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1.  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
2.  Examination of ancestral informative markers and self-reported race with tumor characteristics of breast cancer among black and white women 
Background
African American (AA) women have a higher mortality from breast cancer (BC) compared to European American (EA) women. This may be due to the higher proportion of AA women with tumors that are diagnosed at more advanced stages and are characterized as being estrogen receptor negative (ER-)/ progesterone receptor negative (PR-). Our study sought to determine whether self-reported race and percent African ancestry were associated with BC tumor characteristics.
Methods
In a multi-center, population-based case-control study of BC, we determined percent African ancestry using ancestry informative markers (AIM) among women self-reporting race as AA or Black.
Results
BC tumor characteristics were associated with self-reported race (including a 30% reduction in ER+/PR+ tumors [95% confidence interval [CI]: 0.6-0.9] and a 1.5-fold increased risk of high grade [95% CI: 1.2-1.9] for AA women compared to EA women). AIMs among AA women were not associated with BC tumor characteristics (AA women with ≥ 95% versus < 80% African ancestry, odds ratio [OR]=1.0 for ER+/PR+ [95% CI: 0.6-1.8] and OR=0.9 for high-grade tumors [95% CI: 0.6-1.4]). Similar findings were observed for BC stage.
Conclusion
While BC subtypes were associated with self-reported race, BC subtypes were not associated with percent African ancestry.
Impact
These study results suggest that subtle differences in percent African ancestry are less important than the overall presence of African ancestry in relation to BC tumor characteristics.
doi:10.1007/s10549-012-2099-0
PMCID: PMC3697473  PMID: 22648732
3.  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
4.  Family history of breast cancer in relation to tumor characteristics and mortality in a population--based study of young women with invasive breast cancer 
BACKGROUND
Inherited predisposition may be associated with distinctive breast cancer phenotypes and/or mortality. Past studies have had inconsistent results and little is known about the contributions of screening and treatment.
METHODS
Within a population-based cohort of 1260 women diagnosed with invasive breast cancer before age 46, we assessed how family history of breast cancer relates to mortality and tumor characteristics. Analyses were repeated excluding BRCA1/BRCA2 carriers. Medical records were reviewed for treatment history and tumors were centrally reviewed and tested. Cox proportional hazard modeling was used to assess the risk of dying in relation to family history; logistic regression was used to assess the association of family history to tumor characteristics.
RESULTS
Compared to women with no family history, women with first-degree family history of breast cancer had a 40% reduction (95% CI 0.5–0.8) in the risk of dying. Mortality in women with only a second-degree family history was similar to those with no family history. The risk of dying was further reduced in those with a greater number of affected relatives. These relationships did not appear to be attributable to differences in screening, detection method, or treatment. Tumors in women with a first-degree family history had generally more favorable prognostic profiles.
CONCLUSION
Our findings suggest that breast cancer patients with a first-degree family history, compared to their counterparts without such a profile, may have a better prognosis.
IMPACT
These findings support the need for future research directed at replicating these results and identifying factors underlying this possible relationship.
doi:10.1158/1055-9965.EPI-11-0781
PMCID: PMC3242640  PMID: 21960690
breast cancer; family history; BRCA1; BRCA2; tumor markers; survival
5.  Gene Expression in Uninvolved Oral Mucosa of OSCC Patients Facilitates Identification of Markers Predictive of OSCC Outcomes 
PLoS ONE  2012;7(9):e46575.
Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers worldwide, with approximately 60% 5-yr survival rate. To identify potential markers for disease progression, we used Affymetrix U133 plus 2.0 arrays to examine the gene expression profiles of 167 primary tumor samples from OSCC patients, 58 uninvolved oral mucosae from OSCC patients and 45 normal oral mucosae from patients without oral cancer, all enrolled at one of the three University of Washington-affiliated medical centers between 2003 to 2008. We found 2,596 probe sets differentially expressed between 167 tumor samples and 45 normal samples. Among 2,596 probe sets, 71 were significantly and consistently up- or down-regulated in the comparison between normal samples and uninvolved oral samples and between uninvolved oral samples and tumor samples. Cox regression analyses showed that 20 of the 71 probe sets were significantly associated with progression-free survival. The risk score for each patient was calculated from coefficients of a Cox model incorporating these 20 probe sets. The hazard ratio (HR) associated with each unit change in the risk score adjusting for age, gender, tumor stage, and high-risk HPV status was 2.7 (95% CI: 2.0–3.8, p = 8.8E-10). The risk scores in an independent dataset of 74 OSCC patients from the MD Anderson Cancer Center was also significantly associated with progression-free survival independent of age, gender, and tumor stage (HR 1.6, 95% CI: 1.1–2.2, p = 0.008). Gene Set Enrichment Analysis showed that the most prominent biological pathway represented by the 71 probe sets was the Integrin cell surface interactions pathway. In conclusion, we identified 71 probe sets in which dysregulation occurred in both uninvolved oral mucosal and cancer samples. Dysregulation of 20 of the 71 probe sets was associated with progression-free survival and was validated in an independent dataset.
