Consumption of deep-fried foods and risk of prostate cancer.

BACKGROUND: Evidence suggests that high-heat cooking methods may increase the risk of prostate cancer (PCa). The addition of oil/fat, as in deep-frying, may be of particular concern, and has not specifically been investigated in relation to PCa. Potential mechanisms include the formation of potentially carcinogenic agents such as aldehydes, acrolein, heterocyclic amines, polycyclic aromatic hydrocarbons, and acrylamide. METHODS: We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between tertiles of intake of deep-fried foods from a food frequency questionnaire (French fries, fried chicken, fried fish, doughnuts and snack chips) and PCa risk, adjusted for potential confounders, among 1,549 cases and 1,492 controls. We additionally examined associations with more aggressive PCa (defined as regional/distant stage, elevated Gleason score or prostate-specific antigen level). RESULTS: Compared with <1/week, there was a positive association with PCa risk for intake ≥1/week of French fries (OR = 1.37; 95% CI, 1.11-1.69), fried chicken (OR = 1.30; 95% CI, 1.04-1.62), fried fish (OR = 1.32; 95% CI, 1.05-1.66), and doughnuts (OR = 1.35; 95% CI, 1.11-1.66). There was no association for snack chips (OR = 1.08; 95% CI, 0.89-1.32). Most of the estimates were slightly stronger for more aggressive disease (OR = 1.41; 95% CI, 1.04-1.92 for fried fish). CONCLUSION: Regular consumption of select deep-fried foods is associated with increased PCa risk. Whether this risk is specific to deep-fried foods, or whether it represents risk associated with regular intake of foods exposed to high heat and/or other aspects of the Western lifestyle, such as fast food consumption, remains to be determined.

MSMB gene variant alters the association between prostate cancer and number of sexual partners.

BACKGROUND: Recently, a genetic variant (rs10993994) in the MSMB gene associated with prostate cancer (PCa) risk was shown to correlate with reduced prostate secretory protein of 94 amino acids (PSP94) levels. Although the biological activity of PSP94 is unclear, one of its hypothesized functions is to protect prostatic cells from pathogens. Number of sexual partners and a history of sexually transmitted infections (STIs) have been positively associated with PCa risk, and these associations may be related to pathogen-induced chronic prostatic inflammation. Based on these observations, we investigated whether MSMB genotype modifies the PCa-sexual history association. METHODS: We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between number of sexual partners and PCa by fitting logistic regression models, stratified by MSMB genotype, and adjusted for age, family history of PCa, and PCa screening history among 1,239 incident cases and 1,232 controls. RESULTS: Compared with 1-4 female sexual partners, men with ≥ 15 such partners who carried the variant T allele of rs10993994 were at increased risk for PCa (OR = 1.32; 95% CI, 1.03-1.71); no association was observed in men with the CC genotype (OR = 1.03; 95% CI, 0.73-1.46; P = 0.05 for interaction). Similar estimates were observed for total sexual partners (any T allele OR = 1.37; 95% CI, 1.07-1.77; CC genotype OR = 1.11; 95% CI, 0.79-1.55; P = 0.06 for interaction). CONCLUSIONS: The rs10993994 genotype in the MSMB gene modifies the association between number of sexual partners and PCa risk. These findings support a hypothesized biological mechanism whereby prostatic infection/inflammation may enhance risk of PCa.

HOXB13 mutations in a population-based, case-control study of prostate cancer.

BACKGROUND: Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population. MATERIALS AND METHODS: We determined the distribution and frequency of the G84E HOXB13 variant in 1,310 incipient PC cases and 1,259 age-mated controls from a population-based, case-control study of PC. RESULTS: The G84E mutation was more frequent in cases than controls (1.3% vs. 0.4%, respectively), and men with the HOXB13 G84E variant had a 3.3-fold higher relative risk of PC compared with noncarriers (95% CI, 1.21-8.96). There was a stronger association between the G84E variant and PC among men with no first-degree relative with PC (OR, 4.04; 95% CI, 1.12-14.51) compared to men with a family history of PC (OR, 1.49; 95% CI, 0.30-7.50; P = 0.36 for interaction). We observed some evidence of higher risk estimates associated with the variant for men with higher versus lower Gleason score (OR, 4.13; 95% CI, 1.38-12.38 vs. OR, 2.71; 95% CI, 0.88-8.30), and advanced versus local stage (OR, 4.47; 95% CI, 1.28-15.57 vs. OR, 2.98; 95% CI, 1.04-8.49), however these differences were not statistically different. CONCLUSIONS: These results confirm the association of a rare HOXB13 mutation with PC in the general population and suggest that this variant may be associated with features of more aggressive disease.

