bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4704: Racial/ethnic differences in double-strand-break repair signaling in breast cancer
Authors: Rodriguez-Gil Jorge L. , Hill Jeff W. , Allen Glenn O. , Thomas Venetta , Hu Jennifer J.
Published: February 2011

To evaluate whether deficient DNA repair contributes to elevated DNA damage and breast carcinogenesis, we used a newly developed flow-cytometry assay for rapid assessment of H2AX phosphorylation (gamma-H2AX) in response to double strand breaks (DSBs) in peripheral lymphocytes from 64 breast cancer cases and 71 controls. Basal or ionizing radiation (IR)-induced gamma-H2AX was not influenced by age, smoking status, family history (FH), age at menarche, age at first birth or parity and body mass index (BMI). With limited sample size, basal or IR-induced gamma-H2AX level did not differ between breast cancer cases (mean+SD, 6.65+1.18; 29.23+6.88) and controls (6.48+0.95; 27.19+7.26). In subgroup analysis of women with younger age at first live birth (<24), breast cancer cases have a significantly higher IR-induced gamma-H2AX level (29.87+6.45) than that in controls (26.60+7.19). In cases, African Americans (AA) had a significantly higher IR-induced gamma-H2AX level (32.17+6.76) than that in Caucasians (28.08+6.65), particularly in the younger age group (<50), never smokers, negative FH, and higher BMI (>25 kg/m2). In younger cases, a higher gamma-H2AX was observed in AA (p=0.042) compared to Caucasians (32.71+5.43 vs. 27.32+5.33). In never smokers, AA cases had a significantly higher level of IR-induced gamma-H2AX than Caucasians (32.70+5.77 vs. 27.58+6.41, p=0.03). In cases without FH, AA had a significantly higher level of IR-induced gamma-H2AX than Caucasians (32.38+6.90 vs. 28.02+7.09, p=0.044). In cases with a higher BMI, AA had a significantly higher level of IR-induced gamma-H2AX than Caucasians (33.36+5.94 vs. 26.93+6.00, p=0.001). Our results, although based on a relatively small group of subjects, indicate that DSBs response is significantly higher in AA breast cancer cases. Future larger studies are warranted to test whether this racial/ethnic difference in IR-induced gamma-H2AX levels contribute to breast cancer risk, tumor phenotypes, treatment response, and/or clinical outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4704.
Abstract 4709: NXF2 is a Candidate Biomarker of Mechanical Stress in Breast Cancer
Authors: Wang Jiaxu , Barnes Rebecca , West Nathan , Watson Peter
Published: February 2011

Mechanical stress has been implicated as an important factor influencing tumour cell biology. Due to the nature of early stages of breast cancer and its ductal environment and associated stromal changes, origins in ductal changes in gland tension are likely to occur and the associated mechanical forces may contribute to the progression of breast cancer. To identify specific changes in gene expression that might serve as biomarkers of mechanical stress in breast cancer, we applied static tensile forces (0.65 pN/μm2) to breast cancer cell lines via collagen-coated magnetite beads, profiled gene expression changes by Microarray chips, validation by RT-PCR and immunoblotting. Our results showed that mechanical stretch forces altered cell signaling in both MDA-MB-231 and MDA-MB-468 breast cancer cell lines by array chip analysis and 7.24.% genes (4.67% up and 2.57% down regulation) were regulated by mechanical stress in 16822 profiling genes in MDA-MB-231 cell line and 5.79% genes (2.22% up and 3.57% down regulated) was regulated in MDA-MB-468 cell lines. The 0.48% (82/16822) up regulation and the 0.125% (21/16822) down regulation was in complete concordance with Microarray in both cell lines. The validation of the gene expression with significant changes of >1.5-fold in MDA-MB-231 cell line, RT-PCR revealed the up-regulation of LCE2D and NXF2 and down-regulation of PIGH and RAPD1B and confirmed the force-induced genes identified by Microarray. Mechanical stress also increased 2.75 fold NXF2 protein expression level with confirmation of immunoblotting. There were no significant expression changes found relating to hypoxia stress control gene NDRG1, which changed the highest gene in hypoxia control chip. We conclude that mechanical stress promotes early breast cancer progression mediated by multiple signal transduction pathways and that NXF2 is a potential mechanical stress marker in breast cancer progression.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4709.
Abstract 471: RNAi target evaluation in clinically relevant murine model of colon cancer metastasis
Authors: Rychahou Piotr G. , Evers B. M.
Published: February 2011