doi:10.1371/journal.pone.0046575
PMCID: PMC3460916  PMID: 23029552
6.  A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility 
Human Molecular Genetics  2011;20(15):3109-3117.
Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10−5] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10−7) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.
doi:10.1093/hmg/ddr207
PMCID: PMC3131044  PMID: 21551455
7.  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
8.  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
9.  Fine scale mapping of the breast cancer 16q12 locus 
Human Molecular Genetics  2010;19(12):2507-2515.
Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5′ end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case–control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case–control studies exhibit a different pattern of association suggestive of an additional causative variant.
doi:10.1093/hmg/ddq122
PMCID: PMC2876886  PMID: 20332101
10.  Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer 
Introduction
Multiple past studies have reported a reduced risk of breast cancer-related mortality (BCM) in relation to pre-diagnostic use of hormone therapy (HT); however, the extent to which this reduction is due to heightened screening or tumor biology is unknown.
Methods
Using a population-based cohort of 1,911 post-menopausal women diagnosed with invasive breast cancer at ages 45-79 from 1993-1999, we investigated the extent to which the reduced risk in BCM observed in relation to HRT might be explained by screening patterns or tumor features.
Results
Estrogen-progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥65 years: HR = 0.45 [95% CI: 0.26-0.80]; <65 years: HR = 1.03 [95% CI: 0.60-1.79]). Estrogen-alone therapy (ET) use was not associated with risk of BCM (ever use: ≥65 years: HR= 0.76 [95% CI: 0.51-1.12]; <65 years: HR = 1.20 [95% CI: 0.71-2.02]). HT users had a much greater frequency of mammography (p-value < 0.001). EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI: 0.38-0.85]) and an association with lobular tumors (OR = 1.68 [95% CI: 1.07-2.65]).
Conclusion
Beyond the influence of EPT use on screening uptake, these data indicate that the improved survival associated with pre-diagnostic EPT use may be due in part to the development of more favorable tumor characteristics.
doi:10.1007/s10549-010-1174-7
PMCID: PMC3059400  PMID: 20878463
breast cancer; mortality; hormone therapy; prognosis
11.  Common variation in KITLG and at 5q31.3 proximate to SPRY4 predispose to testicular germ cell cancer 
Nature genetics  2009;41(7):811-815.
Introductory paragraph
Evidence suggests that testicular germ cell tumors (TGCT) have a strong underlying genetic component. We performed a genome-wide scan among 277 TGCT cases and 919 controls. Seven markers at 12p22 within c-KIT ligand (KITLG) reached genome-wide significance (P < 5.0 × 10−8). In independent replication, TGCT risk was increased 3-fold per copy of the major allele at rs3782179 and rs4474514 (OR=3.08, 95% CI 2.29, 4.13; OR=3.07, 95% CI 2.29, 4.13, respectively). We also replicated associations with rs4324715 and rs6897876 at 5q31.3 near sprouty 4 (SPRY4; P < 5.0 × 10−6 in discovery). Risk of TGCT was increased nearly 40% per copy of the major allele (OR=1.37, 95% CI 1.14, 1.64; OR=1.39, 95% CI 1.16, 1.66, respectively). All of the genotypes were associated with both seminoma and non-seminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as TGCT susceptibility genes.
doi:10.1038/ng.393
PMCID: PMC2865677  PMID: 19483682
12.  PHYSICAL ACTIVITY IN ADOLESCENCE AND TESTICULAR GERM CELL CANCER RISK 
Cancer causes & control : CCC  2009;20(8):1281-1290.