Coffee and tea consumption in relation to prostate cancer prognosis.

BACKGROUND: Bioactive compounds found in coffee and tea may delay the progression of prostate cancer. METHODS: We investigated associations of pre-diagnostic coffee and tea consumption with risk of prostate cancer recurrence/progression. Study participants were men diagnosed with prostate cancer in 2002-2005 in King County, Washington, USA. We assessed the usual pattern of coffee and tea consumption two years before diagnosis date. Prostate cancer-specific outcome events were identified using a detailed follow-up survey. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: The analysis of coffee intake in relation to prostate cancer recurrence/progression included 630 patients with a median follow-up of 6.4 years, during which 140 prostate cancer recurrence/progression events were recorded. Approximately 61 % of patients consumed at least one cup of coffee per day. Coffee consumption was associated with a reduced risk of prostate cancer recurrence/progression; the adjusted HR for ≥4 cups/day versus ≤1 cup/week was 0.41 (95 % CI: 0.20, 0.81; p for trend = 0.01). Approximately 14 % of patients consumed one or more cups of tea per day, and tea consumption was unrelated to prostate cancer recurrence/progression. CONCLUSION: Results indicate that higher pre-diagnostic coffee consumption is associated with a lower risk of prostate cancer recurrence/progression. This finding will require replication in larger studies.

A history of allergies is associated with reduced risk of oral squamous cell carcinoma.

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. CONCLUSION: 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.

Integration of Real-World Data and Genetics to Support Target Identification and Validation.

Even modest improvements in the probability of success of selecting drug targets which are ultimately approved can substantially reduce the costs of research and development. Drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. A key enabler of identifying and validating these genetically validated targets is access to association results from genome-wide genotyping, whole-exome sequencing, and whole-genome sequencing studies with observable traits (often diseases) across large numbers of individuals. Today, linkage between genotype and real-world data (RWD) provides significant opportunities to not only increase the statistical power of genome-wide association studies by ascertaining additional cases for diseases of interest, but also to improve diversity and coverage of association studies across the disease phenome. As RWD-genetics linked resources continue to grow in diversity of participants, breadth of data captured, length of observation, and number of participants, there is a greater need to leverage the experience of RWD experts, clinicians, and highly experienced geneticists together to understand which lessons and frameworks from general research using RWD sources are relevant to improve genetics-driven drug discovery and development. This paper describes new challenges and opportunities for phenotypes enabled by diverse RWD sources, considerations in the use of RWD phenotypes for disease gene identification across the disease phenome, and challenges and opportunities in leveraging RWD phenotypes in target validation. The paper concludes with views on the future directions for phenotype development using RWD, and key questions requiring further research and development to advance this nascent field.

Increased risk of orofacial clefts associated with maternal obesity: case-control study and Monte Carlo-based bias analysis.

Our objective was to evaluate whether infants born to obese or diabetic women are at higher risk of non-syndromic orofacial clefting. We conducted a population-based case-control study using Washington State birth certificate and hospitalisation data for the years 1987-2005. Cases were infants born with orofacial clefts (n = 2153) and controls infants without orofacial clefts (n = 18 070). The primary exposures were maternal obesity (body mass index > or =30) and diabetes (either pre-existing or gestational). We estimated adjusted odds ratios (ORs) to compare, for mothers of cases and controls, the proportions of obese vs. normal-weight women and diabetic vs. non-diabetic women. We additionally performed Monte Carlo-based simulation analysis to explore possible influences of biases. Obese women had a small increased risk of isolated orofacial clefts in their offspring compared with normal-body mass index women [adjusted OR 1.26; 95% confidence interval 1.03, 1.55]. Results were similar regardless of type of cleft. Bias analyses suggest that estimates may represent underlying ORs of stronger magnitude. Results for diabetic women were highly imprecise and inconsistent. We and others have observed weak associations of similar magnitude between maternal obesity and risk of non-syndromic orofacial clefts. These results could be due to bias or residual confounding. However, it is also possible that these results represent a stronger underlying association. More precise exposure measurement could help distinguish between these two possibilities.

