bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A83: A prospective study of dietary vitamin D intake and total all-cause mortality and cancer mortality in men and women
Authors: Murphy Neil , Michaud Dominique , Vineis Paolo , Gallo Valentina , Riboli Elio
Published: January 2011

Introduction: Recent research investigating the vitamin D-cancer hypothesis has generally focused on outcomes of cancer incidence, with few studies examining the effects of vitamin D on mortality. Using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we analysed the relationships between dietary vitamin D consumption and total all-cause mortality and cancer specific mortality.

Methods: Vitamin D intakes were estimated from dietary questionnaires administered at recruitment. Risk estimates for total all-cause mortality and cancer specific mortality were obtained by using Cox proportional hazards models, stratified by age at recruitment and study centre, and adjusted for smoking status, body mass index, physical activity, and intakes of total energy, alcohol, calcium, saturated fat, cholesterol and vegetables. Our main analysis included all participants. In secondary analyses, we excluded individuals who reported previous chronic disease at baseline (stroke, cancer, and myocardial infarction).

Results: After a mean follow-up of 9.7 years there were 21,345 all-cause deaths and 8,332 cancer-related deaths among the 475,862 participants. For total all-cause mortality, no associations were observed when the highest intake quintile of vitamin D was compared against the lowest in men (HR 0.88, 95% CI: 0.75-1.04; P-trend 0.13) and women (HR 0.99, 95% CI: 0.87-1.12; P-trend 0.83). For total cancer mortality, a statistically significant 23% reduction in risk was observed among men in the highest vitamin D intake quartile compared with the lowest (HR 0.77, 95% CI: 0.60-0.99). No association was observed for total cancer mortality amongst women (Q5 vs. Q1 HR 1.04, 95% CI: 0.88-1.23). For male colorectal cancer mortality, a reduced risk was observed when participants in the highest intake quartile were compared with those in the lowest intake quartile (HR 0.50, 95% CI: 0.19-1.30; P-trend 0.05). No significant associations were observed for vitamin D intake and colorectal cancer mortality amongst women. Results from the secondary analyses (i.e., excluding existing conditions at baseline) were generally similar to the primary analysis; however the association for colorectal cancer risk amongst men was slightly stronger and statistically significant (HR 0.30, 95% CI: 0.10-0.94; P-trend <0.01).

Conclusion: Results from this large prospective study suggest that higher dietary vitamin D intakes may reduce the risk of overall cancer mortality and colorectal cancer mortality in men.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A83.
Abstract A84: Red and processed meat-derived mutagen exposure and colorectal cancer risk in a population-based case-control study
Authors: Miller Paige E. , Lazarus Philip , Lesko Samuel M. , Muscat Joshua E. , Harper Gregory , Cross Amanda J. , Sinha Rashmi , Liao Jason , Ashmore Joseph H. , Hartman Terry J.
Published: January 2011

A recent report issued jointly by the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) concluded that the evidence to support a positive association between greater intakes of red and processed meat and colorectal cancer was convincing, but the evidence for specific meat components explaining these associations remained inconclusive. To explore potential underlying mechanisms for these observations, we examined associations of mutagens generated through meat cooking and meat processing methods with colorectal cancer in a large multisite population-based case-control study in a contiguous 19-county area in central and northeast Pennsylvania. Participants (863 healthy controls, 483 incident colon and 196 incident rectal cancer cases) completed a detailed lifestyle questionnaire and the 137-item National Cancer Institute's Diet History Questionnaire (DHQ). The DHQ included a detailed cooked and processed meat module to estimate intakes of heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), nitrites, and nitrates. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between meat exposures and colorectal cancer stratified by sub-site of the large intestine were estimated from unconditional logistic regression models. After multivariate adjustment for age, total energy intake, sex, body mass index, energy-adjusted total fruit and vegetable intake, and past regular NSAID use, positive associations with HCAs and PAHs, as measured by total mutagenic activity, were stronger for rectal cancer (OR = 1.55, 95% CI: 0.97, 2.47; P for trend = 0.049) than colon cancer, whereas positive associations with nitrites plus nitrates were stronger for colon cancer (OR = 1.31, 95% CI: 0.91-1.87; P for trend = 0.031). Our findings support the hypothesis that greater exposure to HCAs, PAHs, nitrites, and nitrates is a plausible mechanism by which red and processed meat may increase colorectal cancer risk. Our sub-site analyses indicate that associations between meat-derived exposures and colon and rectal cancer may differ, which underscores the need for additional studies that examine dietary risk factors for colon and rectal cancer as separate endpoints. The investigation of interactions between genetic polymorphisms and meat exposures in relation to colorectal cancer risk is underway in our study population.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A84.
Abstract A95: KCNK5 regulates proliferation of ER-negative breast cancer cells
Authors: Shen Qiang , Markaverich Jamie
Published: January 2011