Objective
Several, but not all, studies have observed increased risks of testicular germ cell cancer (TGCC) associated with bicycling and other recreational activities. To further examine whether physical activity (PA) in adolescence is associated with TGCC risk, the authors conducted a case-control study in western Washington State.
Methods
Cases (n=391) were men diagnosed with TGCC who were identified through a population-based cancer registry. Controls (n=1023) were men identified from the general population in western Washington State by using random digit telephone dialing. Participants were queried about various specific PA in grades 7–12 including bicycling, horseback riding, competitive sports, physical education class, as well as moderate, vigorous, and sedentary activities in general.
Results
In multivariate analyses, bicycling, vigorous-intensity activities, and sedentary activities were not associated with TGCC risk, while horseback riding and wrestling were associated with decreased risks, and moderate-intensity activities, soccer, basketball and intermediate duration of competitive activities were associated with increased risks.
Conclusions
The lack of internal consistency of the findings within the current study and of findings among prior studies, suggests that PA contributes little, if any, to the risk of TGCC.
doi:10.1007/s10552-009-9347-6
PMCID: PMC2890221  PMID: 19399630
testicular cancer; physical activity; case-control study; adolescent
13.  FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation 
Human Molecular Genetics  2009;18(9):1692-1703.
Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, Ptrend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
doi:10.1093/hmg/ddp078
PMCID: PMC2733817  PMID: 19223389
14.  Risk Factors for Triple-Negative Breast Cancer in Women Under Age 45 
Little is known about the etiologic profile of triple-negative breast cancer (TNBC; ER-/PR-/HER2-), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook the study to assess the risk of TNBC among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive (OC) use. Study participants were ascertained in two prior population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20-45 in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992 for whom complete data was obtained for ER, PR and HER2 status (n=897; including n=187 TNBC cases). Controls were age matched and ascertained via random digit dialing. OC use ≥1 year was associated with a 2.5-fold increased risk of TNBC (95% CI 1.4-4.3) and no significantly increased risk of non-TNBC (P heterogeneity .008). Further, the risk among OC users conferred by longer OC duration and by more recent use was significantly greater for TNBC than non-TNBC (P heterogeneity .02 and .01, respectively). Among women ≤40 years, the relative risk of TNBC associated with OC use ≥1 year was 4.2 (95% CI 1.9-9.3), whereas there was no significantly increased risk with OC use for non-TNBC among women ≤40 years, nor for TNBC or non-TNBC among women 41-45 years of age. In conclusion, significant heterogeneity exists for the association of OC use and breast cancer risk between TNBC and non-TNBC among young women, lending support to a distinct etiology.
doi:10.1158/1055-9965.EPI-08-1005
PMCID: PMC2754710  PMID: 19336554
Triple-negative breast cancer; oral contraceptives
15.  Association of Marijuana Use and the Incidence of Testicular Germ Cell Tumors 
Cancer  2009;115(6):1215-1223.
Background
The incidence of testicular germ cell tumors (TGCT) has been increasing the past 4–6 decades, but exposures accounting for this rise have not been identified. Marijuana use has also grown over this time period, and chronic marijuana use produces adverse effects on the human endocrine and reproductive systems. We tested the hypothesis that marijuana use is a risk factor for TGCT.
Methods
A population-based case-control study of 369 men age 18–44 years diagnosed with a TGCT from January 1999– January 2006 was conducted in King, Pierce and Snohomish Counties in Washington State. Their responses to questions on lifetime marijuana use were compared to those of 979 age-matched controls residing in the same three counties during the case diagnosis period.
Results
Men with a TGCT were more likely to be current marijuana smokers at reference date compared to controls, OR (odds ratio) =1.7, 95% CI (Confidence Interval) =1.1–2.5. When we conducted analyses according to histologic type, most of the association between current marijuana use and TGCT was in nonseminomas-mixed histology tumors, OR current use=2.3, 95% CI=1.3–4.0. Age at first use among current users appeared to modify risk (age<18 OR=2.8 vs. age≥18 OR=1.3) as did frequency of use (daily or weekly OR=3.0 vs.