Significant challenges remain before RNA interference (RNAi) becomes a reality in practice. Identifying the appropriate genes to target and evaluating these agents in clinically relevant animal models of metastatic cancer are critical. Short- and long-term side effects and potential in vivo toxicities of RNAi therapy are largely unknown due to lack of animal models to simultaneously evaluate RNAi effect on both cancer cells, tumor microenvironment and the host organism. The purpose of our present study was to establish a murine model for metastatic colon cancer which will allow us to evaluate the effect of RNAi on tumor metastases as well as potential side effects to the normal host. METHODS. Murine colon cancer cell lines, CT26 and MC26, expressing green fluorescent protein (GFP) were injected intrasplenically into either Balb/C or Swiss-Webster mice at concentrations of 1×106, 2.5×106 and 5×106 in a volume of 100 uL. Tumor growth and metastasis were monitored for 30 days. To demonstrate siRNA delivery into colon cancer metastasis to the liver, Cy3-labeled siRNA was used. siRNA formulated in DOTAP was administered via tail vein, and mice were sacrificed at 1, 4 and 24 h postinjection. Frozen-section fluorescence microscopy was used to evaluate siRNA delivery and distribution in metastatic liver tumors. RESULTS. We observed extensive metastases in Balb/C mice injected intrasplenically with CT26 cells. The optimal concentration for metastasis was 2.5×106 cells. No intrasplenic tumor growth or metastasis was observed in Swiss-Webster mice after intrasplenic CT26 tumor cell injection or in Balb/C and Swiss-Webster mice after MC26 injection. We also demonstrated Cy3-labeled siRNA delivery into metastatic liver tumors as early as 1 h postinjection. CONCLUSIONS. Intrasplenic injection of CT26 cells offers a clinically relevant murine model for metastatic colorectal cancer and will facilitate evaluation of RNAi therapeutic targets against metastatic cancer. This model will also be useful in the assessment of the effects of RNAi on the tumor microenvironment and possible toxicity to normal host cells. Furthermore, this model may predict the clinical course and the ultimate in vivo response to RNAi therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 471.
Abstract 4713: Serum thyroglobulin, a biomarker for iodine deficiency, and risk of upper gastrointestinal cancers
Authors: Lin Shih-Wen , Fan Jin-Hu , Dawsey Sanford M. , Sun Xiu-Di , Taylor Philip R. , Qiao You-Lin , Abnet Christian C.
Published: February 2011

Objectives: Gastric cancer is the second leading cause of cancer death worldwide and has been hypothesized to be associated with iodine deficiency. While iodine concentrations are highest in the thyroid, iodine also concentrates in gastric tissue where it may act as an antioxidant for the stomach and possibly the esophagus. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC). Iodine deficiency is correlated with increased serum thyroglobulin, and this study aimed to determine whether serum thyroglobulin is associated with GNCA, GCA, and ESCC in a Chinese population with very high rates of upper gastrointestinal (UGI) cancers.

Methods: We examined the association between serum thyroglobulin levels and the three UGI cancers in a study nested in the Linxian General Population Nutrition Intervention Trial. At baseline, blood was drawn from participants, ages 40-69 years, and outcomes were identified during 15 years of follow-up. Approximately 200 subjects of each case type and 400 non-case controls were selected for serum thyroglobulin concentration measurements. All samples were first screened for thyroglobulin antibody, and thyroglobulin concentrations were then measured by radioimmunoassay (RIA) for thyroglobulin-antibody-positive samples or by immunometric assay (IMA) for thyroglobulin-antibody-negative samples. Thyroglobulin concentrations were analyzed as quartiles using logistic regression models adjusted for numerous potentially confounding factors.

Results: 25% of females and 5% of males in the controls were thyroglobulin-antibody-positive. Compared to participants in the lowest quartile, those in the highest quartile of serum thyroglobulin had adjusted odds ratios of 0.82 (95% confidence interval 0.50-1.36) for GNCA, 1.12 (0.66-1.90) for GCA, and 0.73 (0.44-1.21) for ESCC.

