bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA15: Measuring evolution in neoplasms
Authors: Malev Carlo C.
Published: June 2012

Neoplastic progression is a process of somatic evolution, yet few evolutionary tools have been adapted to measure the dynamics of progression. We have recently shown that traditional analyses of cross-sectional sampling of neoplasms usually infers the wrong order of events in progression. In contrast, phylogenetic methods applied to multiple samples within a neoplasm can accurately infer the order of events. Furthermore, longitudinal sampling can be used to estimate mutation rates, including chromosomal aberration rates, using phylogenetic methods developed to study viral evolution in vivo.

We have applied these tools to study the dynamics of progression in Barrett's esophagus and the effects of non-steroidal anti-inflammatory drugs on that somatic evolution.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA15.
Abstract IA17: Microfluidic measurements of single cell mass reveal how growth and division are coordinated
Authors: Manalis Scott
Published: June 2012

Cell growth during the cell cycle must be coordinated with genome replication and segregation, but the mechanisms underlying this coordination are poorly understood, particularly in mammalian cells. My lab is developing suspended microchannel resonators that can precisely measure the size of single cells – mass, volume and density – over time. Using a microfluidic system for culturing single cells over multiple generations while cell mass and cell cycle progression were continuously measured, we monitored over 1,000 hours of single cell growth from mouse lymphoblasts (L1210). I will present recent data from this system and discuss preliminary experiments where the precision cell sizing capabilities of the resonator are used for biomarker analysis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA17.
Abstract PR13: The canonical Wnt pathway participates in anchorage-independent growth in a subset of heterogeneous tumor cells derived from a single murine pancreatic tumor
Authors: Heung Man Yeung , Serrels Bryan , Morton Jennifer P. , Sansom Owen J. , Brunton Valerie , Frame Margaret C.
Published: June 2012

Pancreatic adenocarcinoma is a difficult cancer to treat with poor response rates to current therapies. Using a mouse model of pancreatic adenocarcinoma driven by endogenous expression of KRASG12D and p53R172H, we isolated heterogeneous tumor cell clones from a single tumor. Each of the cell clones has a unique genetic and protein expression signature, and they proliferate at different rates in vitro. Notably, only some of them are able to grow into colonies under anchorage-independent (AI) condition. We found that clones which can undergo AI growth have significantly higher phospho-ERK levels than the others, and the MEK inhibitors PD184352 and UO126 can suppress only some AI growth. We therefore looked for additional drivers of this cancer-associated AI growth and discovered that the canonical Wnt pathway, indicated by high transcription levels of Axin2 and Lgr5, is associated with AI growth in the pancreatic cancer cell clones that are less sensitive to the MEK inhibitors. In addition, two tankyrase inhibitors, XAV939 and IWR1, which stabilize Axin1 and enhance β-catenin degradation, inhibit AI growth in Wntactive cells, but not in ERK-dependent cells. Both tankyrase inhibitors downregulate Wnt-dependent Axin2 and Lgr5 transcription, without affecting phospho-ERK levels. Importantly, knockdown of β-catenin also impairs anchorage-independent growth only in Wnt-active cells. Thus, we have demonstrated for the first time that the canonical Wnt pathway is activated and contributes to AI growth in subclones of pancreatic cancer cells downstream of KRASG12D and p53R172H, and that Axin2 and Lgr5, but not all classical Wnt target genes (for example c-Myc), are involved. Hence, targeting Wnt in pancreatic cancer may be a viable option in treating KRAS- and p53-driven pancreatic cancer, but will probably need to be combined with multiple pathway inhibitors to deal with tumor heterogeneity.

This abstract is also presented as Poster A46.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR13.
Abstract PR14: Germline submicroscopic chromosome imbalances in pediatric cancer
Authors: Cappeli Leonardo , Krepischi Ana C.V. , Heck Benjamin , Gonçalves Amanda , Brentani Ricardo R. , Costa Cecilia M.L. , de Camargo Beatriz , Rosenberg Carla
Published: June 2012

The development of cancer is a multi-step process and, therefore, the probability of cancer occurrence increases with age. Pediatric cancer then either involves a succession of infrequent events occurring in a short period of time, which supposedly only happens rarely, or alternatively, some of the steps required for cancer development are already present in the individuals' germlines. Support for the presence of genomic alterations in the germline of these patients is given by the association of pediatric cancer with congenital abnormalities, observed both as the frequent presence of congenital abnormalities among these patients and as an increase of cancer among children with congenital abnormalities. We investigated DNA copy number variations (CNVs) in a cohort of 55 pediatric cancer patients attending the AC Camargo Hospital, São Paulo, Brazil. In particular, we focused on those alterations not commonly found in the general population (rare CNVs). No selection criteria were used other than age at diagnosis < 20 years and the families agreeing to participate in the study. In addition to CNV profiling by array-CGH (180K – Agilent Technologies), the patients were also physically examined by a clinical geneticist. Eighteen copy number alterations were detected in 16 patients; these rare CNVs included complex rearrangements and triplications, not often observed among common variants. The size of the alterations ranged from 58 to 2,600 Kb, with an average of 438 Kb, which is over twice the average length of rare copy number variations identified with the same array-CGH platform in a sample of 100 reference individuals studied in our laboratory. Many of the sixty-four genes mapping within the chromosome imbalances detected in patients represent good candidates for cancer manifestation and/or congenital abnormalities. Our results suggest that constitutive submicroscopic chromosome imbalances are a contributor to the etiology of pediatric cancer, that the combined presence of pediatric cancer and congenital abnormalities is strongly suggestive of constitutive chromosome imbalances being present, and that further CNV studies will lead finally to identification of genes involved in predisposition to pediatric cancer.