Conclusions
We observed an association between marijuana use and occurrence of nonseminoma germ cell tumors of the testis. Additional studies of TGCTs are needed to test this hypothesis, including molecular analyses of cannabinoid receptors and endocannabinoid signaling that may provide clues to biologic mechanisms.
doi:10.1002/cncr.24159
PMCID: PMC2759698  PMID: 19204904
Marijuana Use; testicular tumors
Purpose
To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can sub-classify OSCC on the basis of survival.
Experimental Design
We analyzed the expression of 131 genes in 119 OSCC, 35 normal and 17 dysplastic mucosae to identify cluster-defined sub-groups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression the top predictive models of OSCC-specific survival were determined, and compared by Receiver Operating Characteristics (ROC) analysis.
Results
The 3-year overall mean survival (± SE) for a cluster of 45 OSCC patients was 38.7 ± 0.09%, compared to 69.1 ± 0.08% for the remaining patients. Multivariate analysis adjusted for age, sex and stage showed that the 45 OSCC cluster patients had worse overall and OSCC-specific survival (HR=3.31, 95% CI: 1.66, 6.58; HR=5.43, 95% CI: 2.32, 12.73, respectively). Stepwise Cox regression on the 131 probe sets revealed that a model with a term for LAMC2 (laminin, gamma 2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk-score marker (‘PCA’) and two other models that combined stage with either LAMC2 or PCA. The Area Under the Curve for models combining stage with either LAMC2 or PCA was 0.80 or 0.82, respectively, compared to 0.70 for stage alone (p=0.013 and 0.008, respectively).
Conclusions
Gene expression and stage combined predict survival of OSCC patients better than stage alone.
doi:10.1158/1078-0432.CCR-08-1816
PMCID: PMC2683360  PMID: 19228736
Objective
To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral squamous cell carcinoma (OSCC).
Design
We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. HPV DNA was detected using PCR followed by the Roche Linear Array HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software (IPA 5.0).
Subjects
Tumor tissue from 119 primary OSCC patients and normal oral tissue from 35 patients without cancer, all of whom were treated at three University of Washington-affiliated medical centers.
Results
HPV DNA was found in 41 of 119 (34.5%) tumors and 2 of 35 (5.7%) normal tissue samples, with 39 of 43 HPV being HPV type 16; there was a higher prevalence of HPV DNA in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycle. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (e.g., TYMS, STMN1, CCND1 and RBBP4) are involved in chemotherapy or radiation sensitivity.
Conclusion
These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors.
doi:10.1001/archoto.2008.540
PMCID: PMC2761829  PMID: 19221247
Human papillomavirus; oral cancer; gene expression
Testicular germ cell carcinoma (TGCC) is the most common malignancy among men aged 20–34. Although the pathogenesis of TGCC is poorly understood, sub-optimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess anti-androgenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p’-DDE, and whether the p,p-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor (AR) gene. We conducted a population-based case-control study among 18–44 year-old male residents of three Washington State counties. Cases (n=246) were diagnosed during 1999–2003 with a first, primary TGCC. Controls (n=630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatography-high resolution mass spectrometry analysis of organochlorine pesticide residues, and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p’-DDE was modified by AR CAG (<23 vs.23+ repeats) or GGN (<17 vs.17+ repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy.
doi:10.1158/1055-9965.EPI-08-0032
PMCID: PMC2766345  PMID: 18708392
testicular cancer; organochlorines; DDE; pesticides; androgen receptor
Background
Alcohol consumption has been comprehensively investigated as an etiologic risk factor for breast cancer but has received little attention in terms of its impact on prognosis after breast cancer, particularly for young women.
Methods
1286 women diagnosed with invasive breast cancer at or before 45 years of age from two population-based case-control studies in the Seattle-Puget Sound region were followed from their diagnosis of breast cancer (between January 1983 and December 1992) for survival through June 2002, during which time 364 women had died. Cox proportional hazards modeling was used to assess the effect of pre-diagnostic alcohol consumption on the risk of dying.
Results
After adjusting for age and diagnosis year, compared to non-drinkers, women who consumed alcohol in the 5 years prior to diagnosis had a decreased risk of death [>0 to <3 drinks per week: HR(hazard ratio) = 0.7 (95% CI: 0.6–0.95); 3 to <7 drinks per week: RR = 0.6 (95% CI: 0.4–0.8); ≥ 7 drinks per week: RR = 0.7 (95% CI: 0.5–0.9)]. This association was unchanged upon additional adjustment for potential confounders including most notably treatment, stage at diagnosis, and mammogram history.