Reading in children with orofacial clefts versus controls.

OBJECTIVE: To examine reading and related skills in children with and without orofacial clefts. METHODS: Forty-two children with orofacial clefts were recruited from an urban craniofacial center. A demographically similar sample of 43 children without clefts was recruited using community advertisements and a research registry. Participants completed assessments of basic reading, phonological awareness, phonological memory, reading fluency, and rapid naming. Parents completed a semi-structured interview regarding educational and medical history. RESULTS: Children with clefts scored significantly lower than controls on measures of basic reading, phonological memory, and reading fluency. CONCLUSIONS: This is one of the first studies of reading in children with orofacial clefts to include a control sample. The findings suggest that children with clefts are less adept readers than demographically matched peers without clefts, supporting the need to monitor academic achievement in this population.

Real-world treatment patterns, healthcare resource utilisation and costs in patients with systemic lupus erythematosus treated with belimumab: a retrospective analysis of claims data in the USA.

Objective: To examine the effects of belimumab initiation on healthcare resource utilisation (HCRU) and costs in SLE. Methods: This retrospective observational cohort study used healthcare administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database to identify patients with SLE billing codes who received ≥1 intravenous belimumab infusion between March 2011 and December 2015. The first belimumab administration was the 'index date'. During the 6-month postindex period, nine belimumab infusions were recommended: three during the initiation period and six during the maintenance period. HCRU and cost data for inpatient admissions, emergency department visits, physician office visits, hospital-based outpatient visits, laboratory services, other outpatient services and outpatient pharmacy prescriptions were compared in the 6-month pre/postindex periods. Results: Of the 1879 patients with SLE included, 43% received ≥3 intravenous initiation administrations. An average of 5.3 (SD: 2.4) of the nine recommended belimumab administrations were received within 6 months. In the 6-month preindex versus postindex periods, significant reductions were noted for inpatient hospitalisations (18% vs 9%, p<0.001; mean visits: 0.3 vs 0.14, p<0.001) and emergency department visits (40% vs 24%, p<0.001; mean visits; 3.53 vs 1.96, p<0.001). Mean total costs were higher in the 6-month postindex versus preindex period ($41 426 vs $29 270; p<0.001). Conclusions: In this study of real-world intravenous belimumab for SLE, adherence to recommended infusion schedules was low. Outpatient healthcare and associated costs were higher in the 6 months after belimumab was initiated, although inpatient costs were lower. Reasons for non-adherence with belimumab and implications should be investigated.

Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort.

Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions. Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status. Results: In a population of 1431 participants (57% male; mean FEV1% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status. Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.

Analysis of Healthcare Resource Utilization and Costs after the Initiation of Biologic Treatment in Patients with Ulcerative Colitis and Crohn's Disease.

BACKGROUND: This retrospective cohort study aimed to describe and quantify healthcare resource utilization and costs for patients with ulcerative colitis (UC) and Crohn's disease (CD) following initiation of biologic therapy. METHODS: Resource utilization and costs were analyzed at baseline and 1- and 2-years after initiating a biologic. Data were extracted from a US administrative health insurance claims database for adults ≥18 years. Eligible patients were continuously enrolled in a health plan with medical and pharmacy benefits for ≥12 months prior to, and 12 months (primary analysis) or 24 months (secondary analysis) after index date (biologic initiation). RESULTS: In total, 4864 and 2692 patients with UC, and 8910 and 5227 patients with CD were identified in the 1- and 2-year follow-up cohorts, respectively. Of 1-year follow-up cohort patients, 45% received the same biologic initiated at index for ≥1 year. Infliximab and adalimumab were the most commonly initiated biologics in patients with UC or CD. The highest proportion of patients who continued with the same biologic after 1- and 2-years had initiated therapy with infliximab for both indications (although at the 1-year follow-up for CD, the highest proportion continued to use natalizumab, but this was a small sample [n=15]).Generally, the proportion of patients having inpatient admissions and emergency department (ED) visits decreased after receiving the same biologic for 1 year compared with baseline, although the proportion having outpatient visits did not change. Mean per patient all-cause costs for inpatient hospitalizations, ED visits and outpatient visits decreased for patients with UC or CD who received the same biologic for 1 year, while mean pharmacy costs per patient increased. CONCLUSIONS: This descriptive analysis shows that although biologics effectively reduced inpatient and ED resource utilization and corresponding costs in patients with UC and CD, total management costs increased, driven by increased pharmacy costs.