Funding: FAPESP; CNPq

This abstract is also presented as Poster B7.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR14.
Abstract A101: Metformin prevents mammary tumors in p53-null mammary gland mice
Authors: Mazumdar Abhijit , Hill Jamal L. , Zhang Yun , Kittrell Frances S. , Medina Daniel , Brown Powel
Published: June 2012

Background: Breast cancer prevention is now possible using antiestrogen drugs such as tamoxifen and raloxifene; however, antiestrogens are ineffective against estrogen receptor (ER)-negative breast cancers. Since ER-negative breast cancers are highly aggressive and particularly difficult to treat, preventive agents against these life-threatening cancers are urgently needed. Metformin, a first line treatment for adult-onset diabetes, recently was shown to be associated with reduced incidence of cancer (including breast cancer) in epidemiologic studies. Metformin activates AMP-dependent kinase (AMPK) and stimulation of AMPK by metformin reduces cell proliferation in both estrogen receptor alpha (ERa)-positive and -negative human breast cancer cell lines. We hypothesized that the metformin would effectively prevent the growth and development of ER-negative breast cancer. To test this hypothesis, we tested metformin's ability to prevent mammary tumors in two mouse models: the MMTV-erbB2 transgenic mouse model that develops ER-negative mammary tumors and the p53-null mammary gland mouse model that develops both ER-positive and ER-negative mammary tumors.

Methods: MCF7, BT474, MDA MB 468 and MDA MB 453 cells were treated with10mM metformin and cell proliferation was measured using an MTS assay. Virgin female MMTV-erbB2 mice (Jackson Lab) were housed in the institutional animal facilities and fed a purified diet (AIN-76A; Harlan Teklad). Mice were separated into 2 treatment groups: 1) Vehicle control (PBS via gastric gavage daily), 2) Metformin (250mg/kg via gastric gavage daily; from 3 months to 12 months of age). P53-null Balb/C mammary glands from donor mice were transplanted into both cleared inguinal mammary fat pads of Balb/C p53 wild-type mice. Mice were observed daily for tumor formation and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the generalized Wilcoxon test.

Results: Metformin (at 10mM) significantly reduced proliferation of breast cancer cells irrespective to their ER, Her2 and p53 status. In the MMTV-erbB2 mice, metformin treatment did not prevent or delay mammary tumor formation. However, in p53-null mammary gland mice, metformin completely prevented mammary tumor formation.

Conclusions: Metformin treatment totally prevented mammary tumor development in p53-null mammary gland mice. These results suggest that metformin will be most useful in preventing breast cancers with P53 mutations such as occurs in Li-Fraumeni syndrome individuals or individuals with ERa-negative or “triple-negative” breast cancer. These results support testing metformin in clinical trials for the prevention of ER-negative and p53-mutant breast cancers. This research was supported by the NIH/NCI R01 CA78480 grant (PHB).

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A101.
Abstract A111: Endogenous conversion of n-6 PUFAs to n-3 PUFAs prevents progression of K-Ras activated pancreatic lesion development to pancreatic ductal carcinoma in Fat-1 transgenic mice
Authors: Mohammed Altaf , Janakiram Naveena B. , Brewer Misty , Duff Ashley , Lightfoot Stan , Brush Richard S. , Anderson Robert E. , Rao Chinthalapally V.
Published: June 2012