Conclusions: Using serum thyroglobulin, a sensitive biomarker of iodine deficiency, we found no association between serum thyroglobulin concentrations and risk of UGI cancer in the overall study population. Our results do not support the hypothesis that iodine deficiency is associated with an increased risk of UGI cancers in this population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4713.
Abstract 4714: Oral human papillomavirus infection among HIV infected and uninfected men who have sex with men
Authors: Beachler Daniel C. , Jacobson Lisa P. , Margolick Joseph B. , Gillsion Maura L. , D'Souza Gypsyamber
Published: February 2011

Introduction: Human papillomavirus (HPV) causes a subset of oropharyngeal cancers but the prevalence and risk factors for oral HPV infection are not well understood. Initial studies suggest HIV-infected individuals have an increased incidence of HPV-related cancers including oropharyngeal cancer.

Methods: Oral exfoliated cells were collected using a swish and gargle with 10ml of Scope mouthwash in 149 HIV-infected and HIV-uninfected men who have sex with men (MSM) in the Baltimore center of the MACS. Samples were tested for 37 types of HPV DNA using PGMY09/11 consensus primers and line blot hybridization. Logistic regression was used to explore risk factors for infection.

Results: Prevalent oral HPV infection was common among the 62 HIV-infected and the 87 HIV-uninfected MSM (39% vs 28%, p=0.15). HPV16 was the most common HPV type detected and was found in an alarming 13% of MSM (8.2% of HIV-infected and 16% of HIV-uninfected MSM, p=0.15). The most common other oncogenic oral HPV infections detected were HPV 66, 68, 83 (2.0% prevalence each), and 45, 53, 58, 59, 73 (1.3% each). In this study 32% of men reported multiple oral sex partners in the past six months. Oral HPV16 prevalence was significantly associated with number of recent oral sexual partners among HIV uninfected (p-trend=0.04) but not HIV infected participants. The majority of HIV-infected participants were currently on HAART (74%), had CD4 cell count>500 (65%) and HIV viral load <500 copies/ml (78%). Oral HPV prevalence was similar among current HAART users (41%) compared to former or never HAART users (27% and 40% respectively) and prevalence increased non-significantly with low CD4 and high HIV viral load. In multivariate analysis of HIV infected but not HIV-uninfected MSM, current marijuana users were over ten times more likely (OR=11.5 95%CI=1.5-17) to have prevalent high risk HPV infection.

Conclusions: Oral HPV16 prevalence is high among both HIV uninfected and HIV infected MSM suggesting they may be at increased risk for HPV-associated oropharyngeal cancers. Oral HPV risk factor profiles differed by HIV status. Oral HPV prevalence was similar among HIV infected HAART users and non-users suggesting HAART may not improve oral HPV clearance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4714.
Abstract 4717: A search for overlapping HLA risk loci between NHL and autoimmune diseases
Authors: Conde Lucia , Bracci Paige M. , Smith Martin T. , Akers Nicholas K. , Riby Jacques , Agana Luz , Holly Elizabeth A. , Halperin Eran , Skibola Christine F.
Published: February 2011

Non-Hodgkin lymphoma (NHL) is a group of B- and T-cell neoplasms originating primarily from the lymph nodes, and represents the most common hematological malignancy in the United States. We recently conducted a genome-wide association study (GWAS) using DNA pools and identified a new risk locus for follicular lymphoma (FL) in the Class 1 human leukocyte antigen (HLA) region on chromosome 6. Currently, we are following up these results in a second GWAS using a subset of 757 NHL cases and 811 controls from a larger case-control study of NHL based in the San Francisco Bay Area using the Illumina HumanCNV370-Duo BeadChip. In the preliminary scan, we found additional evidence of Class 1 HLA loci that influence FL susceptibility, as well as loci in the Class 2 region, suggesting the importance of HLA genetic variation in FL risk. There is also clear evidence that HLA Class 1 and Class 2 loci confer genetic susceptibility to autoimmune diseases such as Crohn's disease (CD), type 1 diabetes (T1D), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Thus, because a history of autoimmune disease may increase risk of NHL, we explored whether HLA-region risk loci are common between these autoimmune diseases and NHL.

