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1.  A 13-gene signature prognostic of HPV-negative OSCC: discovery and external validation 
Purpose
To identify a prognostic gene signature for HPV-negative OSCC patients.
Experimental Design
Two gene expression datasets were used; a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC) (n=97), and a validation dataset from the MD Anderson Cancer Center (MDACC) (n=71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131–gene signature previously identified to be prognostic in OSCC patients to identify a prognostic model specific for high-risk HPV-negative OSCC patients. The models were tested with the MDACC dataset using a receiver operating characteristic analysis.
Results
A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (± SE) of patients with high risk scores was 47.1 (±9.24)% compared with 6.35 (± 4.42)% for patients with low risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score (0.78, 95%CI: 0.74-0.86) and risk score plus tumor stage (0.79, 95%CI: 0.75-0.87) were substantially higher than for the model with tumor stage (0.54, 95%CI: 0.48-0.62).
Conclusions
We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of HPV-negative OSCC patients. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted.
doi:10.1158/1078-0432.CCR-12-2647
PMCID: PMC3593802  PMID: 23319825
gene signature; prognosis; HPV-negative; OSCC
2.  A history of allergies is associated with reduced risk of oral squamous cell carcinoma 
Cancer causes & control : CCC  2012;23(12):1911-1919.
Purpose
A history of allergies is associated with a decreased risk of several types of cancers. Potential mechanisms include enhanced immune surveillance against tumor cells early in disease development and/or carcinogenic infectious agents. We tested whether allergies are inversely associated with oral squamous cell carcinoma (OSCC), accounting for factors that may modify the association, such as tumor site, stage, and HPV infection.
Methods
We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between allergy history (including different types of allergies) and OSCC, adjusted for potential confounders, among 400 cases and 613 controls. Analyses were also stratified by site, stage, and measures of HPV infection.
Results
We observed a weak inverse association between history of any allergy and OSCC (OR=0.81, 95% CI, 0.61–1.08). This association was present only for allergies to airborne allergens (dust/pollen/mold); OR=0.67; 95% CI, 0.48–0.93. The inverse associations with airborne allergies were slightly stronger for oropharyngeal SCC (OR=0.56; 95% CI, 0.35–0.90) than for oral cavity SCC (OR=0.71; 95% CI, 0.49–1.05), and present only for later stage cancers (OR=0.42; 95% CI, 0.26–0.66) as opposed to earlier stage cancers (OR=0.98; 95% CI, 0.66–1.46). Inverse associations were not particularly present or stronger among HPV-16 seropositive individuals or for HPV DNA positive OSCC.
Conclusions
There is an inverse association between history of allergies to dust, pollen or mold and OSCC. Whether the inverse association involves heightened immune surveillance, increased immune response to HPV or other antigen, or other carcinogenic mechanism, remains to be determined in more definitive studies.
doi:10.1007/s10552-012-0068-x
PMCID: PMC3499679  PMID: 23011537
allergies; oral squamous cell carcinoma; HPV; HSV
3.  No association between antibodies to sexually transmitted infections and colorectal hyperplastic polyps in men: Minnesota Cancer Prevention Research Unit Polyp Study 
Background
Oncogenic human papillomaviruses (HPV) are sexually transmitted and linked to several epithelial malignancies, but an association between HPV and colorectal neoplasia is not established. Previously, we reported a 3-fold increase in the odds of colorectal hyperplastic polyps associated with oncogenic HPV seropositivity in men, but detected no HPV DNA in colorectal tissues from these same men.
Methods
To test the reproducibility of our prior HPV antibody results and to explore the hypothesis that colorectal hyperplastic polyps may be associated with sexual behavior in men, we conducted a case-control study of hyperplastic polyps and antibodies to 8 oncogenic HPV types (including 16 and 18), herpes simplex virus-2 (HSV-2), and hepatitis C virus (HCV). Study participants were men, ages 30–74 years, enrolled in the Minnesota Cancer Prevention Research Unit Polyp Study who had an index colonoscopy from 1991–1994 and received a diagnosis of hyperplastic polyps (n=97), or were polyp-free (n=184). Plasma was assessed for antibodies to the 8 oncogenic HPV types, HSV-2, and HCV using a bead-based multiplex assay.
Results
The adjusted odds ratio (OR) for the association between hyperplastic polyps and seropositivity to oncogenic HPV (all 8 types combined) was 0.84, 95% confidence interval (CI): 0.44–1.58; for HSV-2, OR=0.98, 95% CI: 0.48–1.99; and for HCV, OR=0.61, 95% CI: 0.11–3.26.