Treatment Patterns and Sequencing in Patients With Inflammatory Bowel Disease.

PURPOSE: Treatment options for patients with ulcerative colitis (UC) or Crohn disease (CD) have increased considerably in recent years with the advent of new biologics, but little is known about treatment pathways in clinical practice. We aimed to characterize treatment patterns and sequences in patients with UC or CD newly initiated on a biologic or an immunosuppressant (IMS). METHODS: This retrospective cohort study used US health insurance claims data dated from January 1, 2009, to December 31, 2013, from patients with UC or CD newly initiated on a biologic or an IMS. Treatment patterns and sequences were described during a 24-month follow-up period. FINDINGS: Among 5543 patients with UC and 7561 patients with CD, 2403 and 4677 patients, respectively, were initiated on a biologic; 3140 and 2884 patients were initiated on an IMS. In patients initiated on a biologic, monotherapy was chosen in 71% for UC (primarily infliximab [68%]) and in 79% for CD (primarily adalimumab [52%]). Approximately one third of patients remained on the first-line biologic during the follow-up period; 69% (UC) and 70% (CD) of patients were initiated on a second-line therapy, among whom 25% (UC) and 39% (CD) received a different biologic monotherapy, suggesting intolerance, inadequate response, or loss of response to first-line therapy. In patients initiated on an IMS, 58% (UC) and 66% (CD) were initiated on monotherapy; combination therapy with a corticosteroid was prescribed in 41% (UC) and 30% (CD) of patients; and second-line therapy was initiated in 72% (UC) and 75% (CD) of patients. IMPLICATIONS: While current treatment options seem effective in a proportion of patients with UC and CD, others require multiple lines of therapy, suggesting anunmet need for alternative treatments in UC and CD to achieve disease control.

Association Between Glucocorticoid Exposure and Healthcare Expenditures for Potential Glucocorticoid-related Adverse Events in Patients with Rheumatoid Arthritis.

OBJECTIVE: Oral glucocorticoid (OGC) use for rheumatoid arthritis (RA) is debated because of the adverse event (AE) profile of OGC. We evaluated the associations between cumulative doses of OGC and potential OGC-related AE, and quantified the associated healthcare expenditures. METHODS: Using the MarketScan databases, patients ≥ 18 years old who have RA with continuous enrollment from January 1 to December 31, 2012 (baseline), and from January 1 to December 31, 2013 (evaluation period), were identified. Cumulative OGC dose was measured using prescription claims during the baseline period. Potential OGC-related AE (osteoporosis, fracture, aseptic necrosis of the bone, type 2 diabetes, ulcer/gastrointestinal bleeding, cataract, hospitalization for opportunistic infection, myocardial infarction, or stroke) and AE-related expenditures (2013 US$) were gathered during the evaluation period. Multivariable regression models were fitted to estimate OR of AE and incremental costs for patients with AE. RESULTS: There were 84,357 patients analyzed, of whom 48% used OGC during the baseline period and 26% had an AE during the evaluation period. A cumulative OGC dose > 1800 mg was associated with an increased risk of any AE compared with no OGC exposure (OR 1.19, 99.65% CI 1.09-1.30). Incremental costs per patient with any AE were significantly greater for cumulative OGC dose > 1800 mg compared with no OGC exposure (incremental cost = $3528, 99.65% CI $2402-$4793). CONCLUSION: Chronic exposure to low to medium doses of OGC was associated with significantly increased risk of potential OGC-related AE in patients with RA, and greater cumulative OGC dose was associated with substantially higher AE-related healthcare expenditures among patients with AE.

Association Between Weight Change, Clinical Outcomes, and Health Care Costs in Patients with Type 2 Diabetes.