Using genetic data available from the Wellcome Trust Case-Control Consortium (WTCCC) for CD and the software package BEAGLE 3.0.3, we imputed SNPs to look for association signals in the HLA region. SNPs were imputed based on CD genotyped SNPs and haplotype information from unrelated CEU samples in the HapMap phase II data. A Cochran-Armitage test for an additive genetic effect implemented in PLINK v1.05 was subsequently performed to test the genotype-phenotype associations of genotyped and imputed SNPs. Our preliminary results suggest associations in the HLA Class 2 region near the HLA-DQA2 and HLA-DQB2 genes, providing evidence that overlapping risk loci may exist between FL and CD. We are currently expanding our analysis to include genetic data for other autoimmune diseases available from WTCCC such as T1D and RA. These analyses will contribute new data about genetic variation in plausible HLA region pathways and will help to identify potentially functional genetic factors that contribute to lymphoma susceptibility.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4717.
Abstract 4725: Interrogating region 4 of 8q24.13 for prostate cancer risk in African Americans
Authors: Hernandez Wenndy , Benn-Torres Jada , Hooker Stanley E. , Robbins Christiane , Carpten John , Kittles Rick A.
Published: February 2011

In the USA, African American (AA) men are at higher risk of developing and dying from prostate cancer (Pca). Strong and replicable associations between prostate cancer risk and regions 1, 2, and 3 of 8q24 among cohorts of European ancestry have been found but few for those of African ancestry. Recently, we discovered in a study of AAs, a fourth region of Pca risk at 126 Mb of 8q24.13 surrounding SNP rs7008482. Region 4 is 2 Mb upstream of the other three regions on 8q24 and contains two interesting candidate genes for Pca risk. To further interrogate region 4, we performed fine-mapping within a 500-Kb region (126.1Mb-126.6Mb). SNPs were selected for fine-mapping of the region based on the following characteristics: tagging SNPs from Yoruba HAPMAP data and non-synonymous or potential regulatory SNPs. We genotyped 250 SNPs in 263 AA Pca cases and 562 AA healthy controls. A structured-association analysis taking into account African ancestry, (local 8q24 ancestry and genomic ancestry) revealed that several SNPs within two genes KIAA0196 and NSMCE2 were significantly associated with Pca risk. The majority of the associated SNPs were common and exhibited low to moderate risk which may contribute to high population attributable risk in African Americans. Among these, rs16900305, located in an intronic region of KIAA0196, exhibited the strongest association (P=0.0003). KIAA0196 has been shown to be over-expressed in clinical prostate carcinomas and in approximately 30% of hormone-refractory tumors. Our findings strongly support region 4 in 8q24.13 as a candidate locus influencing prostate cancer risk among African Americans. Given the two interesting genes in this region and strong associations in a high risk group for Pca, further attention to this region is warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4725.
Abstract 4726: Prostate cancer risk profiles based on 24 single nucleotide polymorphisms, age, and family history
Authors: Kraft Peter , Lindstrom Sara ,   Breast and Prostate Cancer Cohort Consortium
Published: February 2011

Genome-wide association studies (GWAS) have identified over two dozen loci associated with risk of prostate cancer in men of European ancestry. Although much work remains to be done to identify the causal alleles at these loci and understand their function, the current set of GWAS-identified marker alleles could be used to predict individualized risks of prostate cancer diagnosis, which might then be used to inform individuals’ screening and treatment choices. However, despite initial optimism about their clinical utility, genetic risk profiles for prostate cancer have had low discriminatory and predictive power.

We evaluated the performance of various risk models based on an expanded set of 24 SNPs known to alter prostate cancer risk in 9,109 prostate cancer cases and 9,045 matched controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). As we found no evidence of pairwise gene-gene interactions, we considered two models for the log odds of disease which assume additivity across loci: a simple sum of risk alleles carried and a step function by deciles of the weighted allele sum.

Using the allele sum model, the area under the ROC curve (AUC) was 0.598. Adding information about family history increased this estimate to 0.612. We observed no difference in AUC estimates when stratifying for age of onset (AUCs: ≤60 years: 0.603, 60-70 years: 0.604, 70-80 years: 0.593, >80 years: 0.552).

Per-allele increases in the odds of diagnosis with stage C or D cancer were similar to those for stages A and B (p=0.96), but the multiplicative increase in odds for high grade cancer (Gleason > 7) for each risk allele was attenuated by a factor of 0.97 relative to low grade cancer (p=0.03). We observed no interaction between family history of prostate cancer and number of risk alleles carried (P=0.83)

Compared to the 10th percentile, men in the highest 90th percentile are at a 3.6-fold risk (95% CI: 3.2-4.2) of developing prostate cancer assuming an allele sum model and at a 3.8-fold risk (95% CI: 3.3-4.3) assuming a weighted allele sum model.