Prevention and treatment of estrogen receptor (ER)-negative breast cancer are clinical challenges to reduce breast cancer incidence and mortality. All ER-negative breast cancer and a significant portion of ERpositive breast cancer are not preventable using currently available preventive drugs such as tamoxifen and raloxifene. Furthermore, ER-negative breast cancer does not respond to hormonal therapies and inclines to develop metastasis. Thus, novel targets are urgently needed to achieve effective prevention and treatment of ER-negative breast cancer. The ion channels for transporting potassium ions are deregulated in breast cancers. Specifically, the KCNK5 ion channel is differentially overexpressed at mRNA levels in ERnegative vs ER-positive breast cancers. Several lines of evidence suggest that KCNK5 may be a promising target for ER-negative breast cancer prevention and treatment. We hypothesize that KCNK5 is required for malignant transformation of breast cells and development of ER-negative breast cancer. In our studies, we found that majority of ER-negative breast cancer cells expressed moderate to high level of KCNK5 protein whereas minimal/low levels of KCNK5 in ER-positive cells. We also found that transient knockdown of KCNK5 mRNA with siRNA significantly inhibited proliferation of two ER-negative breast cancer cells (HCC1569 & BT20) that express high levels of KCNK5 protein. We are now testing whether gain of KCNK5 function by overexpressing KCNK5 in ER-negative breast cancer cells (HCC1937 & BT549, expressing relatively low level of KCNK5 protein) will promote cell growth. The proposed studies will provide useful pre-clinical information regarding the role of KCNK5 in ER-negative breast cancer development, which currently is poorly understood.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A95.
Abstract A96: Trans-resveratrol decreases breast proliferation and alters mammary promoter hypermethylation in women at increased risk for breast cancer
Authors: Qin Wenyi , Zhu Weizhu , Rottinghaus George , Chen Yin-Chieh , Zhang Ke , Sauter Edward R.
Published: January 2011

Trans-resveratrol, present in high concentration in the skin of red grapes and red wine, has a dose-dependent antiproliferative effect in vitro, prevents the formation of mammary tumors, and has been touted as a chemopreventive agent. We conducted in vitro experiments in hormone sensitive breast cancer cells and observed that trans-resveratrol downregulated DNA methyltransferase gene expression in a dose dependent fashion. Based upon this preclinical observation, we determined if transresveratrol had dose related anti-proliferative and methylation effects in humans. 16 adult women at increased breast cancer risk were randomized in double-blind fashion to placebo, 5 or 50 mg trans-resveratrol twice daily for 12 weeks. We collected serum, breast nipple aspirate fluid (NAF) and mammary duct (MD) specimens from all participants at all time points. Breast specific and systemic antiproliferative effects were assessed measuring the cancer promoting prostaglandin (PG)E2 in NAF and serum as well as changes in MD cytology, while methylation assessment of three cancer related genes (p16, RASSF-1α, APC) was performed on MD specimens. Serum resveratrol increased after consuming both trans-resveratrol doses (p<.001 for both). Cytology was not significantly changed by resveratrol treatment. RASSF-1α methylation significantly decreased after high (but not low) dose resveratrol, and the decrease correlated with increasing levels of serum resveratrol. RASSF-1α methylation also correlated with change in NAF levels of PGE2 (p=.0087). This work provides novel insights into the anticancer effects of trans-resveratrol in women at increased breast cancer risk, including prostaglandin inhibition and a decrease in methylation of the tumor suppressor gene RASSF-1α.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A96.
Abstract A97: Quality assessment of colonoscopy reporting: Results from a statewide cancer screening program
Authors: Li Jun , Nadel Marion
Published: January 2011

Objectives: Appropriate documentation of the colonoscopy procedure is an important component of patient care and one measure of quality. However, direct evaluation of colonoscopy reporting has been minimal. The aim of this study was to assess the quality of colonoscopy reporting.

Methods: We retrospectively collected data from 110 colonoscopy reports, where at least one polyp was noted. These reports were completed by 110 endoscopists from 2005-2006 through a statewide colorectal cancer screening program in Maryland, representing a variety of reporting formats from endoscopists throughout the state. We evaluated 25 key data elements recommended by the Standardized Colonoscopy Reporting and Data System (CO-RADS), including procedure indications, risk and comorbidity assessments, procedure technical descriptions, colonoscopy findings, and specimen retrieval and submission for pathology.

Results: All 110 reports stated an indication for the endoscopy, 36% included patient's medical comorbidities, 73% documented the bowel preparation quality, and 82% documented specific cecal landmarks. For the 177 individual polyps identified, information on size and morphology was documented for 87% and 53%, respectively. For these key data elements, ambiguous descriptors were sometimes used.

Conclusions: There was considerable variation among these colonoscopy reports. The absence of key data elements may impact the ability to make recommendations for recall intervals for colorectal cancer screening. Measurement of quality indicators in colonoscopy practice can identify areas for quality improvement.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A97.
Abstract B100: Rotating night shift work and risk of ovarian cancer
Authors: Poole Elizabeth M. , Schernhammer Eva S. , Tworoger Shelley S.
Published: January 2011

Introduction: Night shift work has been associated with higher risks of breast, endometrial, colorectal, prostate cancer and non-Hodgkin's lymphoma. These associations may be driven by a diminished ability of the pineal gland to produce melatonin among those exposed to light at night. Melatonin likely has multiple anti-cancer mechanisms, including down-regulation of the reproductive axis and direct actions of melatonin on estrogen receptors — both of note for ovarian cancer. Moreover, melatonin exhibits a growth-inhibitory effect on ovarian cancer cell lines. Few epidemiological studies have evaluated an association between night shift work and ovarian cancer risk. Within the NHS and NHSII cohorts, we prospectively assessed the association of rotating night shift work with ovarian cancer risk.