Developing novel strategies to prevent or delay the progression of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with a dismal 5-year survival rate (<5%), is of utmost importance. Preclinical studies suggest that omega-3 fatty acid (n-3 PUFA)-rich diets may be beneficial for pancreatic cancer prevention. Nutritional intervention studies are often complex and there is no clear evidence whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection without potential confounding factors of interference. Thus, experiments were designed using fat-1 transgenic (n-3 fatty acid desaturase) mice, which can convert n-6 PUFA to n-3 PUFA endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC. LSL-KrasG12D/+ and p48Cre/+ mice were bred with Fat-1 mice and offspring of activated p48Cre/+-LSL-KrasG12D/+ and Fat-1-p48Cre/+-LSL-KrasG12D/+ were generated. Six-week old transgenic mice p48Cre/+-LSL-KrasG12D/+ (12/group), Fat-1-p48Cre/+-LSL-KrasG12D/+ (12/group), and wild-type (12/group) mice were fed (AIN-76A) a diet containing 10% safflower oil for 35 weeks. Pancreata were collected, weighed, and evaluated histopathologically for PanINs and PDAC. To understand the mechanisms, we analyzed levels of fatty acids and assessed the proliferation, apoptosis, and cell cycle markers by GC, IHC, IHF, Western blotting, Real time and/or RT-PCR. Results show a dramatic reduction in incidence of PDAC (85.8% p<0.02) in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. Importantly, significant reduction of pancreatic ducts with carcinoma (90%, p< 0.0001) and a significant suppression of PanIN 3 (∼50%; p<0.001) were observed in Fat-1-p48Cre/+-LSL-KrasG12D/+ transgenic mice. The levels of n-3 PUFA, -Linoleic acid, DPA and DHA were much higher (∼90%) in pancreatic tissues of Fat-1-p48Cre/+-LSL-KrasG12D/+ mice than that of p48Cre/+-LSL-KrasG12D/+ and WT animals. Importantly, molecular analysis of pancreas showed a significant down-regulation of fatty acid synthase, insulin receptor, insulin receptor substrate-1, PCNA, COX-2, 5-LOX, FLAP, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+. These data highlight the potential for use of n-3 fatty acids for chemoprevention of pancreatic cancer and represent an important strategy to delay/prevent pancreatic cancer in high-risk individuals. {Supported by Kerley-Cade Chair Endowment for Cancer Research}

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A111.
Abstract A19: Label-free analysis of tissue polarity in live three-dimensional culture of breast epithelium by Raman imaging of lipid phase
Authors: Yue Shuhua , Cárdenas-Mora Juan Manuel , Chaboub Lesley S. , Lelièvre Sophie A. , Cheng Ji-Xin
Published: June 2012

The formation of the basoapical polarity axis in epithelia is critical for maintaining the homeostasis of differentiated tissues. Factors that influence cancer development notoriously affect tissue organization. Apical polarity appears as a specific tissue feature that, once disrupted, would facilitate the onset of mammary tumors. Thus, developing means to rapidly measure apical polarity alterations would greatly favor screening for factors that endanger or protect the breast epithelium. A Raman scattering based platform was used for label-free determination of apical polarity in live breast epithelial structures (acini) produced in three-dimensional cell culture. The coherent anti-Stokes Raman scattering signal permitted the visualization of the apical and basal surfaces in the equatorial plane of an acinus. Raman microspectroscopy subsequently revealed that in polarized acini lipids were more ordered at the apical membranes compared to basal membranes, and that an inverse situation occurred in acini that lost apical polarity upon treatment with Ca2+-chelator EGTA. This method overcame variation between different cultures by tracking the status of apical polarity longitudinally for the same acini. Therefore the disruption of apical polarity by dietary breast cancer risk factor, 6 fatty acid, could be observed significantly with this method, even when the effect was too moderate to permit a conclusive assessment by visually scoring the acinus population for apical location of tight junction marker ZO-1. Analysis of apical polarity markers and cytoskeleton by fluorescence microcopy revealed that the change of lipid ordering upon apical polarity loss corresponded to actual disruption of the apical polarity complex. Our label-free platform will enable rapid identification of environmental factors that either initiate or prevent the very early stage of breast neoplasia. Identifying risk and protective factors will facilitate the design of primary prevention strategies to reduce breast cancer incidence. Furthermore, the use of the membrane lipid phase as readout to assess tissue polarity should be applicable to other types of epithelia where over 90% of cancers originate.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A19.
Abstract A28: DCIS disease-free survival in the population-based Wisconsin In Situ Cohort
Authors: Sprague Brian , McLaughlin Vicki , Hampton John , Newcomb Polly , Trentham-Dietz Amy
Published: June 2012

Ductal carcinoma in situ (DCIS) now makes up 20% of new breast cancer diagnoses. Women diagnosed with DCIS face an increased risk of developing invasive breast cancer. A number of randomized trials have demonstrated the effectiveness of radiation and tamoxifen in reducing the risk of invasive cancer after a DCIS diagnosis. However, few population-based studies have examined disease-free survival according to treatment in community practice. We examined disease-free survival in the Wisconsin In Situ Cohort (WISC) Study, a longitudinal study of health outcomes among a large population-based cohort including 1959 DCIS cases enrolled between 1995 and 2006. Data on the initial DCIS diagnosis, treatments, second breast cancer events, and prognostic factors were collected from the statewide cancer registry, patient interviews, and pathology reports. Multivariate Cox proportional hazards regression was used to evaluate disease-free survival in relation to treatment while adjusting for prognostic patient and tumor characteristics. After an average of 7.0 years of follow-up, 133 second breast cancer events occurred. The overall five-year disease-free survival rate was 94.6% (95% CI: 93.3–95.6%). Use of mastectomy declined over time, from 46% of DCIS cases in 1995–1997 to 30% of cases in 2004–2006. Tamoxifen use increased from 14% in 1995–1997 to 47% in 2004–2006. Overall five-year disease-free survival rates were 100% for women undergoing a bilateral mastectomy, 94.7% for women undergoing ipsilateral mastectomy, 95.4% for women treated with breast conserving surgery (BCS) and radiation, 89.9% for women treated with BCS only, and 86.5% for women receiving no further treatment beyond biopsy. These differences were driven mainly by variation in rates of ipsilateral events, whereas five-year disease survival for contralateral events was above 96% regardless of treatment type. No statistically significant differences were observed for any type of second event according to tamoxifen use. These results of this study provide population-based data that can be used to guide treatment choice for DCIS.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A28.
Abstract A32: Genomic and epigenomic alterations in arsenic-related lung squamous cell carcinomas
Authors: Becker-Santos Daiana D. , Vucic Emily A. , Lam Stephen , Lam Wan L. , Martinez Victor D.
Published: June 2012