Conclusions
Our study suggested no association between colorectal hyperplastic polyps and antibodies to specific sexually transmitted infections in men.
Impact
Factors associated with sexually transmitted infections are unlikely to play a role in the etiology of colorectal hyperplastic polyps in men.
doi:10.1158/1055-9965.EPI-12-0651
PMCID: PMC3436996  PMID: 22736792
HPV; colorectal hyperplastic polyps; antibodies; sexually transmitted infections
4.  Genetic variation in CD83 and risks of cervical and vulvar cancers: A population-based case–control study 
Gynecologic oncology  2011;124(3):525-528.
Objectives
The CD83 glycoprotein is a marker of dendritic cell maturation that may contribute to the T cell response to oncogenic human papillomavirus (HPV) infection. Whether single nucleotide polymorphisms (SNPs) in CD83 influence the risk of HPV-related genital cancers has not been adequately studied. We investigated whether the common genetic variation of the CD83 region was associated with the risks of cervical and vulvar cancers in a population-based case–control study conducted in the Seattle-Puget Sound Region.
Methods
A total of 17 tagSNPs were genotyped in the CD83 region of 886 cervical cases, 517 vulvar cases and 1100 controls. Odds ratio (OR) and 95% confidence intervals (CI) were computed to assess the risk of cervical and vulvar cancers. The interaction between the tagSNPs and cigarette smoking was also explored.
Results
TagSNPs in the CD83 chromosomal region were not associated with risk of either cervical or vulvar cancer. TagSNP rs853360 was associated with a decreased risk of cervical squamous cell carcinoma (SCC) (OR = 0.80; 95% CI: 0.66–0.98).
Conclusions
Our results do not suggest that the common genetic variation of CD83 is related to cervical or vulvar cancers. The association between tagSNP rs853360 and risk of cervical SCC is likely to be due to chance. If larger or pooled studies confirm our results, CD83 has little or no influence in the risk of HPV-related cancers.
doi:10.1016/j.ygyno.2011.11.017
PMCID: PMC3727898  PMID: 22134374
Keywords: Human papillomavirus; Cervix; Vulva; Epidemiology; Genetics
5.  Impact of Cancer on Work and Education Among Adolescent and Young Adult Cancer Survivors 
Journal of Clinical Oncology  2012;30(19):2393-2400.
Purpose
To examine the impact of cancer on work and education in a sample of adolescent and young adult (AYA) patients with cancer.
Patients and Methods
By using the Adolescent and Young Adult Health Outcomes and Patient Experience Study (AYA HOPE)—a cohort of 463 recently diagnosed patients age 15 to 39 years with germ cell cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, sarcoma, and acute lymphocytic leukemia from participating Surveillance, Epidemiology, and End Results (SEER) cancer registries—we evaluated factors associated with return to work/school after cancer diagnosis, a belief that cancer had a negative impact on plans for work/school, and reported problems with work/school after diagnosis by using descriptive statistics, χ2 tests, and multivariate logistic regression.
Results
More than 72% (282 of 388) of patients working or in school full-time before diagnosis had returned to full-time work or school 15 to 35 months postdiagnosis compared with 34% (14 of 41) of previously part-time workers/students, 7% (one of 14) of homemakers, and 25% (five of 20) of unemployed/disabled patients (P < .001). Among full-time workers/students before diagnosis, patients who were uninsured (odds ratio [OR], 0.21; 95% CI, 0.07 to 0.67; no insurance v employer-/school-sponsored insurance) or quit working directly after diagnosis (OR, 0.15; 95% CI, 0.06 to 0.37; quit v no change) were least likely to return. Very intensive cancer treatment and quitting work/school were associated with a belief that cancer negatively influenced plans for work/school. Finally, more than 50% of full-time workers/students reported problems with work/studies after diagnosis.
Conclusion
Although most AYA patients with cancer return to work after cancer, treatment intensity, not having insurance, and quitting work/school directly after diagnosis can influence work/educational outcomes. Future research should investigate underlying causes for these differences and best practices for effective transition of these cancer survivors to the workplace/school after treatment.
doi:10.1200/JCO.2011.39.6333
PMCID: PMC3675694  PMID: 22614977
6.  Effects of Cell Grafting on Coronary Remodeling After Myocardial Infarction 
Background
With recent advances in therapeutic applications of stem cells, cell engraftment has become a promising therapy for replacing injured myocardium after infarction. The survival and function of injected cells, however, will depend on the efficient vascularization of the new tissue. Here we describe the arteriogenic remodeling of the coronary vessels that supports vascularization of engrafted tissue postmyocardial infarction (post‐MI).