Methods: Total number of years of rotating night shift work (defined as at least 3 nights per month in addition to days and evenings during that month) was queried in 1988 for NHS and in 1989 for NHSII. Duration was updated in 1991, 1993, 2001, and 2005 for NHSII. We used Cox proportional hazards regression to model the incidence rate ratios (RR) and 95% confidence intervals (CI) of ovarian cancer for each shift work category (1-2 years, 3-5 years, 6-9 years, 10-14 years, 15-19 years, 20-29 years, and 30+ years), compared to those who never worked rotating shifts, adjusting for age in months, cohort, tubal ligation, duration of oral contraceptive use, parity, BMI, smoking status, menopausal status, family history of ovarian cancer, and duration of breastfeeding. In our analysis, we updated the values for these covariates when new data were available and otherwise carried forward the values from the previous cycle or the last cycle when each covariate was assessed.

Results: There were 666 cases of ovarian cancer among 2,856,537 person-years of follow-up time. Overall, rotating shift work was not associated with ovarian cancer risk: 15-19 years vs. none: OR: 1.21; 95% CI: 0.78-1.86; 20-29 years vs. none: OR: 0.65; 95% CI: 0.35-1.19; 30+ years vs. none: OR: 0.79; 95% CI: 0.40-1.54. Estimates were unchanged when adjusted for menstrual irregularity.

Conclusion: In this large prospective study, overall, there was no association between duration of rotating night shift work and risk of ovarian cancer. Additional analyses stratifying by hormonal receptor status. menopausal status and other potential effect modifiers are ongoing and may reveal subgroup associations.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B100.
Abstract B103: HPV vaccine adherence in urban youth
Authors: Tracy J. Kathleen , Terplan Mishka , Lydecker Alison D. , Schluterman Nicholas
Published: January 2011

This abstract is being presented as a short talk in Concurrent Session 15. A full abstract is printed in the Proferred Abstracts section (PR-11) of the Conference Proceedings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B103.
Abstract B13: High-risk human papillomavirus prevalence in oral and oropharyngeal premalignant lesions: A critical literature review
Authors: Hatton Elizabeth R. , Jayaprakash Vijay , Reid Mary E. , Loree Thom R. , Rigual Nestor R. , Frustino Jennifer L. , Johnson Timothy R. , Sullivan Maureen A.
Published: January 2011

Introduction: During the past decade, there has been a significant increase in the incidence of human papillomavirus (HPV) related squamous cell cancer of the oropharynx, especially those of the tonsil and tongue base. HPV-16 and HPV-18 have been linked to these malignant neoplasms. Generally, oral epithelium undergoes a sequence of histopathological pre-malignant transformations before the development of invasive carcinoma. A study evaluating the prevalence of HPV-16/18 types in histopathologically diagnosed oral pre-malignant lesions (OPL) is lacking. Therefore, we conducted a comprehensive literature review to estimate the prevalence of HR HPV types in different grades of OPLs.

Study Design: A critical literature search was conducted using Pubmed and SCOPUS databases for the key terms human papillomavirus infection, head and neck cancer, oral cancer, oral hyperplasia, oral dysplasia, and oral leukoplakia. A total of 90 articles related to HPV in oral tissue and pre-malignant lesions were identified. Of these, 29 articles evaluated the prevalence of HPV in histopathological OPLs (hyperplasia and dysplasia). In addition, 11 out of these 29 articles determined the prevalence of HPV in histologically evaluated leukoplakic samples. Only research articles published from 1990 — 2009 were used for this review.

Results: Overall, the 29 articles evaluated high-risk (HR) HPV in 1,171 OPLs. This included 140 hyperplasias, 467 dysplasias, 425 leukoplakic lesions without dysplasia, and 139 leukoplakic lesions with dysplasia. The prevalence of any type of HPV in hyperplasia, dysplasia, leukoplakia without dysplasia, and leukoplakia with dysplasia was 24%, 25%, 28%, and 20% respectively. The prevalence of HR HPV-16/18 in these lesions was 24%, 21%, 26% and 26% respectively. The difference in prevalence of different grades of OPLs was not statistically significant. The prevalence of any HPV type in mild, moderate, and severe dysplastic lesions was 43%, 39%, and 33% respectively. The prevalence of HR HPV-16/18 in mild, moderate, and severe dysplastic lesions was 39%, 32%, and 28% respectively.

Conclusion: High-risk HPV infection has been noted even in early stage histopathological OPLs like hyperplasias and mild dysplasias, and their prevalence rate is very similar to high grade OPLs, and oral (OC) and oropharyngeal cancers (OPC). Larger studies are needed to obtain a more precise estimate of the prevalence and persistence of HR HPV in histopathologically diagnosed OPLs in order to better understand the etiopathogenesis of HPV related OC and OPC.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B13.
Abstract B18: Personalizing the frequency of mammography: Cost effectiveness of screening mammography for women age 40 to 80 by breast density and other risk factors
Authors: Cummings Steven R. , Schousboen John T. , Loh Andrew , Kerlikowske Karla
Published: January 2011

Background: Current guidelines recommend mammography starting at age 40 or 50 years regardless of individual risk of breast cancer and do not take into account a woman's risk of breast cancer or breast density.