Background: Arsenic is a potent human carcinogen. It is estimated that over 100 million people worldwide are exposed to toxic levels of arsenic, mainly through drinking water. Skin, bladder, and lung are key target organs for arsenic-induced carcinogenesis. Lung cancer is the main cause of deaths due to arsenic toxicity, with this metalloid acting as the major etiological agent in cancers that occur in never smokers. Lung squamous cell carcinomas (SqCCs) occur at higher rates than other subtypes following arsenic exposure. The mechanisms for arsenic carcinogenesis are not fully understood, but it has been proposed that neoplastic effects as a result of arsenic biotransformation can occur at both the genetic and epigenetic levels. In this study, a rare panel of lung tumors from a population with chronic arsenic exposure, including SqCC tumors from patients with no smoking history, was analyzed to identify arsenic-associated copy-number alterations (CNAs) and DNA methylation changes.

Methods: 52 lung SqCCs were analyzed by whole-genome tiling path comparative genomic hybridization. Twenty-two were derived from arsenic-exposed patients from Northern Chile (10 never smokers and 12 smokers), and 30 additional cases were obtained for comparison from smokers without arsenic exposure from North America. In addition, 22 blood samples from healthy individuals from Northern Chile were examined to identify naturally occurring germline DNA copy-number variations that could be excluded from analysis. DNA methylation analysis was performed using Illumina's Infinium Human Methylation 450K array.

Results: We identified several DNA copy number alterations and DNA methylation changes associated with chronic arsenic exposure. These alterations were not accountable to either natural copy-number variations or smoking status. The most recurrent events were represented by DNA losses at chromosomes 1q21.1, 7p22.3, 9q12, and 19q13.31. The only arsenic-associated DNA gain occurred at 19q13.33, which contains genes previously recognized as oncogenes.

Conclusions: Our study has provided insights into the molecular mechanisms of arsenic-induced lung neoplasia. The unique and recurrent arsenic-associated genetic and epigenetic alterations suggest that this group of tumors may be considered as a distinct disease subclass.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A32.
Abstract A36: Identification of chromatin-based patterns across lung cancer grades
Authors: Druliner Brooke R. , Dennis Jonathan H.
Published: June 2012

A hallmark of the transformed phenotype is altered chromosomal structure. The development and progression of lung cancer, one of the most common cancers, is driven by the interplay of genetic and epigenetic changes. Although there have been numerous studies on chromosomal aberrations in lung cancer, and cancer in general, broad assessment of chromatin structure information has been understudied, and its role in malignant transformation remains poorly characterized. Cancer progression is classified by tumor grade, which is determined by examining morphological changes that cells undergo as they de-differentiate. Given that chromosomal aberrations are well-documented in nearly all cancers, it is surprising that there is currently no information on the role of chromatin structure in the progression of cancer. We have identified chromatin-based patterns across different lung adenocarcinoma cancer grades.

To address the role of chromatin structure in the progression of cancer, we compared the chromatin structure from primary lung adenocarcinomas of grades one, two and three to their normal adjacent tissue, from multiple individuals, using an innovative microarray strategy. We measured chromatin structure across cancer grades between normal and tumor samples at three levels of resolution: nucleosome distribution, chromatin accessibility and three-dimensional molecular cytology. We used micrococcal nuclease (MNase) as a surrogate for highly diffusible molecules such as transcription factors, mobile elements, replication and repair machinery, and small RNAs. Our work indicates that grade one lung adenocarcinomas have greatly altered nucleosome distributions compared to the adjacent normal tissue, but nearly identical chromatin accessibility. Conversely, the grade three samples show massive disruptions in chromosomal accessibility, but only modest changes in nucleosome distribution when tumor and normal samples are compared. This data has allowed us to develop a model in which we propose that early grade lung adenocarcinomas are linked to changes in nucleosome distributions, while later grade cancers are linked to large-scale chromosomal changes. These results indicate that we should be able to use these chromatin structural changes to identify grade sub-type specific cancer biomarkers.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A36.
Abstract A58: Green tea and silybin for breast cancer: A pilot presurgical study
Authors: Lazzeroni Matteo , Gonzaga Aliana Guerrieri , DeCensi Andrea , Bonanni Bernardo , Serrano Davide , Johansson Harriet , Gandini Sara , Bassi Fabio , Pruneri Giancarlo , Aristarco Valentina , Riva Antonella , Petrangolini Giovanna
Published: June 2012

The importance of new effective agents for breast cancer chemoprevention is highlighted by the fact that to date tamoxifen and raloxifene administration has not been completely accepted to reduce breast cancer risk, mostly because they are both associated with rare but serious toxic effects. Moreover, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not reduce the risk of ER-negative breast cancer. These results show that new approaches are needed also for the prevention of the latter.