Methods and Results
Following MI, murine hearts were injected with a skeletal myoblast cell line previously shown to develop into large grafts. Microcomputed tomography at 28 days postengraftment revealed the 3‐dimensional structure of the newly formed conducting vessels. The grafts elicited both an angiogenic response and arteriogenic remodeling of the coronary arteries to perfuse the graft. The coronaries upstream of the graft also remodeled, showing an increase in branching, and a decrease in vascular density. Histological analysis revealed the presence of capillaries as well as larger vascular lumens within the graft. Some graft vessels were encoated by smooth muscle α‐actin positive cells, implying that vascular remodeling occurs at both the conducting arterial and microvascular levels.
Conclusions
Following MI and skeletal myoblast engraftment, the murine coronary vessels exhibit plasticity that enables both arteriogenic remodeling of the preexisting small branches of the coronary arteries and development of large and small smooth muscle encoated vessels within the graft. Understanding the molecular mechanisms underlying these 2 processes suggests mechanisms to enhance the therapeutic vascularization in patients with myocardial ischemia.
doi:10.1161/JAHA.113.000202
PMCID: PMC3698786  PMID: 23723253
coronary angiography; grafting; myocardial infarction; myocardial revascularization; vascular remodeling
7.  HPV-positive oral cavity and oropharyngeal cancer patients do not have better QOL trajectories 
Objective
To determine the role of human papillomavirus (HPV) status on quality of life (QOL) in patients with oral cavity and oropharyngeal squamous cell carcinoma (OSCC). Since OSCC that are associated with high-risk HPV have an improved response to treatment and survival, we hypothesized that patients with these tumors would have better QOL trajectories.
Study Design
Prospective cohort study.
Setting
Tertiary care academic medical center and two affiliated hospitals.
Subjects and Methods
Head and neck-specific QOL was determined using the University of Washington Quality of Life (UW-QOL) scale version 4 in patients with newly diagnosed invasive OSSC (n=228).
Results
Pre-treatment QOL was higher in patients with high-risk HPV-associated tumors compared to patients with HPV-negative or low-risk HPV-associated tumors (p=0.015). Patients with high-risk HPV-associated tumors had larger decreases in QOL from pre-treatment to immediate post-treatment compared to patients with HPV-negative or low-risk HPV-associated tumors (p=0.041). There was no association between HPV status and one year post-treatment QOL.
Conclusion
Among OSCC patients, high-risk HPV-associated tumors were associated with higher pre-treatment QOL and a larger decrease in QOL from pre-treatment to immediate post-treatment, suggesting that treatment intensity in this unique population may adversely affect QOL.
doi:10.1177/0194599811434707
PMCID: PMC3535430  PMID: 22275190
head and neck cancer; quality of life; epidemiology/outcomes research; head and neck surgery; human papillomavirus; oropharyngeal squamous cell carcinoma
8.  Tertiary Lymphoid Organs in Lymphatic Malformations 
Abstract
Background
Examine lymphatic malformation lymphoid aggregates for the expression of tertiary lymphoid organ markers. Determine how lymphoid aggregate density relates to lymphatic malformation clinical features.
Methods and Results
Retrospective cohort study. Tissue and clinical data were reviewed from 29 patients in the Vascular Anomaly Database who represented the spectrum of head and neck lymphatic malformations and had >5 years of follow-up. Archived formalin-fixed, paraffin-embedded lymphatic malformation tissue was immunohistochemically stained with antibodies for tertiary lymphoid organ markers, which included follicular and mature myeloid dendritic cells, high endothelial venules, segregated B and T-cells, lymphatic endothelial cells, and lymphoid homing chemokines (CXCL13, CCL21). Lymphoid aggregate density (count/mm2) was quantified by 2 independent, blinded reviewers. Lymphoid aggregate density and lymphatic malformation clinical features were characterized using analysis of variance. Larger lymphatic malformation tissue lymphoid aggregates stained consistently for tertiary lymphoid organ markers. In oral cavity and neck specimens from the same patients (n = 9), there were more tertiary lymphoid organ in oral cavity than in neck specimens (p = 0.0235). In lymphatic malformation neck tissue, de Serres stage 4 lymphatic malformations displayed the highest tertiary lymphoid organ density. No significant association was seen between tertiary lymphoid organ density and other clinical features.