Conclusion
These results suggest that women who consume alcohol prior to a diagnosis of breast cancer have improved survival which does not appear to be attributable to differences in stage, screening or treatment.
doi:10.1158/1055-9965.EPI-07-2897
PMCID: PMC2605937  PMID: 18664549
breast cancer; survival; alcohol consumption; wine; modifiable risk factor
Introduction
The involvement of vitamin D receptor (VDR), which is a key mediator in the vitamin D pathway, in breast cancer etiology has long been of interest.
Methods
We examined the association between polymorphisms in the 3' end of the VDR gene, specifically BsmI and Poly(A), and breast cancer risk within a large, population-based, case-control study of breast cancer. Cases (n = 1,631) were Caucasian and African-American women, aged 35 to 64 years, who were diagnosed with incident, invasive breast cancer between July 1994 and April 1998. Control individuals (n = 1,435) were women without breast cancer ascertained through random digit dialing.
Results
Accounting for age, study site, and sampling weights, we observed a significantly increased risk for breast cancer among Caucasian, postmenopausal carriers of the bb genotype of BsmI (odds ratio = 1.53, 95% confidence interval = 1.04 to 2.27). However, no associations with the bb genotype were observed in African-American women. Overall, there were no significant associations between the Poly(A) genotype and breast cancer risk in either racial group. Smoking status (ever/never) modified the association between both the BsmI and Poly(A) genotypes and breast cancer risk. The respective associations between these genotypes and breast cancer risk did not significantly vary by oral contraceptive use, hormone replacement therapy, or body mass index.
Conclusion
Our results provide additional support for an increased risk for breast cancer in postmenopausal Caucasian women with the BsmI bb genotype and shed light on possible differential effects by menopausal status and race.
doi:10.1186/bcr1833
PMCID: PMC2246187  PMID: 18067661
Breast Cancer Research  2004;6(6):R629-R635.
Introduction
The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America.
Methods
We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington.
Results
There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09).
Conclusion
The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA.
doi:10.1186/bcr933
PMCID: PMC1064080  PMID: 15535844
breast cancer; case–control study; CHEK2; population based
Cancer causes & control : CCC  2012;23(5):671-681.
Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case–control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP–hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP–HT interactions in women overall within CYP1B1 (rs1800440; phet = 0.003) and within CYP17A1 (rs743572; phet = 0.009) in which never users of HT were at a decreased risk of breast cancer, while investigated among racial groups, we detected evidence of an SNP–HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.
doi:10.1007/s10552-012-9925-x
PMCID: PMC3356164  PMID: 22418777
Breast cancer; Genetic variation; Racial disparities; Gene–environment interactions; Hormone therapy
PLoS Genetics  2013;9(1):e1003169.
In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC–specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03–11.11) and 3.45 (95% CI: 1.84–6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA–mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials.
Author Summary
Neck lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). To identify genes associated with this critical step of OSCC progression, we compared DNA copy number aberrations and gene expression differences between tumor cells found in metastatic lymph nodes versus those in non-metastatic primary tumors. We identified 95 transcripts (87 genes) with metastasis-specific genome abnormalities and gene expression. Tested in an independent cohort of 133 OSCC patients, the 95 gene signature was an independent risk factor of disease-specific and overall death, suggesting a disease progression phenotype. We knocked down the expression of over-amplified genes in five OSCC cell lines. Knockdown of 18 of the 26 tested genes suppressed the cell growth in at least one cell line. Interestingly, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC. The knockdown of G3BP1 increased programmed cell death in the p53-mutant but not wild-type OSCC cell lines. Taken together, we demonstrate that CNA–associated transcripts differentially expressed in carcinoma cells with an aggressive phenotype (i.e., metastatic to lymph nodes) can be biomarkers with both prognostic information and functional relevance. Moreover, results suggest that G3BP1 is a potential therapeutic target against late-stage p53-negative OSCC.
doi:10.1371/journal.pgen.1003169
PMCID: PMC3547824  PMID: 23341773
Molecular Cancer  2010;9:143.
Background
Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.
Results
We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with p = 0.044 or 0.011, respectively).
Conclusions
Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.
doi:10.1186/1476-4598-9-143
PMCID: PMC2893102  PMID: 20537188

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