Phytochemicals present in fruits, vegetables, wine, and some medical herbs, especially botanical polyphenolic antioxidants, have received increasing attention in the last decade as potential chemopreventive agents for different human cancers. However, so far there is a limited knowledge of the processes regulating the absorption of phytochemicals (and/or their metabolites) into the body, and how they reach their biological target. In spite of epidemiological studies and scientific evidences supporting the beneficial role of phytochemicals in blocking cancer initiation and progression, the trials have though failed to yield predicted results in randomized intervention studies.

Treatment in a window of opportunity (WOP) before surgery may improve clinical benefits and represents a very useful tool in selecting new chemopreventive agents against breast cancer. With this approach we will be able to study the kinetics of phytochemicals on the target organ as well as the effect on cell proliferation and other biomarkers by comparing the difference between pre- and post-treatment specimens.

In the present pilot pre-surgical trial, we will study the bioavailability of two natural products formulated in a phosphatydilcholine complex, Greenselect® Phytosome® (a standardized caffeine-free green tea extract) and Siliphos® (the polyphenolic flavonoid silybin isolated from milk thistle) in breast cancer tissue. Ten histologically confirmed primary breast cancer patients will receive Greenselect® Phytosome® 300 mg / day and ten patients will receive Siliphos® 2.8 g / day for four weeks before surgery. The primary endpoint is to assess the concentration of the active ingredients and their metabolites by high performance liquid chromatography (HPLC) in plasma, tumor and surrounding non-neoplastic tissues.

The study may provide important information for the development of future phase II clinical trials, specifically designed to explore the possible role of these two natural products in breast carcinogenesis. Moreover, the study will help to understand the biology and mechanisms of action of these potential chemopreventive agents.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A58.
Abstract A59: Selenoprotein gene variants and risk of esophageal and gastric cancer in a Chinese population
Authors: Lin Shih-Wen , Freedman Neal D. , Taylor Philip R. , Qiao You-Lin , Abnet Christian C. , Hyland Paula , Hu Nan , Fan Jin-Hu , Yu Kai , Dawsey Sanford M. , Wheeler Bill , Ding Ti , Tang Ze-Zheng
Published: June 2012

Objectives: Observational studies and intervention trials suggest that selenium has potential cancer prevention properties. We previously found that selenium supplementation reduces cancer mortality, particularly gastric cancer mortality, in a high-risk region in China, and that low serum selenium concentration is associated with increased risks of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). In humans, selenium may exert chemopreventive actions through the 25 known selenoproteins, which contain residues of selenocysteine, the 21st amino acid. Therefore, genetic variants in selenoprotein genes may influence susceptibility to ESCC and GCA, yet no previous studies have comprehensively investigated these potential associations. Thus, we examined the association between genetic variants in selenoprotein and selenium metabolism genes and risks of ESCC and GCA.

Methods: We included 1027 ESCC and 753 GCA cases plus 1452 controls from two epidemiologic studies in the high-risk region in China. We genotyped 272 tag single nucleotide polymorphisms (SNPs) in all 25 known selenoprotein genes and 4 selenium metabolism genes. For each gene, we calculated a standardized summary p-value using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).

Results: In gene-based tests, the selenoprotein gene SELS (selenoprotein S) was associated with ESCC risk (p=0.00070); TXNRD2 (thioredoxin reductase 2) showed borderline non-significant associations with both ESCC (p=0.063) and GCA (p=0.051). In SNP-based tests for these two genes, rs8029790 (tagged to SELS in the upstream noncoding region) was associated with a 1.30-fold increased risk of ESCC (CI=1.14, 1.47; p=0.000052), whereas rs2073750 (tagged to intron in TXNRD2) was associated with risks of both ESCC (OR=0.84, CI=0.74, 0.94; p=0.0029) and GCA (OR=0.82, CI=0.72, 0.93; p=0.0026).

Conclusions: The potential anticarcinogenic properties of selenium may be due to its presence as the amino acid selenocysteine in human selenoproteins. The association of SNPs in selenoprotein genes SELS and TXNRD2 with ESCC and GCA risk suggests that selenium and these selenoproteins may play an important role in cancer development. Our findings warrant further research on elucidating the functional effects of these SNPs on selenoproteins in the context of upper gastrointestinal (UGI) carcinogenesis so that we can better understand the role of selenium supplementation in cancer prevention.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A59.
Abstract A60: Vitamin D related genetic variation, plasma vitamin D, and risk of lethal prostate cancer
Authors: Shui Irene M. , Stampfer Meir J. , Giovannucci Edward , Mucci Lorelei A. , Kraft Peter , Lindstrom Sara , Penney Kathryn , Nimptsch Katharina , Hollis Bruce W. , Tamimi Rulla M. , Platz Elizabeth
Published: June 2012

Background: The association of vitamin D status with prostate cancer is controversial, with no association observed for overall incidence, but a potential link with lethal disease.