Methods: We used Markov microsimulation models to estimate the most cost-effectiveness intervals for screening mammography. Data about Breast Imaging Reporting and Data System (Bi-Rads) breast density, age, risk factors and risk of breast cancer, the natural history of breast cancer, estimates of progression in stages of breast cancer between mammograms, the cost of mammograms and medical care for breast cancer came from the Surveillance Epidemiology and End Results program, Breast Cancer Surveillance Consortium, and the medical literature. Simulations were done for cohorts receiving subsequent mammography between ages 40 to 79 years. We considered a strategy to be cost-effective if it cost ≤ $100,000 per lifetime quality adjusted life year (QALY) gained.

Results: Between ages 50 to 79, mammography every 2 years is cost-effective (<$100,000 per QALY) for women with Bi-Rads-3 or −4 breast density, or with BI-RADS 1 or 2 and a family history of breast cancer or history of breast biopsy. Mammography is cost-effective if done less often -every 3 or 4 years — for women with lower (Bi-Rads-1 or −2) breast density and no family history of breast cancer or history of breast biopsy. For women age 40-49, mammography every 2 years is cost-effective for those with Bi-Rads-3 or −4 breast density plus a family history of breast cancer and/or a history of breast biopsy, but it is not cost-effective for 40 to 49 year olds without these risk factors and with lower breast density. In general, the most cost-effective screening interval is longer if false positive results cause a loss of quality of life.

Conclusions: The frequency of mammography should be personalized based on woman's risk of breast cancer, estimated from her age, breast density, family history of breast cancer, history of breast biopsy and the potential effect of false positive mammograms on her quality of life.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B18.
Abstract B19: Evaluation of progression of cirrhosis to hepatocellular carcinoma using site-specific protein glycosylation analysis.
Authors: Kosti Ourania , Goldman Radoslav , Brnakova Zuzana , Shetty Kirti , Karger B. , Rejtar Tomas
Published: January 2011

Hepatocellular carcinoma (HCC) is a major worldwide health problem and a cancer with increasing incidence in the United States mainly due to hepatitis C viral (HCV) infections. Approximately 10-30% of HCV carriers develop cirrhosis; patients with cirrhosis have an annual risk of 1-2% for developing HCC and their prognosis is generally poor. The slow development and late detection of HCC suggest that the identification of biomarkers of disease progression and early detection are needed. Glycosylation is the most common post-translational modification of secreted proteins. Alterations in protein glycosylation are associated with different cancers, including HCC. We hypothesized that the site-specific glycosylation of proteins in HCC patients would differ from that of patients with liver cirrhosis and healthy people. Haptoglobin is a liver secreted glycoprotein with four N-glycosylation sites. Its main function is to bind free hemoglobin released by intravascular hemolysis; haptoglobin prevents the loss of iron and subsequent kidney damage. We used mass spectrometry to define site specific glycoforms of haptoglobin in the serum of 15 patients with HCC, 20 patients with liver cirrhosis due to HCV etiology and 15 disease free controls. We used selected reaction monitoring (SRM) quantification to quantify the changes in N-glycosylation. Quantification of 7-10 glycoforms per glycosylation site (approximately 30 glycoforms in total), revealed that site specific glycosylation of haptoglobin is altered in the diseased liver and is associated with liver damage and the presence of HCC. Results also indicated an increase of fucosylated glycans among patients with liver disease. In this pilot case-control study we demonstrated the development of site specific haptoglobin glycoform in the progression of liver disease. If confirmed by larger and prospective studies, site specific glycosylation of haptoglobin and other proteins, in general, could be used as a marker of HCC risk.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B19.
Abstract B21: Relationship of the global metabolome in blood to smoking behavior: A pilot study
Authors: Hsu Ping-Ching , Zhou Bin , Ressom Habtom , Cheema Amrita , Sheikh Kathryn , Pickworth Wallace , Shields Peter
Published: January 2011

Introduction: Better biomarkers of cancer risk are needed for smokers to enhance early detection and support the FDA as it considers cigarette performance standards and evaluate health claims for modified tobacco products. This study will identify new biomarkers through metabolomics, a powerful method to identify numerous metabolites and profiles.

Study Design: We utilized a previously conducted epidemiology study of well-characterized smokers. These subjects completed an extensive interview and smoked two cigarettes, one hour apart, in a smoking laboratory. Blood and CO measurements were collected before and after each cigarette. Plasma is available for metabolomic profiling. A pilot study was conducted on 5 light smokers and 5 heavy smokers’ plasma from the study and evaluated whether number of cigarettes per day mediates the influence of global metabolome.

Hypothesis: We hypothesized that the number of cigarettes per day exerts their influence on phenotype through global metabolome.

Methods: Using UPLC-TOFMS in our pilot study, we first analyzed global metabolomic profiles of 5 light smokers and 5 heavy smokers’ plasma and evaluated whether number of cigarettes per day mediate the influence of global metabolomic profiles. The data obtained for multivariate data analyses using Scripps’ XCMS. t-test, SVM (Support Vector Machine analysis), and Random Forest from the Metaboanalyst (www.metaboanalyst) were used for feature selection. The OOB (out-of-bag) error was used to measure the performance of Random Forest classification and the performance for SVMs was estimated using leave-one-out cross validation (LOOCV).