Conclusion
This study demonstrates that some lymphoid aggregates within lymphatic malformations represent tertiary lymphoid organs. There was an association between tertiary lymphoid organ density and lymphatic malformation location. Further study is required to define the role of lymphoid neogenesis and tertiary lymphoid organ formation in lymphatic malformation pathogenesis.
doi:10.1089/lrb.2010.0018
PMCID: PMC3607970  PMID: 21688977
9.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
Objective
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
Conclusion
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
doi:10.1161/ATVBAHA.111.226365
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
10.  Tumor and salivary matrix metalloproteinase levels are strong diagnostic markers of oral squamous cell carcinoma 
Background
The matrix metalloproteinases (MMPs) cause degradation of the extracellular matrix and basement membranes, and thus may play a key role in cancer development.
Methods
In our search for biomarkers for oral squamous cell carcinomas (OSCC), we compared primary OSCC, oral dysplasia and control subjects with respect to: (1) expression of MMP1, MMP3, MMP10 and MMP12 in oral epithelial tissue using Affymetrix U133 2.0 Plus GeneChip arrays, followed by qRT-PCR for MMP1, and (2) determination of MMP1 and MMP3 concentrations in saliva.
Results
MMP1 expression in primary OSCC (n=119) was >200-fold higher (p=7.16×10−40) compared with expression levels in non-neoplastic oral epithelium from controls (n=35). qRT-PCR results on 30 cases and 22 controls confirmed this substantial differential expression. The exceptional discriminatory power to separate OSCC from controls was validated in two independent testing sets (AUC%=100; 95% CI, 100-100 and AUC%=98.4; 95% CI, 95.6–100). Salivary concentrations of MMP1 and MMP3 in OSCC patients (33 stage I/II, 26 stage III/IV) were 6.2 times (95% CI, 3.32–11.73) and 14.8 times (95% CI, 6.75–32.56) higher, respectively, than in controls, and displayed an increasing trend with higher stage disease.
Conclusions
Tumor and salivary MMPs are robust diagnostic biomarkers of OSCC.
Impact
The capacity of MMP gene expression to identify OSCC provides support for further investigation into MMPs as potential markers for OSCC development. Detection of MMP proteins in saliva in particular may provide a promising means to detect and monitor OSCC non-invasively.
doi:10.1158/1055-9965.EPI-11-0503
PMCID: PMC3237810  PMID: 21960692
oral squamous cell carcinoma; matrix metalloproteinase; MMP; saliva; gene expression
11.  Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes 
Fertility and sterility  2011;96(6):1401-1406.e3.
OBJECTIVE
To evaluate the relationship between common genetic variation in genes involved in the biosynthesis and signaling of estrogen and progesterone and endometriosis risk.
DESIGN
Genetic polymorphism analysis.
SETTING
Population-based case-control study conducted in Group Health Cooperative enrollees in Western Washington.
PATIENT(S)
Women with newly diagnosed, surgically confirmed endometriosis between 1996 and 2001 (n=256), and age and reference year matched female controls without a history of endometriosis (n=567).
INTERVENTIONS(S)
None.
MAIN OUTCOME MEASURE
We evaluated the relationship between common genetic variation and endometriosis risk, using gene-based tests and single variant analysis of genetic polymorphisms in ESR1, ESR2, PGR, CYP17A1, CYP19A1, HSD17B1, HSD17B2, CYP1A1, CYP1A2, COMT and GSTM1.
RESULTS
The most consistent gene-based association with endometriosis risk was for CYP19A1 (p-value = 0.02). We did not find evidence for consistent significant associations between previously reported candidate SNPs in sex hormone-related genes and endometriosis risk.
CONCLUSION
In summary, we report increased endometriosis risk with CYP19A1 gene-based tests; replication of the association between endometriosis and this gene or gene region is necessary in a larger study population.
doi:10.1016/j.fertnstert.2011.09.004
PMCID: PMC3228888  PMID: 21958689
Population-based; case-control; endometriosis; genetic polymorphisms; sex hormone metabolic pathway; candidate genes
12.  Post-Genomic Update on a Classical Candidate Gene for Coronary Artery Disease: ESR1 
Background
After age, gender is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed gender difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene encoding Estrogen Receptor alpha (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.