Methods: We assessed prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and variation in vitamin D related genes and the risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1328 incident cases diagnosed following blood draw (1993–95) and 1331 controls. Men with prostate cancer were followed through March 2011 for lethal outcomes (n=111). We selected 97 linkage disequilibrium tagSNPs to represent common genetic variation across seven vitamin D related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, VDR). We used a logistic kernel machine test to assess the multimarker pathway global association for ‘SNP-sets’ defined by the seven genes with prostate cancer.

Results: Higher levels of 25(OH)D were associated with about half the risk of lethal prostate cancer (OR comparing extreme quartiles: 0.45; 95% CI:0.25–0.81). This finding did not vary by time from blood draw to diagnosis. We found no significant association of 25(OH)D with overall prostate cancer risk(OR comparing extreme quartiles: 1.05; 95% CI: 0.85–1.30). The total vitamin D pathway SNP-set (seven genes) as well as SNP-sets defined by the individual genes (VDR, RXRA, or CYP27A1) were nominally associated with lethal prostate cancer risk (p<0.05), but not overall prostate cancer (p=0.41). Conclusions: In this large prospective study, plasma 25(OH)D and common variation across vitamin D pathway genes were associated with lethal prostate cancer risk. Studies of vitamin D and prostate cancer should focus on lethal disease.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A60.
Abstract A65: Does the lifetime number of ovulatory cycles predict the risk of breast cancer in BRCA1 and BRCA2 mutation carriers?
Authors: Kotsopoulos Joanne , Sun Ping , Narod Steven
Published: June 2012

Background: In the general population, various reproductive factors are believed to influence breast cancer risk via their effects on the number of ovulatory cycles and subsequently on cumulative endogenous hormonal exposure. It is not clear to what extent this is true for women with a BRCA1 or BRCA2 mutation. We undertook a case-control study to evaluate the effect of the cumulative number of ovulatory cycles and each of the contributing components) on the risk of developing breast cancer among BRCA mutation carriers.

Methods: A matched case-control study was conducted in 2,632 pairs of women with a deleterious mutation in either BRCA1 (n = 1,915 pairs) or BRCA2 (n = 717 pairs). Women diagnosed with breast cancer were matched to unaffected control subjects by year of birth, mutation status, and country of residence. Information about reproductive factors, hormonal exposures and menopausal status was collected from a routinely administered questionnaire and was used to estimate the cumulative number of ovulatory cycles. Conditional logistic regression was used to estimate the association between various exposures and the risk of breast cancer.

Results: The risk of breast cancer decreased with the number of ovulatory cycles (ρ = −0.69;P = 0.03). Age at menarche and breastfeeding were inversely related with risk of breast cancer among BRCA1 (P-trend < 0.0001) but not BRCA2 (P-trend ≥ 0.36) mutation carriers. Parity, oral contraceptive use, and the number of ovulatory cycles, were not associated with risk (P-trend ≥ 0.21). The reduction in breast cancer risk associated with surgical menopause (OR = 0.49; 95%CI 0.37–0.64; P-trend < 0.001) was stronger than that conferred by natural menopause (OR = 0.78; 95%CI 0.58–1.06; P-trend = 0.11). There was a significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR = 0.13; 95%CI 0.02–0.54; P = 0.006).

Conclusions: These data challenge the prevailing hypothesis that the risk of breast cancer in a woman can be predicted by her lifetime number of ovulatory cycles in women with a BRCA1 or BRCA2 mutation. Reproductive risk factors, such as age at menarche and breastfeeding are important in BRCA1, but not BRCA2 carriers. The observation that a postmenopausal oophorectomy protects against breast cancer is consistent with either a direct carcinogenic activity of ovarian androgens or through aromatization of androgen to estrogen. It is important to distinguish between these two possibilities because of the different implications for chemoprevention.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A65.
Abstract A93: Daily aspirin use and cancer mortality in a large United States cohort
Authors: Jacobs Eric J. , Newton Christina C. , Thun Michael J. , Gapstur Susan M.
Published: June 2012

Background: A recent pooled analysis of several randomized trials of daily aspirin for prevention of vascular events reported a 34% reduction (95% confidence interval (CI): 0.50–0.87) in overall cancer mortality during follow-up after five years on aspirin. However, some uncertainty remains about the magnitude of the effect of daily aspirin use, particularly long-term use, on cancer mortality.