These scores can be used to estimate absolute risks of prostate cancer. For example, the risk that a 40-year old European-ancestry man in the highest decile of genetic risk and a family history of prostate cancer will be diagnosed with prostate cancer by age 50 0.67%, or about 2.5 times the average. These risks could be used by individual men when weighing the benefits and risks of prostate cancer screening, although we caution that our predicted risks require external calibration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4726.
Abstract 4728: Genome-wide analysis of genetic alterations in seminoma using high resolution single Nucleotide polymorphism (SNP) arrays
Authors: LeBron Cynthia , Pal Prodipto , Brait Mariana , Dasgupta Santanu , Looijenga Leendert HJ , Netto George , Sidransky David , Hoque Mohammad
Published: February 2011

Testicular germ cell tumors (TGCT's) represent the most common malignancy among young males between the ages 15-40 years. Many genomic alterations have been observed in testicular cancer, however very few of these alterations have been associated with deregulation of gene function. The impact of CNVs on cancer susceptibility and tumor progression is only recently been explored in different cancer types. To our knowledge no comprehensive studies of testicular cancer using high-resolution SNP array have been performed, partially due to the rarity of this disease and low resolution of previous cytogenetic techniques. To identify new genomic alterations we performed a genome-wide analysis of copy-number changes and loss of heterozygosity (LOH) in 24 seminomas and validated our findings by a complementary approach. We have also confirmed the several previously reported genomic alterations in seminoma and discovered eight novel genomic alterations including amplifications and homozygous deletions. Moreover, a comparison of genomic alterations of early stage and late stage identified CNV that correlate with progression which included deletions in chromosome 4q, 5p, 9q, 13q and 20p and amplifications in chromosomes 9q and 13q. CNV aberrations for candidate genes within selected regions these regions were further validated using quantitative PCR (QPCR). 40-75% correlation was observed between CNV by SNP analysis and QPCR. In conclusion, SNP microarrays are a valuable tool to measure and identify genomic alterations in seminoma, and we identified several genomic alterations, which may help pinpoint cancer causing genes and strengthen our understanding the biology of seminoma.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4728.
Abstract 4732: Association between genetic variants in the 8q24 cancer risk regions and circulating levels of androgens and sex-hormone binding globulin
Authors: Chu Lisa W. , Meyer Tamra E. , Li Qizhai , Menashe Idan , Yu Kai , Rosenberg Philip S. , Huang Wen-Yi , Quraishi Sabah , Kaaks Rudolf , Weiss Jocelyn M. , Hayes Richard B. , Chanock Stephen J. , Hsing Ann W.
Published: February 2011

Multiple genome-wide association studies have identified several independent non-coding regions in chromosome 8q24 associated with risk for cancers of the prostate, breast, colon, and bladder. To explore their biological basis, we investigated the possible association between 164 single nucleotide polymorphism (SNPs) in the 8q24 risk regions, spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, and 3αdiol G) and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Age-adjusted linear regression using SNPs in an additive genetic model showed that three adjacent SNPs centromeric to prostate cancer risk region 2 (rs12334903, rs1456310, and rs980171) were associated with measured total testosterone (P<1.1×10−3) and calculated bioavailable testosterone (P<6.3×10−4). Suggestive associations were seen for a cluster of 9 SNPs in prostate cancer risk region 1 and androstenedione (P<0.05). These preliminary findings, although in need of confirmation in larger studies, suggest that genetic variations in the 8q24 cancer risk regions may correlate with androgen levels, which in turn may provide some clues for the strong link between 8q24 and prostate cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4732.
Abstract 4736: Pleiotropic effect of 5p and 8q chromosome regions: Analyses on the TURIN EPIC cohort
Authors: Ricceri Fulvio , Guarrera Simonetta , Sacerdote Carlotta , Polidoro Silvia , Allione Alessandra , Rosa Fabio , Veldhoven Karin Van , Vineis Paolo , Matullo Giuseppe
Published: February 2011

BACKGROUND

Common sequence variants in 8q24 and 5p15 chromosomal regions have recently been associated with several cancer types and other pathologies. Notably, for most of them a strong environmental risk component has been described.