BACKGROUND: Previous research suggests that weight loss is associated with decreases in health care costs among individuals with type 2 diabetes mellitus (T2DM) and that weight change can affect clinical measures, including hemoglobin A1c (A1c), low-density lipoprotein cholesterol (LDLC), and blood pressure. Previous research has also demonstrated more pronounced impact of weight change among patients with T2DM who are obese and have no evidence of cardiovascular disease (CVD). OBJECTIVES: To (a) examine the association between weight change and all-cause and diabetes-related health care costs among patients with T2DM; (b) examine the association between weight change and select clinical measures among patients with T2DM; and (c) analyze a subgroup of obese patients with no previous CVD. METHODS: This retrospective, observational cohort study used U.S. insurance claims linked to laboratory and electronic medical records. This study included patients with T2DM aged 18 years or older who added or switched to a nonmetformin antidiabetes medication after metformin monotherapy between January 1, 2007, and June 30, 2012 (date of add/switch was the index date). The primary predictor was percentage weight change (PWC) between a weight measurement at index and a follow-up measurement 6 months later; PWC ranged from negative (weight loss) to positive (weight gain). Outcomes, measured in the 12-month period beginning at the time of follow-up weight measurement, included all-cause and diabetes-related health care costs and achievement of thresholds for A1c, blood pressure, and LDL-C. Multivariable models quantified the association between PWC (linear effect) and study outcomes. RESULTS: A total of 1,520 patients (mean age 55 years; 47% female) were included, with 780 patients (mean age 53 years; 51% female) in the subgroup sample. Mean (SD) index weight and PWC were 224.6 (52.8) lbs and +0.2% (4.7%) in the primary analysis, and 241.3 (47.3) lbs and -0.2% (4.6%) in the subgroup sample. In adjusted analyses, decreasing PWC was associated with decreasing diabetes-specific pharmacy costs (P < 0.001) in the primary analysis sample and with decreasing all-cause pharmacy costs (P = 0.018), diabetes-specific total costs (P = 0.039), diabetes-specific medical costs (P = 0.002), and diabetes-specific pharmacy costs (P < 0.001) in the subgroup sample. PWC was not associated with all-cause total health care costs or all-cause medical costs in either sample. In adjusted analyses, decreasing PWC was also associated with increasing odds of attaining the A1c goals of < 6.5% (P < 0.001) and < 7.0% (P < 0.001) in the primary analysis sample and increasing odds of attaining the A1c goals of < 6.5% (P < 0.001), < 7.0% (P < 0.001), and < 8.0% (P = 0.010) in the subgroup sample. PWC was not associated with any of the other clinical measures in either of the study samples. CONCLUSIONS: This real-world study suggests that among patients with T2DM, weight loss over a short-term (6-month) period is associated with positive impact on attainment of A1c goals and decreased diabetes-specific pharmacy costs over the subsequent 12 months. In the subset of patients who were obese and had no previus CVD, weight loss over the 6-month period was also associated with decreased all-cause pharmacy costs, diabetes-specific medical costs, and diabetes-specific total health care costs. Future research is warranted to examine whether these associations change over longer-term periods of follow-up. DISCLOSURES: This study was sponsored by AstraZeneca and Bristol-Myers Squibb. Truven Health Analytics received funding from Bristol-Myers Squibb and AstraZeneca to conduct this study. Mukherjee is an employee of Bristol-Myers Squibb. Bell and Sternhufvud are employees of AstraZeneca. Johnston, Stott-Miller, and McMorrow are employees of Truven Health Analytics. Nancy Smith is a consultant to Bristol-Myers Squibb and is employed by GreenKey Resources. Study concept was created by Mukherjee, Sternhufvud, Bell, and Johnston. Stott-Miller and McMorrow took the lead in data collection, along with Johnston, with data interpretation performed by Mukherjee, Sternhufvud, Smith, Stott-Miller, and Johnston. The manuscript was written by Mukherjee, Johnston, and Stott-Miller, along with Sternhufvud and Smith, and revised by Mukherjee, Smith, and Johnston, along with Sternhufvud and Stott-Miller.

Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.

BACKGROUND: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed. METHODS: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. RESULTS: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10(-6)), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10(-4)). DNA methylation profiles did not differ by recurrence status for the other genes. CONCLUSIONS: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence. IMPACT: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence.

Type II diabetes and metabolic syndrome in relation to head and neck squamous cell carcinoma risk: a SEER-Medicare database study.