Results: In our results, 1199 peaks in the positive mode and 497 peaks in the negative mode were detected and after feature selection, 816 and 361 peaks were selected in the positive mode and negative mode, separately. Those significant features from all three methods (t-test, SVM and Random Forest) were pooled together for identification using Metlin, MMCD and HMDB databases to obtain the KEGG IDs, and the pooled KEGG IDs were used for Ingenuity Pathways Analysis (Ingenuity@ Systems, www.ingenuity.com). Our preliminary results suggest that smoking behavior is associated with several biological pathways such as cell death, gene expression, cell-cell interaction, and lipid metabolism. The Pathways Analysis also reveals several liver, heart and renal toxicity and altered bile acid biosynthesis, phospholipid degradation due to heavy smoking.

Future Studies: We will further evaluate whether smoking topography and inhalation, as measured by a nicotine boost and CO boost, and whether nicotine metabolism is associated with smokers’ global metabolome by level of smoking.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B21.
Abstract B22: Is there a role of estrogen and progesterone receptors in differentiating primary neuroendocrinal lung tumors from metastatic adenocarcinoma?
Authors: Hassan Wafaa , Darwish Atef , Darwish Abeer
Published: January 2011

Background: The distinction between primary lung carcinoma and metastatic tumors is essential for patient management and treatment. However for metastatic tumors, a wedge resection is often the procedure of choice, whereas for primary pulmonary neoplasms the standard treatment is to perform at least a lobectomy with mediastinal lymph node sampling. Computed tomography scans, histology and immunohistochemical stains still have some limitations in differentiating primary neuroendocrinal lung tumors and metastatic adenocarcinoma. Estrogen and progesterone receptors, although more frequently immunoreactive in breast carcinomas and gynecologic tumors than in primary lung tumors, can be positive in metastatic pulmonary adenocarcinoma.

Objective: To assess estrogen and progesterone receptor expression in primary pulmonary neuroendocrine tumors.

Design: Fifty seven neuroendocrine lung neoplasms including small cell carcinomas (25), carcinoids (19), large cell neuroendocrine carcinomas (6), and combined small cell carcinomas (7) were evaluated in this cross-sectional study for estrogen and progesterone receptors. Lung metastasis from gynecologic tumors (27) and non-small cell lung carcinomas (30) were also stained for comparison.

Settings: Chest and gynecology departments of Assuit and Woman's Health University hospitals.

Results: Neuroendocrine primary lung neoplasm demonstrated focal to diffuse estrogen and progesterone expression. There was no correlation with the size of the tumor, the sex or the age of the patients. In comparison with neuroendocrine lung carcinomas, lung metastasis from gynecologic adenocarcinomas (20 endocervical cancer, 7 endometrial cancer) expressed estrogen and progesterone receptors more frequently (p<0.7). Non-small cell carcinomas had less immunoreactivity for estrogen and progesterone than primary neuroendocrinal lung tumors and gynelogic lung metastasis (p<0.4).

Conclusions: Although estrogen and progesterone receptor staining is frequently associated with gynecologic tumors, it can also be observed in “nontarget” organs. Therefore, presence of estrogen and progesterone expression in lung metastasis from gynecologic adenocarcinomas should not exclude a primary pulmonary neoplasm.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B22.
Abstract B29: Role of inflammatory-related gene expression in clear cell renal cell carcinoma
Authors: Tan Weiqi , Hildebrandt Michelle AT , Pu Xia , Huang Maosheng , Tamboli Pheroze , Wood Christopher G. , Wu Xifeng
Published: January 2011

Renal cell carcinoma (RCC) is the 10th most common cancer in United States with clear-cell renal carcinoma (ccRCC) being the most common. Many genes and signaling pathways have been implicated in ccRCC development, including the inflammation pathway. However, less is known about how gene expression variation within this pathway influences ccRCC development and clinical outcomes. Gene expression in tumor and adjacent normal tissues from 93 patients with ccRCC was detected using a genome-wide expression array and a panel of 661 inflammation-related genes was then analyzed. Differential expression patterns between tumor and adjacent normal tissue were observed. Association between expression and recurrence or survival was evaluated with those genes showing significant association further tested in a validation set of 258 ccRCC tumor samples. A total of 151 genes with at least a 2-fold change in gene expression between adjacent normal and tumor were identified, with a majority of the genes being upregulated in the tumors. Eleven inflammation-related genes (BLNK, APP, IL8, CARD9, SOD2, IL10RA, GADD45G, ADORA3, CXCL1, CIITA, and NCF2) were found to be significantly associated with recurrence and/or overall survival in 93 ccRCC tumors and selected for further validation. Expression of CIITA and NCF2 was significantly associated with overall survival in the replication dataset with high expression levels associated with significant 2.65-fold (95% CI=1.28-5.49, P=0.0088) and a 2.26-fold (95% CI=1.12-4.58, P=0.023) increased risk of dying, respectively. Our results suggest expression of CIITA and NCF2 genes may be significant prognostic biomarkers for risk of dying in patients with ccRCC.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B29.
Abstract B30: Susceptibility loci for lung cancer: Are COPD genes the missing link?
Authors: Young Robert P. , Hopkins Raewyn J. , Hay Bryan A. , Whittington Christopher F. , Gamble Gregory D.
Published: January 2011

Epidemiological studies show COPD, characterized by reduced FEV1, is the most important independent risk factor for susceptibility to lung cancer. When spirometry is routinely measured, co-existing COPD is found in 50-80% of lung cancer cases compared to only 15-20% of randomly selected matched smokers. Recent GWA studies have identified a number of susceptibility loci for COPD, lung function and lung cancer. Several of these loci overlap suggesting that the gene conferring susceptibility to lung cancer might include COPD-related genes.

