of genomic integrity. We evaluated 5077 tag single-nucleotide polymorphisms (SNPs) from 340 candidate gene regions hypothesized to be involved in DNA repair, epigenetics, tumor suppression, apoptosis, telomere function and cell cycle control and signaling pathways in a case–control study of 344 PTC cases and 452 matched controls. We estimated odds ratios for associations of single SNPs with PTC risk and combined P values for SNPs in the same gene region or pathway to obtain gene region-specific or pathway-specific P values using adaptive rank-truncated product methods. Nine SNPs had P values <0.0005, three of which were in HDAC4 and were inversely related to PTC risk. After multiple comparisons adjustment, no SNPs remained associated with PTC risk. Seven gene regions were associated with PTC risk at P < 0.01, including HUS1, ALKBH3, HDAC4, BAK1, FAF1_CDKN2C, DACT3 and FZD6. Our results suggest a possible role of genes involved in maintenance of genomic integrity in relation to risk of PTC.

The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4×44 K). Associations of differential gene expression (log2(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.

Background

Although modifiable risk factors have been included in previous models that estimate or project breast cancer risk, there remains a need to estimate the effects of changes in modifiable risk factors on the absolute risk of breast cancer.

Methods

Using data from a case–control study of women in Italy (2569 case patients and 2588 control subjects studied from June 1, 1991, to April 1, 1994) and incidence and mortality data from the Florence Registries, we developed a model to predict the absolute risk of breast cancer that included five non-modifiable risk factors (reproductive characteristics, education, occupational activity, family history, and biopsy history) and three modifiable risk factors (alcohol consumption, leisure physical activity, and body mass index). The model was validated using independent data, and the percent risk reduction was calculated in high-risk subgroups identified by use of the Lorenz curve.

Results

The model was reasonably well calibrated (ratio of expected to observed cancers = 1.10, 95% confidence interval [CI] = 0.96 to 1.26), but the discriminatory accuracy was modest. The absolute risk reduction from exposure modifications was nearly proportional to the risk before modifying the risk factors and increased with age and risk projection time span. Mean 20-year reductions in absolute risk among women aged 65 years were 1.6% (95% CI = 0.9% to 2.3%) in the entire population, 3.2% (95% CI = 1.8% to 4.8%) among women with a positive family history of breast cancer, and 4.1% (95% CI = 2.5% to 6.8%) among women who accounted for the highest 10% of the total population risk, as determined from the Lorenz curve.

Conclusions

These data give perspective on the potential reductions in absolute breast cancer risk from preventative strategies based on lifestyle changes. Our methods are also useful for calculating sample sizes required for trials to test lifestyle interventions.

Background

Familial testicular germ cell tumours (TGCTs) and bilateral TGCTs comprise 1–2% and 5% of all TGCTs, respectively, but their genetic basis remains largely unknown.

Aim

To investigate the contribution of known testicular cancer risk variants in familial and bilateral TGCTs.

Methods and results

The study genotyped 106 single nucleotide polymorphisms (SNPs) in four regions (BAK1, DMRT1, KITLG, TERT-CLPTM1L) previously identified from genome-wide association studies of TGCT, including risk single nucleotide polymorphisms (SNPs) rs210138 (BAK1), rs755383 (DMRT1), rs4635969 (TERT-CLPTM1L) in 97 cases with familial TGCT and 22 affected individuals with sporadic bilateral TGCT as well as 871 controls. Using a generalised estimating equations method that takes into account blood relationships among cases, the associations with familial and bilateral TGCT were analysed. Three previously identified risk SNPs were found to be associated with familial and bilateral TGCT (rs210138: OR 1.80, CI 1.35 to 2.41, p = 7.03×10−5; rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70×10−4; rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07×10−3). Evidence for a second independent association was found for an SNP in TERT (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24×10−3). Another association with an SNP was identified in KITLG (rs2046971: OR 2.33, p=1.28×10−3); this SNP is in high linkage disequilibrium (LD) with reported risk variant rs995030.

Conclusion

This study provides evidence for replication of recent genome-wide association studies results and shows that variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT. These findings imply that familial TGCT and sporadic TGCT share a common genetic basis.

Background

When detected in early stage (I-II), epithelial ovarian cancer 5-year survival is 70–90%, whereas in late stage (III-IV) 5-year survival slips to < 30%. In our previous report, proteomic biomarkers and cancer antigen 125 (CA125) exhibited a sensitivity of 84% at a specificity of 98% for identifying sera from stage I patients at the time of surgery, significantly improving sensitivity of CA125 alone. The challenge, however, is to detect ovarian cancer prior to clinical diagnosis. This study was part of a large effort to compare different multi-marker biomarker panels for the early detection of ovarian cancer. We evaluated several biomarkers alone and combined with CA125 in pre-diagnostically collected sera from women in the PLCO Cancer Screening Trial.