The aim of this study is to investigate for the first time in a cohort study the association among SNPs in those regions and several diseases.

METHODS

We conducted the study on Turin EPIC (European Perspective Investigation in Cancer and Nutrition) cohort: 10,604 volunteers recruited from 1993 to 1998, aged 35 to 64 years old. Each subject compiled a detailed questionnaire on life style and diet, provided a blood sample and was followed-up for life status, cancer, cardiovascular and diabetes incidence.

We selected from literature two SNPs in 5p15 region (rs401681, rs2736098) and five SNPs in 8q24 region (rs672888, rs1447295, rs9642880, rs16901979, rs6983267) which proved to be associated with several diseases in previous studies.

We calculated Hazard Ratios for each cancer site and cause of mortality under different genetic models, and incident diabetes Odd Ratios.

RESULTS

We observed 830 incident cancers (737 excluding skin carcinomas) and 342 overall death in the cohort since 1993.

Considering all cancers together, we observed a statistically significant increase in risk when the variant allele in SNP rs6983267 was present (HR 1.19, p<0.01, per allele model); this increase is higher in men (HR 1.35, p<0.001, per allele model).

We also found statistically significant associations among SNPs in 8q24 region and cancers of head and neck, colon-rectum, liver, lung, prostate, bladder, brain, thyroid, lymphomas, all cancers together and diabetes. We also observed statistically significant results for 5p15 region and melanoma.

CONCLUSIONS

Our analyses confirm for the first time in a cohort study the hypothesis of a pleiotropic effect on several disease susceptibility of 8q24 and 5p15 regions. We are also investigating if those associations are mediated by individual risk factors (diet, body mass index, smoking and blood pressure).

Further functional analyses are needed to better elucidate the mechanisms underlying the risk increase conferred by genetic variation in 8q24 and 5p15 regions.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4736.
Abstract 474: Cx43 mutant mice show delayed formation of palpable mammary gland tumors but are more susceptible to lung lesions
Authors: Plante Isabelle , Barr Kevin , Stewart Micheal K.G. , Allan Alisson , Laird Dale W.
Published: February 2011

Gap junctional intercellular communication is essential for the regulation of cell proliferation, differentiation and tissues homeostasis. Gap junctions are composed of channels, formed by proteins called connexins (Cx). It has been proposed that connexins can act as tumor suppressors in a wide variety of tumor types. However, their role in breast cancer remains poorly understood. We previously showed that Gja1Jrt/+ (G60S) mice, harboring a G60S dominant-negative Cx43 mutation, have reduced levels of Cx43 in the mammary gland. This study aimed to determine if low levels of Cx43 render mice more susceptible to breast cancer and/or result in more aggressive tumors. G60S mice were crossbred with ErbB2 mice (or FVB control mice), that spontaneously develop mammary gland tumors. Similar to G60S mice, G60S-ErbB2 mice showed decreased Cx43 protein levels and fewer gap junction plaques, compared to control ErbB2 mice (WT-ErbB2). Mice were exposed to 5 weekly doses of 7,12-dimethylbenz(a)anthracene (DMBA) starting at 7 weeks old and sacrificed when tumors reached approximately 1 cm3 or when mice showed signs of illness. Tumor onset and progression were evaluated by palpation every week. Surprisingly, while tumors were detected in 50% of WT-ErbB2 and WT-FVB mice by 32 and 36 weeks of age, respectively, only 14% of G60S-ErbB2 and 44% of G60S-FVB mice had palpable tumors by week 42, suggesting that low levels of Cx43 delay the onset of tumors. Tumor growth rates were similar in all groups, but while tumors from WT-ErbB2 and WT-FVB mice reached the threshold of 1 cm3, most Cx43 mutant mice started to show labored breathings around 40 weeks, independent of the presence of palpable tumors. Lung examination revealed the presence of lesions in 80% of WT-FVB and 69% WT-ErbB2 mice, compared to 100% for G60S-ErbB2 and G60S-FVB mice. Moreover, Cx43 mutant mice had an average of 20 visible lung lesions compared to only 6 for WT groups. Preliminary results showed that at least some of the mutant mice present signs of mammary gland hyperplasia, suggesting that low levels of Cx43 could potentially result in more aggressive hyperplasic breast cells that metastasize to the lungs. Future experiments will determine whether lesions are of lung or breast origin. Together, our results suggest that low levels of Cx43 delayed the presence of palpable tumors in mammary gland, but increased the number of lung lesions. Supported by the CBCRA, CIHR and FRSQ.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 474.
Abstract 4742: NOTCH2 in breast cancer: Association of SNP rs11249433 with gene expression in ER-positive breast tumors without p53 gene mutations
Authors: Fu Yi-Ping , Edvardsen Hege , Kaushiva Alpana , Arhancet Juan , Howe Tiffany M. , Kohaar Indu , Shah Anushi , Porter-Gill Patricia , Fossa Sophie D. , Naume Bjørn , Ambs Stefan , Børresen-Dale Anne-Lise , Kristensen Vessela N. , Prokunina-Olsson Ludmila
Published: February 2011