Methods: We examined the association between daily aspirin use and overall cancer mortality among 100,140 men and women in the Cancer Prevention Study II Nutrition Cohort with no history of cancer. Hazard ratios (HRs) were calculated adjusting for smoking and other risk factors. Results: During follow-up between 1997 and 2008, 5,138 participants died from cancer. Compared to no use, daily aspirin use at baseline in 1997 was associated with slightly lower cancer mortality (HR = 0.93, 95% CI: 0.86–1.00), although this association was not formally statistically significant and did not vary by duration of daily use (HR = 0.93, 95% CI: 0.85–1.01 for < 5 years use, HR = 0.94, 95% CI: 0.85–1.03 for ≥ 5 years use). In time-dependent analyses including 3,373 cancer deaths and using updated information from periodic follow-up questionnaires, daily aspirin use was associated with lower cancer mortality, but results did not differ by duration (HR = 0.84, 95% CI: 0.76–0.94 for < 5 years, HR = 0.85, 95% CI: 0.76–0.96 for ≥ 5 years). Associations between daily aspirin use and cancer mortality appeared similar for low-dose and adult-strength aspirin.

Conclusions: These results are consistent with an association between recent daily aspirin use and modestly lower cancer mortality, but suggest any reduction in cancer mortality may be smaller than that observed with long-term aspirin use in the pooled trial analysis.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A93.
Abstract B103: Effect of over-the-counter vitamin D supplementation on circulating 25-hydroxyvitamin D concentration
Authors: Hibler Elizabeth , Hu Chengcheng , Jurutka Peter , Martinez M. Elena , Wagoner Chad , Jacobs Elizabeth
Published: June 2012

Background: Vitamin D is a proposed chemopreventive and treatment agent for a variety of cancers. Studies have identified cellular anti-cancer mechanisms as well as associations between low circulating 25(OH)D levels and increased risk of cancer. Recommendations exist for vitamin D supplementation, though published cholecalciferol supplement trials have tested only pharmacological preparations or multivitamins. It is unknown whether intake of over-the-counter (OTC) cholecalciferol supplements, at the estimated average requirement (EAR) recommended by the Institute of Medicine (IOM), changes circulating vitamin D metabolite concentrations and associated biomarkers in healthy adults.

Objective: To determine the effect of 400 IU of OTC cholecalciferol supplements on circulating 25(OH)D concentrations in healthy adults.

Methods: This study was a blinded, randomized, placebo-controlled trial conducted from September 2009 through March 2010 in Tucson, Arizona. A total of 60 healthy male and female residents, aged 35 to 50 years, were recruited. Participants were randomized to receive either 400 IU/d cholecalciferol or a placebo for 30 days. Serum samples were collected every 15 days (± 3 days) and analyzed to determine if the change in circulating 25(OH)D concentration was significantly different between the groups.

Results: After 30 days of supplementation, the net change in circulating concentration of 25(OH)D in the supplement versus placebo group was 2.2 ng/ml (8.5% change, p-value = 0.06). Individuals with low baseline 25(OH)D (<20 ng/ml) had a net change of 4.0 ng/ml (24.4% change, p-value = <0.01), while participants with higher baseline concentration (>30 ng/ml) did not increase significantly (net change 0.3 ng/ml, 0.8%, p-value = 0.84).

Conclusions: Use of OTC cholecalciferol supplements is a common practice, yet there is limited evidence to demonstrate the effectiveness of OTC vitamin D supplements to change circulating 25(OH)D levels. These initial results demonstrate that 400 IU OTC cholecalciferol is sufficient for maintaining the 25(OH)D concentrations of Arizonans throughout the winter, and provide support for the IOM recommended EAR of 400 IU/day in this population. Further research on the optimal dose for chemoprevention is ongoing.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B103.
Abstract B19: Mouth cancer awareness in Grampian region of Scotland, UK
Authors: Macfarlane Tatiana V. , Cunningham Claudia , Bovaird Iain , Morgan Rochelle , Watkins Ray
Published: June 2012

Aim: The purpose of this project was to determine the level of mouth cancer awareness and to investigate the associated factors in a UK general population sample.

Material and Methods: A Dental Health Survey was conducted on 3,353 adult residents in the Grampian region of the UK (adjusted participation rate 58%). Participants completed a questionnaire consisting of questions on oral health, behaviour, quality of life and cancer awareness.

Results: Overall, 81% of participants reported that they were aware of mouth cancer. Mouth cancer awareness was related to younger age (P<0.001), higher levels of education (P<0.001) and better general health (P<0.001). There was no significant association found with gender, deprivation, rurality, oral health or mouthwash use. However, current smokers and participants who consumed alcohol every day were more aware of mouth cancer (P=0.004 and P<0.001 respectively). When asked about risk factors for mouth cancer the following were identified: smoking (84%), poor oral hygiene (60%), drinking alcohol heavily (59%), poor diet (37%), stress (15%), being overweight (6%), drinking hot liquids (5%), eating spicy food (3%), using mouthwash (2%) and kissing someone (1%). Smokers were more likely to indentify smoking as a risk factor for mouth cancer (P=0.016). Similarly, those who consumed alcohol daily were more likely to identify heavy alcohol drinking as a risk factor (P<0.001).