In this case control study of Caucasian smokers matched for smoking exposure with COPD (n=458), lung cancer (N=454) and healthy smoker status (n=488) we compared the genotype frequencies of 12 loci on chromosomes 1q23, 4q22-24, 4q31, 5p15, 5q33, 6p21, 6q24 and 15q25. All subjects underwent spirometry, completed a modified ATS respiratory questionnaire and gave blood for DNA. Genotyping was done using Taqman real-time PCR (ABI 7900).

We found (1) the AA genotype of CHRNA3/5 (previously associated with lung cancer) conferred susceptibility to lung cancer (OR=1.76, P=0.005) and COPD (OR-1.47, P=0.06), (2) the GG genotype of HHIP (previously associated with reduced risk of COPD) conferred protection from COPD (OR=0.59, P=0.006) and lung cancer (OR=0.70, P=0.05) and the CC genotype of FAM13A (previously associated with reduced risk of COPD) conferred protection from COPD (OR=0.71, P=0.02) and lung cancer (OR=0.64, P=0.003). These overlapping effects in lung cancer were independent of co-existing COPD.

We conclude the genes conferring susceptibility to lung cancer overlap with those of COPD. Such an observation requires healthy smokers with normal lung function to be used as controls to best identify these COPD-related genes affecting the susceptibility of smokers to lung cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B30.
Abstract B31: Gene-based lung cancer risk test (Respiragene), identifies high-risk smokers for early detection of lung cancer
Authors: Young Robert P. , Hopkins Raewyn J. , Field John , Zulueta Javier , Hay Bryan A.
Published: January 2011

Lung cancer results from the combined effects of smoking and genetic susceptibility. Recent studies show that between 50-90% of lung cancer cases have preexisting COPD and reduced FEV1 has been shown to be the single most important risk factor for lung cancer among smokers. Given the heritability for COPD and lung cancer is 40-75% and 15-25% respectively, it is clear genes conferring risk of COPD also underlies lung cancer susceptibility. In a study of 930 subjects, we have developed a gene-based lung cancer susceptibility model that combines genetic markers (SNPs) associated with COPD and lung cancer, with non-genetic variables (age and family history), to derive a score that helps to distinguish those smokers (and ex-smokers) at greatest risk of lung cancer. The panel includes SNPs validated in candidate and GWAS studies. In a prospective study of 1212 smokers we identified 52 new lung cancers and show their lung cancer scores are very similar to that of the original lung cancer cases (n=446). In a 2nd cross-sectional study of 606 lung cancer cases from the United Kingdom, the lung cancer score was also similarly distributed and showed similar performance in an ROC analysis. In a CT study of 25 lung cancer detected through CT screening in Spain, a similar high score was shown. Current CT screening programs for lung cancer generally target smokers over 50 years with a minimum 20 pack year history and achieve pick up rates of 1%. Using our gene-based model, where age, family history, COPD and genetic variants are combined, lung cancer detection rates maybe even higher.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B31.
Abstract B34: Association of endogenous oxidative and aldehyde stress: Implications for studies of colon carcinogenesis
Authors: Bruce W. Robert , Cani Patrice D. , Cirocco Maria , DaCosta Ralph S. , Giacca Adria , Kim Young-In , Lee Owen , Liu Zhen , Ma David W.L. , Marcon Norman , Minkin Salomon , O'Brien Peter J.
Published: January 2011

The results of a small pilot study provided new insights into the process of colon carcinogenesis.

Background: The known risk factors for colorectal cancer (CRC) suggested that CRC resulted from the interaction of exposure to energy excess and to oxidative stress [McKeown-Eyssen G et al. pp 673-693 in “Endogenous Toxins” Wiley, 2010]. The suggestion was supported by: cellular studies that demonstrated the cytotoxicity and genotoxicity of excess energy substrate (fructose) with oxidative stress (H2O2); animal studies that showed a wide range of pathology associated with fructose-based diets when combined with oxidative stress; and clinical studies that described the association of advanced glycation end-products (AGEs) with chronic diseases associated with the Western lifestyle.

Methods: A pilot case-control study at a hospital-based gastroenterology clinic was conducted to assess methods for future tests of the hypothesis. It was based on an analysis of plasma samples collected from patients with (n = 20) or without (n = 21) colonoscopy-demonstrated polyps.

Results: Although as anticipated none of the differences between polyp and non-polyp plasma samples achieved statistical significance, there were unexpectedly strong associations of the concentrations of the endogenous plasma aldehydes, glyoxal and methylglyoxal (r = 0.92), and glyoxal and 4-hydroxynonenal (r = 0.52) across the collected samples.