Background: A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger with estrogen receptor (ER)-positive than with ER-negative cancer. We aimed to identify a biologically relevant molecular phenotype of this association.

Methods: NOTCH2 expression was measured with custom-designed TaqMan assays on 226 breast tumor samples and 319 blood samples of breast cancer patients. PANTHER analysis based on expression in NCI-60 cell lines (Affymetrix HG-U133 arrays) was used to examine enrichment of pathways, biological processes, or molecular functions for transcripts significantly correlated with NOTCH2 expression.

Results: We found evidence of a functional relationship between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. NOTCH2 expression differed in subgroups of 226 breast tumor samples, being lowest in tumors with mutations in the p53 gene and highest in p53 wild-type/ER-positive tumors (p=0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p=0.0062). This effect is tissue-specific since rs11249433 was not associated with NOTCH2 expression in blood samples of 319 breast cancer patients. Pathway enrichment analysis of NOTCH2 in the NCI-60 cell lines indicated role of NOTCH2 in integrin signaling, cell-cell interactions, and cell structure and motility.

Conclusion: This is the first study to explain genetic association between SNP rs11249433 and breast cancer risk by showing that NOTCH2 expression in breast tumors differs in subgroups of patients and between patients with the risk rs11249433 genotypes when compared to the non-risk genotype. The NOTCH pathway has key functions in stem cell differentiation of ER-positive luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER-positive luminal ductal tumors. The exact mechanisms of regulation of NOTCH2 expression by rs11249433 as well as the role of NOTCH2 in breast cancer development remain to be determined.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4742.
Abstract 4744: Sequence-specific p53-DNA binding to gene regulatory elements is altered by single-nucleotide polymorphisms
Authors: Bandele Omari , Wang Xuting , Noureddine Maher , Campbell Michelle , Pittman Gary , Bell Douglas
Published: February 2011

Single nucleotide polymorphisms (SNPs) may influence disease susceptibility by modifying cellular responses to environmental stresses. Regulatory SNPs occur in non-coding gene regions and can modify gene expression in an allele-specific manner by altering transcription factor binding. The tumor suppressor p53, a transcription factor, coordinates the expression of an intricate network of genes in response to DNA damage. Importantly, sequence-specific DNA binding is essential for p53 tumor suppressive activity. Unfortunately, lack of robust computational methods and laborious experimental assays have hampered the discovery and characterization of the effects of SNPs in p53 response elements (p53REs). Therefore, we developed a refined bioinformatics approach to identify SNPs in bona fide and putative p53-DNA binding sites. We also developed the microsphere assay for protein-DNA binding (MAPD) to assess the impact of genetic variation on p53-RE binding following cellular exposure to DNA-damaging agents.

Thirty-two SNPs (within 12 bona fide and 20 putative p53REs) identified by our bioinformatics approach were evaluated using the MAPD assay. We monitored p53-DNA binding in nuclear extracts from doxorubicin- or IR-treated human lymphoblastoid and U2OS osteosarcoma cells. Significant increases in p53 binding over the negative control were observed for the majority of the p53REs. p53 bound several candidate elements at levels comparable to the positive control (p21 p53RE). Alleles that were predicted to lower p53 binding indeed displayed reduced binding toward 23 of the 32 sequences. Of these alleles, 10 diminished p53 binding by ≥50%. Base substitutions at conserved C and G bases had the greatest impact on p53-DNA binding. In addition, five p53RE SNPs altered gene expression in a set of genotyped lymphoblastoid cell lines. Cellular binding of p53 to putative REs are currently being validated by ChIP-seq. These findings demonstrate that our bioinformatics approach combined with MAPD and gene expression analysis can identify SNPs that alter p53 activity in response to DNA damage and discover novel genes within the p53 transcriptional network. This strategy also can be employed to identify functional SNPs for future studies in human populations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4744.
Abstract 475: Resection of primary tumor improves survival in mouse metastatic breast cancer model
Authors: Rashid Omar M. , Nagahashi Masayuki , Ramachandran Subramaniam , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki
Published: February 2011