Methods and Results
We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N~87,000) to search for population-wide and gender-specific associations between CAD risk and common genetic variants throughout the coding, non-coding and flanking regions of ESR1. In additional samples from the MIGen (N~6,000), WTCCC (N~7,400) and Framingham (N~3,700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes project. Despite the widespread expression of ER alpha in vascular tissues, we find no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of gender.
Conclusions
We suggest that future research on the genetic basis of gender-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.
doi:10.1161/CIRCGENETICS.111.960583
PMCID: PMC3260440  PMID: 21984528
coronary artery disease; estrogen receptor alpha; menopause; polymorphism, single nucleotide; genetic association studies; meta-analysis
13.  No evidence for human papillomavirus in the etiology of colorectal polyps 
Background
While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not.
Methods
We examined the association between oncogenic HPV infection and colorectal polyps in a case-control study of individuals with colorectal adenomas (n=167), hyperplastic polyps (n=87), and polyp-free controls (n=250). We performed real-time PCR for HPV-16 /18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay.
Results
HPV DNA was not found in any of the 609 successfully assayed colorectal tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a previous history of polyps, among men [adenomas (n=31), hyperplastic polyps (n=28), and controls (n=68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (odds ratio=3.0; 95% confidence interval: 1.1–7.9).
Conclusions
Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations.
Impact
After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women.
doi:10.1158/1055-9965.EPI-11-0450
PMCID: PMC3236024  PMID: 21817125
HPV; colorectal adenomas; hyperplastic polyps; DNA; antibodies
14.  A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes 
Asian Journal of Andrology  2012;14(5):766-772.
Single nucleotide polymorphisms (SNPs) in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities. However, no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance (AGD), anoscrotal distance (ASD) and penile width (PW). We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families. We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates. We found that the rs2077647 G allele, located in the coding region of estrogen receptor alpha (ESR1), was associated with a shorter AGD (P=0.02; −7.3 mm, 95% confidence interval (CI): −11.6 to −3.1), and the rs10475 T allele, located in the 3′ untranslated region of activating transcription factor 3 (ATF3), was associated with a shorter ASD (−4.3 mm, 95% CI: −7.2 to −1.4), although this result was not significant (P=0.07) after controlling for multiple comparisons. We observed no association between PW and the SNPs tested. Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD, although the significance of the association was marginal. Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hypospadias and cryptorchidism.
doi:10.1038/aja.2012.27
PMCID: PMC3734991  PMID: 22580635
gene; hypospadias; male; phenotype; polymorphism; reproductive
15.  Defining smooth muscle cells and smooth muscle injury 
Journal of Clinical Investigation  2005;115(2):221-224.
For 3 decades, terms such as synthetic phenotype and contractile phenotype have been used to imply the existence of a specific mechanism for smooth muscle cell (SMC) responses to injury. In this issue of the JCI, Hendrix et al. offer a far more precise approach to examining the mechanisms of SMC responses to injury, focused not on general changes in phenotype but on effects of injury on a single promoter element, the CArG [CC(A/T)6GG] box, in a single gene encoding smooth muscle (SM) α-actin. Since CArG box structures are present in some, but not all, SMC genes, these data suggest that we may be progressing toward establishing a systematic, molecular classification of both SMC subsets and the response of SMCs to different injuries.
doi:10.1172/JCI200524272
PMCID: PMC546433  PMID: 15690076
16.  Can a Metastatic Gene Expression Profile Outperform Tumor Size as a Predictor of Occult Lymph Node Metastasis in Oral Cancer Patients? 
Purpose
To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis using molecular features.
Experimental Design
We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCC with 40 node-negative (≥18 months) OSCC. Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and Receiver Operating Characteristics (ROC) analysis were used to generate predictive models and to compare these with models using tumor size alone.
Results
We identified five genes differentially expressed between node-positive and node-negative OSCC after adjusting for tumor size and Human Papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32 and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher Area Under the Curve (AUC) for identifying occult nodal metastasis compared to that of a model using tumor size alone (respective AUC: 0.85 and 0.61; p = 0.011). A model combining tumor size and gene expression did not further improve prediction of occult metastasis. Independent validation using 31 metastatic and 13 non-metastatic cases revealed a significant under-expression of CTONG2002744 (p = 0.0004).