Conclusions: The associations were likely a consequence of the known interaction of endogenous aldehydes with oxidative stress: endogenous aldehydes increased oxidative stress; oxidative stress increased the formation of endogenous aldehydes [e.g. Vander Jagt DL. Drug Metab Drug Interact 2008;23:93-124]. The products of such interactions, AGEs and advanced lipid oxidation endproducts (ALEs), could explain the known accumulation of fluorescent lipofuscin observed with dysplastic adenomas.

Impact: Exposure to endogenous aldehydes and oxidation products is complex. Endogenous aldehyde derived — AGEs could provide robust biomarkers of this exposure including information relating to the tissues, cells and cellular organelles affected.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B34.
Abstract B37: Relationship of human rectal aberrant crypt foci and formation of colorectal polyp
Authors: Takahashi Hirokazu , Sakai Eiji , Uchiyama Takashi , Sugiyama Michiko , Hosono Kunihiro , Endo Hiroki , Nakajima Atsushi
Published: January 2011

In experimental models of colonic carcinogenesis, aberrant crypt foci (ACF) are the earliest detectable abnormality and precede adenomas. Herein, we wanted to determine the adenoma incidence over a 1-year period after polypectomy. Eighty-nine subjects were recruited from the population of Japanese individuals who underwent polypectomy at Yokohama City University Hospital. All patients had baseline adenomas (> 6mm) removed at year 0 colonoscopy. ACF were defined as lesions in which the crypts were more darkly stained with methylene blue than normal crypts and had larger diameters, often with oval or slit-like lumens and a thicker epithelial lining. A total of 366 ACFs were identified in 89 patients; all had baseline adenomas (> 6mm) removed at the first examination (year 0) colonoscopy and returned for the second (year 1). ACF in the lower rectum were assessed at year 0 and study group were divided into two groups depend on ACF numbers, 0-3 or over 4. All participants were examined in the number and maximum size of adenoma. There was no statistical difference in number and maximum size of ACF at year 0, however, maximum size of adenoma was larger in over 4 group than 0-3 group at year 1. The meaning of the number of ACF is not elucidated; however, the number of ACF may be a predictive factor of relatively large adenoma incidence in the pilot phase study.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B37.
Abstract B42: Cell-based, genome-wide assessment of chromosome-specific telomere length by quantitative fluorescent in situ hybridization in esophageal adenocarcinoma patients
Authors: Gong Yilei , Gu Jian , Ajani Jaffer , Luo Sherri , Hawk Ernest , Wu Xifeng
Published: January 2011

Chromosomal instability is one of the early hallmarks of human carcinogenesis. Shortened telomeres may predispose to chromosomal instability leading to the development of some cancers, including esophageal adenocarcinoma (EAC). However, whether the telomere changes associated with cancer risk occur at the global or chromosome-specific level remain largely unknown. Here, we developed a novel two-step quantitative fluorescent in situ hybridization (FISH) assay to measure the overall and genome-wide chromosome-specific telomere length in peripheral blood lymphocytes (PBLs). In this assay, overall telomere FISH is first carried out using peptide-coupled nucleic acid (PNA) probe. The relative intensity of each telomere signal is obtained by digital capture of the microscopic image and quantified. Then we perform the second FISH with centromere and subtelomere probes on the same slide to label each chromosome. Therefore, we can identify and quantify the telomere length for the p arm or q arm of each chromosome. We next used this assay to measure the overall and chromosome specific telomere length in a pilot case-control study of 31 EAC cases and 31 matched controls. We found EAC patients had significantly shorter overall telomere lengths in PBLs compared with controls (P = 0.039). Notably, the chromosome-specific telomeres of 8, 10, 14, 16, 17, and 22 were significantly shorter in cases than in controls (P < 0.05). Analysis of chromosome arm-specific telomeres indicated that the telomere lengths of 17p, 17q, 16q, Xp, and 10q, and 13p were shorter in cases than controls (P < 0.04). Cumulative analysis of these six significant telomeres showed that the total length for cases was significantly shorter than controls (P < 0.001). Using median expression as cutoff, we found that patients with short telomeres on chromosome 17, 13p, 22q, or Xp had 4.4-fold increased risk of EAC (P for trend < 0.001). Taken together, our study provides the first epidemiologic evidence that cancer cases have generally short telomeres across all chromosome arms and suggests that short telomeres in specific chromosome arms may exhibit stronger cancer predisposing effects than others depending on cancer types.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B42.
Abstract B43: Identification of prognostic markers for prostate cancer by serum profiling with a carbohydrate antigen microarray
Authors: Gildersleeve Jeff , Campbell Chris , Schlom Jeff , Gulley James
Published: January 2011

Purpose: The purpose of this study was to evaluate carbohydrate antigen array technology as a tool for identifying anti-glycan antibodies in human sera with potential as prognostic markers for prostate cancer.

Methods: A carbohydrate antigen array, or glycan array, containing 220 different glycans and glycoproteins was used to profile the anti-glycan antibody repertoire in sera from 29 prostate cancer patients. The Halabi nomogram was used to predict the survival for each patient. Relationships between antibody levels and the Halabi predicted survival were evaluated as a means to identify potential prognostic markers.