BACKGROUND: Diabetes and metabolic syndrome have been found to increase the risk of various cancers. Previous studies indicated that diabetes may increase the risk of head and neck squamous cell carcinoma (HNSCC). Metabolic syndrome has not been investigated as a risk factor. We tested whether type II diabetes or metabolic syndrome were associated with HNSCC using a very large database of medical administrative records, providing the ability to investigate relatively weak effects and stratify by subgroups. METHODS: We identified persons diagnosed with HNSCC between 1994 and 2007 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. We selected controls from a 5% sample of Medicare beneficiaries and frequency matched to cases on sex and duration of enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between type II diabetes/metabolic syndrome and HNSCC, adjusted for potential confounders, among 14,022 cases and 42,066 controls. RESULTS: We observed a very weak inverse association between type II diabetes and HNSCC (OR=0.92; 95% CI, 0.88-0.96) and a moderate inverse association for metabolic syndrome (OR=0.81; 95% CI, 0.78-0.85). Associations were modified by tobacco use, with null results for type II diabetes among never users (OR=1.00; 95% CI, 0.95-1.06) and inverse associations among ever users (OR=0.80; 95% CI, 0.75-0.86). CONCLUSIONS: We observed moderate inverse associations between metabolic syndrome and HNSCC and weak inverse associations between type II diabetes and HNSCC, which was contrary to the evidence to date. Inadequate control for confounding factors, such as overweight/obesity, may have influenced results.

Germline missense variants in the BTNL2 gene are associated with prostate cancer susceptibility.

BACKGROUND: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified. METHODS: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. RESULTS: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27-5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16-5.46; P = 0.019). CONCLUSIONS: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. IMPACT: Results implicate BTNL2 as a novel prostate cancer susceptibility gene.

History of diabetes and risk of head and neck cancer: a pooled analysis from the international head and neck cancer epidemiology consortium.

BACKGROUND: A history of diabetes is associated with an increased risk of several types of cancers. Whether diabetes is a risk factor for head and neck cancer (HNC) has received little attention. METHODS: We pooled data from 12 case-control studies including 6,448 cases and 13,747 controls, and estimated OR and 95% CI for the associations between diabetes and HNC, adjusted for age, education level, sex, race/ethnicity, study center, cigarette smoking, alcohol use, and body mass index. RESULTS: We observed a weak association between diabetes and the incidence of HNC overall (OR, 1.09; 95% CI: 0.95-1.24). However, we observed a modest association among never smokers (OR, 1.59; 95% CI: 1.22-2.07), and no association among ever smokers (OR, 0.96; 95% CI: 0.83-1.11); likelihood ratio test for interaction P = 0.001. CONCLUSION: A history of diabetes was weakly associated with HNC overall, but we observed evidence of effect modification by smoking status, with a positive association among those who never smoked cigarettes. IMPACT: This study suggests that glucose metabolism abnormalities may be a HNC risk factor in subgroups of the population. Prospective studies incorporating biomarkers are needed to improve our understanding of the relationship between diabetes and HNC risk, possibly providing new strategies in the prevention of HNC.

Retinal and gingival hemorrhaging and chronic hyperglycemia.

OBJECTIVE: To assess the hypothesis that retinopathies are indicative of systemic microvascular injury. RESEARCH DESIGN AND METHODS: The only U.S. national survey assessing microvascular hemorrhaging at two distinct anatomical sites was the National Health and Nutrition Examination Survey (1988-1994). The systemic microvascular injury hypothesis was assessed by modeling the association of retinal and gingival hemorrhaging and the factors that explain this association. RESULTS: Individuals in whom one or more in five gingival sites was hemorrhaging had a 57% increased odds for retinal hemorrhaging (95% CI: 1.26-1.94). This association between retinal and gingival hemorrhaging was 51% explained by A1C concentrations. Retinal and gingival hemorrhaging exhibited the signature J-shaped prevalence patterns when plotted as a function of A1C concentrations. CONCLUSIONS: Gingival hemorrhaging reflected on retinal hemorrhaging, and both shared chronic hyperglycemia as an explanatory marker. These epidemiological findings support the hypothesis that retinopathies are reflective of systemic microvascular injury.

Tumor and salivary matrix metalloproteinase levels are strong diagnostic markers of oral squamous cell carcinoma.

BACKGROUND: The matrix metalloproteinases (MMP) 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: (i) expression of MMP1, MMP3, MMP10, and MMP12 in oral epithelial tissue using Affymetrix U133 2.0 Plus GeneChip arrays, followed by quantitative reverse transcription-PCR (qRT-PCR) for MMP1, and (ii) 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 nonneoplastic 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. CONCLUSION: 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 noninvasively.