Conclusions
These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 are warranted.
doi:10.1158/1078-0432.CCR-10-0175
PMCID: PMC3078996  PMID: 21300763
oral squamous cell carcinoma; oral cancer; genetic expression profiles; gene expression profiling; metastasis; microarrays
17.  Associations between polymorphisms in glucuronidation and sulfation enzymes and sex steroid concentrations in premenopausal women in the United States 
Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGT) and sulfation, catalyzed by sulfotransferases (SULT), are pathways through which sex steroids are metabolized to less active compounds. These enzymes are highly polymorphic and genetic variants frequently result in higher or lower activity. The phenotypic effects of these polymorphisms on circulating sex steroids in premenopausal women have not yet been investigated. One hundred and seventy women ages 40-45 years had a blood sample drawn during the follicular phase of the menstrual cycle for sex steroid measures and to obtain genomic DNA. Urine was collected for 2-hydroxy (OH) estrone (E1) and 16α-OH E1 measures. Generalized linear regression models were used to assess associations between sex steroids and polymorphisms in the UGT1A and UGT2B families, SULT1A1, and SULT1E1. Women with the UGT1A1(TA7/TA7) genotype had 25% lower mean estradiol (E2) concentrations compared to the wildtype (TA6/TA6) (p = 0.02). Similar associations were observed between SULT1A1(R213/H213) and E1 (13% lower mean E1 concentration vs. wildtype; p-value = 0.02) and UGT2B4(E458/E458) and dehydroepiandrosterone (DHEA) (20% lower mean DHEA vs. wildtype; p-value = 0.03). The SULT1E1(A/C) and the UGT1A1(TA7)-UGT1A3(R11) haplotypes were associated with reduced estrogen concentrations. Further study of UGT and SULT polymorphisms and circulating sex steroid measures in larger populations of premenopausal women is warranted.
doi:10.1016/j.jsbmb.2010.12.014
PMCID: PMC3065887  PMID: 21193038
Uridine diphosphoglucuronosyltransferases; sulfotransferases; estrogens; androgens; premenopausal women
18.  Risk of cervical cancer associated with allergies and polymorphisms in genes in the chromosome 5 cytokine cluster 
Background
Human papillomavirus is the acknowledged cause of cervical cancer. We hypothesized that allergies, characterized by hyperimmune reaction to common allergens andwhich have been associated with various cancers, may be related to cervical cancer, and that genetic variation in cytokine genes related to allergies might impact cervical cancer risk.
Methods
We investigated the risk of invasive squamous cell cervical cancer (SCC) associated with self-reported allergies and with variation in allergy-related cytokine genes using data from a case-control study (561 cases, 1258 controls) conducted in Washington State. Logistic regression models yielded odds ratios (OR) and 95% confidence intervals (CI).
Results
Pollen allergy, the most commonly reported allergy, was associated with reduced SCC risk (OR 0.6, 95% CI 0.5–0.8). Of 60 tagging single nucleotide polymorphisms covering eight genes (CSF2, IL3, IL4, IL13, CSF2RB, IL4R, IL13RA1, IL13RA2), several were related to pollen allergies among controls: IL4R rs3024647 (dominant OR 1.5 95% CI 1.0–2.3, p=0.04), CSF2RB rs16997517 (dominant OR 2.2 95% CI 1.0–4.7, p=0.04), and IL13 rs1800925 (per-allele OR 1.7, 95% CI 1.3–2.4, p=0.0007). Two variants were inversely associated with SCC risk: IL4R rs3024656 (per-allele OR 0.8, 95% CI 0.6–1.0, p=0.03) and CSF2RB rs16997517 (dominant OR 0.4, 95% CI 0.2–0.9, p=0.04).
Conclusions
Pollen allergies were related to reduced SCC risk. CSF2RB rs16997517 was directly related to pollen allergies in controls and to reduced SCC risk.
Impact
If other studies confirm these results, the mechanism behind allergy-associated immune response associated with SCC risk may be worth exploring in the context of therapeutic or prophylactic vaccines.
doi:10.1158/1055-9965.EPI-10-0779
PMCID: PMC3057941  PMID: 21071541
Cervical cancer; HPV; allergy; cytokines
19.  Feasibility of Including Cellular Telephone Numbers in Random Digit Dialing for Epidemiologic Case-Control Studies 
American Journal of Epidemiology  2010;173(1):118-126.