Methods

Proximal pre-diagnostic sera from 118 ovarian cancer patients and 951 age-matched controls, 8 per case (4-randomly selected from the general population, 2 with CA125 ≥35 U/mL, 2 with positive family history of breast/ovarian cancer), were analyzed using the CA125 immunoassay and SELDI-TOF-MS to measure 7 proteins [Apolipoprotein A1(Apo-A1), truncated transthyretin(TT), transferrin(TRFR), hepcidin(HEPC), β-2-microglobulin(β2M), Connective Tissue Activating Protein III(CTAPIII), and Inter-alpha-trypsin inhibitor heavy chain 4(ITIH4)]. Data were analyzed by two statistical strategies that combined seven markers and CA125 into one predictive score for disease classification.

Results

CA125 was elevated (≥35 U/mL) in 61.5% of 65 cases with CA125 data sampled <12 months prior to cancer diagnosis, however the 7 biomarker levels were not different between cases, and the three control groups individually, or combined. Two panels, combining CA125 and 7 biomarkers failed to improve the sensitivity of CA125 alone.

Conclusion

In contrast to our prior findings using post-diagnostically collected sera, addition of these biomarkers to CA125 did not improve sensitivity for preclinical diagnosis beyond CA125 alone.

Thymomas are rare tumors of the mediastinum; a limited number of small studies have evaluated the outcomes in these patients. We identified 668 patients with thymoma from the Swedish Cancer Registry, and 2,719 population-based matched controls. We obtained information on autoimmunity from the nationwide inpatient/outpatient hospital discharge Registry. We constructed Kaplan-Meier curves for survival analysis, conditional regression and Cox proportional hazards models to evaluate the association between thymoma and autoimmune diseases, and standardized incidence ratios (SIRs) to evaluate the risk for second cancers following thymoma. Compared with controls, patients with benign or malignant thymoma had a poorer (p <0.001) 5-year (79%, 53% vs. 91%), 10-year (65%, 39% vs. 78%), and 20-year (43%, 18% vs. 55%) overall survival. For thymoma patients, younger age at diagnosis and being diagnosed in recent years were associated with a better survival. Compared with controls, thymoma patients were more likely to have an autoimmune disease at some point during their lives (32.7% vs. 2.4%, respectively, p<0.001), most frequently myasthenia gravis (24.5%), systemic lupus erythematosus (2.4%), and red cell aplasia (1.2%). Thymoma patients had 2-fold excess risk for second cancers compared with the general population, most notably: non-melanoma skin cancer (SIR=10.6, 95% confidence intervals (CI)=6.0–17.3), non-Hodgkin lymphoma (SIR=6.8, 95% CI=3.00–13.0), and cervical (SIR=6.9, 95% CI=1.4–20.1), endocrine (SIR=4.7, 95% CI=1.3–12.0), and prostate cancer (SIR=3.0, 95% CI=1.7–4.8). Despite the improved survival for thymoma patients over time, they have worse survival than controls. Thymoma patients are in need for follow-up to detect and manage autoimmune diseases and cancer.

Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolite can be rapidly hydrolyzed in acidic urine to undergo further metabolic activation and form DNA adducts in the urothelium. We conducted a large multicenter case–control study in Spain to explore the etiology of bladder cancer and evaluated the association between urine pH and bladder cancer risk, alone and in combination with cigarette smoking. In total, 712 incident urothelial cell carcinoma cases and 611 hospital controls directly measured their urine pH with dipsticks twice a day (first void in the morning and early in the evening) during four consecutive days 2 weeks after hospital discharge. We found that a consistently acidic urine pH ≤6.0 was associated with an increased risk of bladder cancer [odds ratio (OR) = 1.5, 95% confidence interval (CI): 1.2–1.9] compared with all other subjects. Furthermore, risk estimates for smoking intensity and risk of bladder cancer among current smokers tended to be higher for those with a consistently acidic urine (OR = 8.8, 11.5 and 23.8) compared with those without (OR = 4.3, 7.7 and 5.8, respectively, for 1–19, 20–29 and 30+ cigarettes per day; Pinteraction for 30+ cigarettes per day = 0.024). These results suggest that urine pH, which is determined primarily by diet and body surface area, may be an important modifier of smoking and risk of bladder cancer.

Background

Telomeres shorten with each cell division and are essential for chromosomal stability. Short telomeres in surrogate tissues (e.g., blood cells) are associated with increased cancer risk in several case-control studies, but findings are inconsistent in prospective studies.

Methods

We systematically reviewed studies published prior to August 30, 2010 on the association between telomere length (TL) in surrogate tissues and cancer. There were 27 reports on 13 cancers and/or incident cancer investigating this association. The majority, 16, were retrospective case-control studies, 11 were prospective studies. Meta-analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals (CIs) for these studies.

Results

Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers. Non-Hodgkin lymphoma, breast, lung and colorectal cancer reports were inconsistent. Single studies on endometrial, prostate, and skin cancers were null. In a random effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95%CI 1.73 – 4.8, P<0.0001). The pooled OR for prospective studies was 1.16 (95%CI 0.87 – 1.54, P=0.32). All studies combined yielded a pooled OR of 1.96 (95%CI 1.37 – 2.81, P=0.0001) for the association of short TL and cancer.

Conclusion and Impact

There is suggestive evidence that short surrogate tissue TL is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers. Additional prospective studies with consistent methodology are needed to confirm this hypothesis.