Results: A number of anti-glycan antibodies found in sera showed statistically significant correlations with the predicted survival for prostate cancer patients. Some examples include fucose-alpha (p = 0.009), fucosebeta (p = 0.023), Sialyl Lewis X (p = 0.014), and the Tn antigen (p = 0.022). For each of these antigens, higher antibody levels were associated with shorter predicted survival.

Conclusions: Anti-glycan antibodies have potential as prognostic markers for prostate cancer, and, based on the preliminary data, larger and more detailed studies are warranted.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B43.
Abstract B44: Reproducibility and short-term intraindividual variability of telomere length measurement using a monochrome multiplexing quantitative PCR
Authors: Kim Sangmi , Sandler Dale , Carswell Gleta , Cawthon Richard , Weinberg Clarice , Taylor Jack
Published: January 2011

Background: Telomeres are repetitive DNA structure at the end of chromosomes that are required for genomic integrity and stability. Numerous epidemiologic studies have examined telomere length in peripheral blood in relation to cancer and other aging-related diseases. In many of these studies, a measurement of telomere length from a single blood draw is quantified using a real-time PCR technique, and assumed to reflect a replicative history of hematopoietic stem cells in individuals. We examined the reproducibility of telomere length measurement and the relative magnitudes of sources of variation using sequential samples collected over a 9-month period.

Methods: Relative telomere length in peripheral blood was estimated using a single tube monochrome multiplex quantitative PCR assay in blood DNA samples from 27 non-pregnant adult women (aged 35 to 74 years) collected in 7 visits over a 9-month period. Each specimen was assayed in triplicate on each of two plates. Reproducibility of the technical triplicates within a plate was assessed using the coefficient of variation (%CV). A linear mixed model was used to estimate the components of variance for telomere length measurements attributed to variation among women and variation between time points within women.

Results: Within-plate technical replicate variability ranged from 8.5 to 15% (mean %CV=12.9). Plates had a significant systematic influence on telomere length measurements, explaining 16% of the variance; however, telomere length measurements between different plates were highly correlated (Pearson's correlation coefficient r=0.93, p<0.01). After controlling for plate effects, 64% of the remaining variance was estimated to be accounted for by variance due to subject. Variance explained by date of collection within a subject was minor, contributing 5% of the remaining variance. Compared to classification into quartiles based on all 7 time point measures and all six technical replicates for each time point, using the six technical replicates from a single time point resulted in the same quartile classification for 73%. Using a single time point and only 3 technical replicates decreased that agreement to 64%. These differences in quartile assignment were almost always only across neighboring quartile categories.

Conclusion: Our data demonstrate good reproducibility of telomere length measurement using blood from a single draw. However, the existence of technical variability, particularly plate effects, reinforces the need for technical replicates and balancing of case and control samples across plates.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B44.
Abstract B46: The effect of sulforaphane on protein expression in benign prostatic hyperplasia tissue
Authors: McCall Rosemary , Traka Maria , Mithen Richard
Published: January 2011

Background: Benign prostatic hyperplasia (BPH) is a common condition that occurs in over 25% of men aged 50+, increasing to 50% amongst those over 80. Although the etiology of the condition has not been ascertained, the majority of BPH specimens contain inflammatory infiltrates indicating inflammation plays an important role in the progression of the disease. Furthermore, a role for inflammation has also been suggested in prostate cancer (PCa). BPH is not a pre-cursor of PCa but using BPH as a model of inflammation could result in findings that may apply and add to our understanding of PCa. Previous work has demonstrated that the consumption of broccoli can alter inflammatory pathways in the human prostate, and this may be due to the action of the isothiocyanate sulforaphane (SF), a phytochemical derived from broccoli. This dietary compound has a range of biological activities, including reducing inflammation.

Hypothesis: Sulforaphane reduces inflammatory pathways and beneficially alters protein expression in BPH tissue.

Methods: We obtained and cultured human BPH tissue for 24 hours with or without 10µM SF and collected tissue and media for further analysis using two distinct approaches. Firstly, in a targeted approach, known inflammatory markers were measured in the media of five tissue samples by commercially available ELISA. Secondly, a global proteomic analysis was carried out to give an unbiased view of the effect of SF on the protein expression within the tissue. Initially, protein was extracted from the tissue of three individuals, run on 2D gels and spots of interest excised from the gel and in-gel trypsin digested. The resulting peptides were analyzed on an LTQ-Orbitrap Mass Spectrometer and the proteins identified by Mascot. Selected proteins were then further quantified in additional tissue samples.

Results: Analysis of the effect of SF on inflammatory markers revealed that SF significantly reduced levels of secreted IL-6 and to a lesser extent IL-8 and FGF-2. Global proteomic analysis demonstrated that there was, as expected, considerable variation between individuals, and that SF altered expression of several proteins in BPH tissue. Reduction of GRP94, an endoplasmic reticulum chaperone protein observed in one individual, was further verified in independent BPH samples. Initial immunohistochemistry in sections of BPH tissue suggests that SF reduces the nuclear localization of this protein. Further experiments are currently ongoing to investigate these effects in more individuals and also to look at the biological consequences.

Conclusion: Natural variation present within humans highlights the need to use a larger number of samples in order to understand the complex effects of SF on prostate tissue. The results suggest that SF can reduce inflammatory markers and alter proteins within the human prostate indicating a possible protective role for SF in pathogenesis of the prostate.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B46.