The usefulness of landline random digit dialing (RDD) in epidemiologic studies is threatened by the rapid increase in households with only cellular telephone service. This study assessed the feasibility of including cellular telephone numbers in RDD and differences between young adults with landline telephones and those with only cellular telephones. Between 2008 and 2009, a total of 9,023 cellular telephone numbers were called and 43.8% were successfully screened; 248 men and 249 women who resided in 3 Washington State counties, were 20–44 years of age, and used only cellular telephones were interviewed. They were compared with 332 men and 526 women with landline telephones interviewed as controls for 2 case-control studies conducted in parallel with cellular telephone interviewing. Cellular-only users were more likely to be college educated and less likely to have fathered/birthed a child than were their landline counterparts. Male cellular-only users were less likely to be obese and more likely to exercise, to be Hispanic, and to have lower incomes, while female cellular-only users were more likely to be single than landline respondents. Including cellular telephone numbers in RDD is feasible and should be incorporated into epidemiologic studies that rely on this method to ascertain subjects, although low screening rates could hamper the representativeness of such a sample.
doi:10.1093/aje/kwq322
PMCID: PMC3025640  PMID: 21071602
bias (epidemiology); case-control studies; epidemiologic methods; selection bias; telephone
20.  Body mass index and risk of head and neck cancer in a pooled analysis of case–control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium 
Background Head and neck cancer (HNC) risk is elevated among lean people and reduced among overweight or obese people in some studies; however, it is unknown whether these associations differ for certain subgroups or are influenced by residual confounding from the effects of alcohol and tobacco use or by other sources of biases.
Methods We pooled data from 17 case–control studies including 12 716 cases and the 17 438 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between body mass index (BMI) at different ages and HNC risk, adjusted for age, sex, centre, race, education, tobacco smoking and alcohol consumption.
Results Adjusted ORs (95% CIs) were elevated for people with BMI at reference (date of diagnosis for cases and date of selection for controls) ≤18.5 kg/m2 (2.13, 1.75–2.58) and reduced for BMI >25.0–30.0 kg/m2 (0.52, 0.44–0.60) and BMI ≥30 kg/m2 (0.43, 0.33–0.57), compared with BMI >18.5–25.0 kg/m2. These associations did not differ by age, sex, tumour site or control source. Although the increased risk among people with BMI ≤18.5 kg/m2 was not modified by tobacco smoking or alcohol drinking, the inverse association for people with BMI > 25 kg/m2 was present only in smokers and drinkers.
Conclusions In our large pooled analysis, leanness was associated with increased HNC risk regardless of smoking and drinking status, although reverse causality cannot be excluded. The reduced risk among overweight or obese people may indicate body size is a modifier of the risk associated with smoking and drinking. Further clarification may be provided by analyses of prospective cohort and mechanistic studies.
doi:10.1093/ije/dyp380
PMCID: PMC2929351  PMID: 20123951
BMI; head and neck cancer; smoking
21.  Maternal and early postnatal polychlorinated biphenyl exposure in relation to total serum immunoglobulin concentrations in 6-month-old infants 
Journal of immunotoxicology  2011;8(1):95-100.
Animal data indicate that developmental tetrachlorodibenzo-p-dioxin exposure alters immune function; however, the potential immunotoxicity of dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs) in the developing infant is an understudied area. The aim of the current study is to examine the association between maternal and early postnatal PCB concentrations in relation to total infant serum immunoglobulin concentrations determined at 6-months-of-age. We selected 384 mother-infant pairs participating in a birth cohort study in Eastern Slovakia. PCB concentrations of several congeners were determined in maternal and cord serum samples and in infant serum samples collected at 6-months-of-age using gas chromatography with electron capture detection. Total immunoglobulin (Ig) G, A, and M concentrations were determined by nephelometry, and IgE concentrations were determined by enzyme-linked immunoassay. Linear regression models with adjustment for potential confounding factors were used to estimate the associations between maternal, cord, and 6-month infant PCB concentrations and total serum immunoglobulins. The median maternal serum concentration of PCB-153 was 140 ng/g lipid, ≈10-fold higher than concentrations in childbearing-age women in the United States during the same period. Maternal, cord, or 6-month infant PCB concentrations were not associated with total serum immunoglobulin levels at 6 months, regardless of the timing of PCB exposure, PCB congener, or specific immunoglobulin. In this population, which has high PCB concentrations relative to most populations in the world today, we did not observe any association between maternal and early postnatal PCB concentrations and total immunoglobulin measures of IgG, IgA, IgM, or IgE.
doi:10.3109/1547691X.2010.549096
PMCID: PMC3086069  PMID: 21299357
Epidemiology; cohort; DAG; roma
22.  A cohort study of developmental polychlorinated biphenyl (PCB) exposure in relation to post-vaccination antibody response at 6-months of age 
Environmental research  2010;110(4):388-395.