Conclusions: Awareness of mouth cancer is high in respondents from the general population and participants were able to identify the most important risk factors. Knowledge of tobacco and alcohol as risk factors was highest amongst those exposed to them. This study demonstrated that the focus of prevention needs to be on efforts to change health behaviour rather than increasing knowledge.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B19.
Abstract B26: Vaginal health assessment study for breast cancer survivors
Authors: Sutherland Elena I. , Feng Lei , Newman Lonzetta L. , Cook Elise Donaville
Published: June 2012

Postmenopausal breast cancer survivors often have urogenital atrophy adversely affecting their quality of life. Symptoms of atrophic vaginitis include: vaginal irritation, dyspareunia, postcoital bleeding, and increased susceptibility to vaginal infections. Endocrine breast cancer therapies further decrease estrogen levels, exacerbating these symptoms. Current non-hormonal vaginal therapies used first-line are often given with vague instructions, or not given at all. Hormonal therapies including estrogen and progesterone may increase the risk of recurrence and are therefore rarely used. This scenario results in breast cancer patients not having resolution of their atrophic vaginitis symptoms. There is a lack of data for atrophic vaginitis symptoms reported by patients and treatments employed in this population of breast cancer survivors. Therefore, we conducted a pilot study of urogenital symptoms in breast cancer survivors.

This is prevalence, cross-sectional study of female patients from the Breast Survivorship Clinic in the Cancer Prevention Center at the UT M.D. Anderson Cancer Center. Patients included in this study are women with a history of invasive breast cancer and are greater than five years after treatment; women with ductal carcinoma in situ (DCIS) are at least six months after treatment.

Approximately 1000 individual patient's charts (over 4,800 clinic visits) were available for review during the time frame studied (July 1, 2010 to June 30, 2011). Two predefined age groups will be evaluated (<60, 60–75), focusing on the patients younger than 60 years of age.

Taking the information from the chart review, we will present the number of breast cancer female patients reporting symptoms of atrophic vaginitis. We will also report the percent of patients with symptoms who actually get treatment and the types of treatment recommended and prescribed.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B26.
Abstract B49: Prevention of colitis-associated colorectal cancer with 8-hydroxydeoxyguanosine
Authors: Han Young-Min , Ock Chan Young , Kim Eun-Hee , Hong Hua , Hong Kyung-Sook , Choi Ki-Seok , Hahm Ki Baik , Chung Myung-Hee
Published: June 2012

Colitis-associated cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or anti-oxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3 which are significantly up-regulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-OHdG) paradoxically can block Rac1 activation and subsequent NOX inactivation in various inflammation models, we hypothesized that attenuated Rac1-STAT3 and COX-NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS) induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which IL-10 knock-out mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2 and iNOS in a dose-dependent manner. In order to document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG-contained diets were given for 20 weeks. As results, mice which consumed 8-OHdG-contained-diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in 8-OHdG treated group. Significantly decreased levels of MDA, MCP-1, MMPs, COX-2, NOX4, and β-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer preventive effect of exogenous 8-OHdG against CAC.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B49.
Abstract B53: Chromatin remodeling as a new target for cancer chemoprevention
Authors: Peng Guang , Pan Mei-Ren , Lin Shiaw-Yih
Published: June 2012

Chromatin remodeling complexes use the energy of ATM hydrolysis to dynamically regulate the structure of chromatin. Growing evidence indicates that these complexes have a widespread role in tumor suppression. However, the mechanisms by which aberrations in these complexes drive tumorigenesis remain largely unknown. In addition to their well-established role in gene transcriptional control, our recent studies provide a novel linkage between chromatin remodeling and homologous recombination (HR)-mediated DNA repair in the maintenance of genomic stability.

Our results showed that an evolutionarily conserved chromatin remodeling complex SWI/SNF is targeted to DNA damage lesions via an interaction with BRIT1, an early DNA damage responsive protein. Chromatin remodeling activity is required for relaxing highly condensed chromatin and facilitating the loading of HR repair proteins to conduct efficient HR repair. Furthermore, our unpublished data identified that another remodeling complex CHD4 functions as an upstream regulator of HR repair by recruiting BRIT1 and BRCA1 to DNA lesions. As a functional consequence of impaired HR repair, our data indicated that cells with depletions of chromatin remodeling complexes SWI/SNF and CHD4 show hypersensitivity to a new class of drugs poly ADP ribose polymerase (PARP) inhibitors via a synthetic lethal interaction.

In conclusion, our studies reveal the interplay between epigenetic regulation and genome maintenance. Chromatin remodeling affects HR repair process, which may lead to the changes in the DNA coding sequencing that are inheritable through cell division. Moreover, Deficient HR repair has been well known to predispose to cancer development, which is highlighted by mutations of HR repair genes BRCA1/BRCA2 in breast and ovarian cancers. Our findings may have important clinical implications in cancer prevention. Chromatin remodeling complexes, such as SWI/SNF and CHD4 might be used as epigenetic markers for prognosis, and prediction in early stage of tumorigenesis, and also for targeted preventive intervention by using PARP inhibitors.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B53.