Background
Extensive experimental data in animals indicate that exposure to polychlorinated biphenyls (PCBs) during pregnancy leads to changes in offspring immune function during the postnatal period. Whether developmental PCB exposure influences immunologic development in humans has received little study.
Methods
The study population was 384 mother-infant pairs recruited from two districts of eastern Slovakia for whom prospectively collected maternal, cord, and 6-month infant blood specimens were available. Several PCB congeners were measured in maternal, cord, and 6-month infant sera by high-resolution gas chromatography with electron capture detection. Concentrations of IgG-specific anti-haemophilus influenzae type b, tetanus toxoid, and diphtheria toxoid were assayed in 6-month infant sera using ELISA methods. Multiple linear regression was used to estimate the relation between maternal, cord, and 6-month infant PCB concentrations and the antibody concentrations evaluated at 6-months of age.
Results
Overall, there was little evidence of an association between infant antibody concentrations and PCB measures during the pre- and early postnatal period. In addition, our results did not show specificity in terms of associations limited to a particular developmental period (e.g. pre- vs. postnatal), a particular antibody, or a particular PCB congener.
Conclusions
At the PCB concentrations measured in this cohort, which are high relative to most human populations today, we did not detect an association between maternal or early postnatal PCB exposure and specific antibody responses at 6-months of age.
doi:10.1016/j.envres.2010.02.010
PMCID: PMC2859670  PMID: 20378105
23.  Marijuana smoking and the risk of head and neck cancer: pooled analysis in the INHANCE Consortium 
Background
Marijuana contains carcinogens similar to tobacco smoke and has been suggested by relatively small studies to increase the risk of head and neck cancer (HNC). Since tobacco is a major risk factor for HNC, large studies with substantial numbers of never tobacco users could help to clarify whether marijuana smoking is independently associated with HNC risk.
Methods
We pooled self-reported interview data on marijuana smoking and known HNC risk factors on 4,029 HNC cases and 5,015 controls from five case-control studies within the INHANCE Consortium. Subanalyses were conducted among never tobacco users (493 cases and 1,813 controls), and among individuals who did not consume alcohol or smoke tobacco (237 cases and 887 controls).
Results
The risk of HNC was not elevated by ever marijuana smoking (odds ratio (OR) =0.88, 95% confidence intervals (CI) =0.67, 1.16), and there was no increasing risk associated with increasing frequency, duration or cumulative consumption of marijuana smoking. An increased risk of HNC associated with marijuana use was not detected among never tobacco users (OR=0.93, 95%CI=0.63, 1.37; three studies) nor among individuals who did not drink alcohol and smoke tobacco (OR=1.06, 95%CI=0.47, 2.38; two studies).
Conclusion
Our results are consistent with the notion that infrequent marijuana smoking does not confer a risk of these malignancies. Nonetheless, because the prevalence of frequent marijuana smoking was low in most of the contributing studies, we could not rule out a moderately increased risk, particularly among subgroups without exposure to tobacco and alcohol.
doi:10.1158/1055-9965.EPI-08-0845
PMCID: PMC3046921  PMID: 19423532
24.  Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk 
Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers.
Methods We pooled individual-level data from case–control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models.
Results Quitting tobacco smoking for 1–4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61–0.81 compared with current smoking], with the risk reduction due to smoking cessation after ≥20 years (OR 0.23, CI 0.18–0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after ≥20 years of quitting (OR 0.60, CI 0.40–0.89 compared with current drinking), reaching the level of never drinkers.
Conclusions Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer.
doi:10.1093/ije/dyp291
PMCID: PMC2817090  PMID: 19805488
Epidemiology; head and neck cancer; cessation; alcohol drinking; tobacco smoking
25.  Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium 
Background Sexual contact may be the means by which head and neck cancer patients are exposed to human papillomavirus (HPV).
Methods We undertook a pooled analysis of four population-based and four hospital-based case–control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral–anal contact. Findings were stratified by sex and disease subsite.
Results Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8).
Conclusions Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection.
doi:10.1093/ije/dyp350
PMCID: PMC2817092  PMID: 20022926
Sexual practices; head and neck cancer; oropharyngeal neoplasms; homosexual; gay men; risk factors; pooled analyses

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