Introduction: Removal of the primary tumor is not currently standard treatment for metastatic breast cancer. It is thought that doing so would induce metastatic proliferation and death. However, multiple retrospective studies over the last decade suggest a possible survival benefit from primary tumor resection. The purpose of this study, therefore, is to evaluate the role of primary tumor resection in metastatic breast cancer using a mouse model. However, because there is no consensus on which model best mimics human breast cancer metastasis, the first objective is to compare the different mouse models. Then, using the best mouse model, the primary tumor in metastatic cancer is removed to evaluate the effect on metastatic progression and survival.

Methods: The models evaluated include tail vein (TV), subcutaneous (SQ), percutaneous mammary (PM) and open mammary (OM) implantation of 4T1-luc2 cells,a luciferase transfected murine estrogen receptor negative breast cancer cell line. Tumor burden was quantified in vivo by measuring the photons emitted after injection of luciferin. After mice were diagnosed with metastatic breast cancer, they were prospectively randomized to two groups; primary tumor resection versus observation. Student's t-test and Kaplan-Meier survival statistical analysis were used.

Results: TV produces a 50% tail tumor rate and SQ produces intradermal and intramuscular implamantation. When compared to other methods, OM provides the most reproducible method of implanting cells into the mammary fat pad. In addition, OM produces more cancer proliferation and invasion 4 days after implantation than the other methods. When compared to SQ, OM produces larger tumors (p<0.02) and greater mortality (40% versus 0% at 28 days). In addition, OM breast cancer cells in mice metastasize to the axillary lymph nodes prior to metastasizing to distant organs, similar to human breast cancer. Although OM takes slightly more time to perform than other methods, it is easy to learn even for the inexperienced. Resection of the primary tumor in metastatic breast cancer does not induce metastatic proliferation. In fact, primary tumor resection instead provides a significant survival benefit in mice, 100% mortality in the observation group at 46 days versus 80% mortality in the surgery group at 75 days (p<0.02).

Conclusions: OM is the mouse model which best mimics human breast cancer metastasis. Reducing tumor burden by primary tumor resection provides a significant survival benefit in mice with metastatic breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 475.
Abstract 4750: Clinical and Immune Data From an Ongoing Phase II Trial of an Adenovirus/PSA Vaccine for Prostate Cancer
Authors: Lubaroff David M. , Williams Richard D. , Vaena Daniel , Joudi Fadi , Smith Mark , Zehr Pamela , Flanders Erica , Eastman Julie , Griffith Karen , Madsen Tammy , Johnson Christine
Published: February 2011

Introduction and Objectives:

Our Phase I adenovirus/PSA vaccine trial has proved that this vaccine is safe. We are conducting a Phase II clinical trial with two separate protocols for patients with recurrent or hormone refractory prostate cancer assessing toxicity, immune responses, and changes in PSA levels.

Methods:

In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men receive the vaccine alone at days 0, 30, and 60; Arm B; men receive the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease receive the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations.

Results:

To date fifteen patients have been enrolled and have been followed a median of 10.5 months. The patients have a median age of 70 years, and median enrollment PSA levels of 1.67 ng/ml in Protocol #1 and 8.70 ng/ml in Protocol #2. In our preliminary results at this early stage of the trial, seventy seven percent of the patients in both protocols demonstrated anti-PSA T cell responses above preinjection levels. Sixty four percent of the patients demonstrated an increase in PSA doubling time (PSADT).

Conclusions:

In an attempt to follow up on the success of our Phase I clinical trial of the Ad/PSA vaccine we have initiated a Phase II trial to investigate the therapeutic efficacy of the vaccine in men with recurrent prostate cancer, either following definitive therapy prior to other treatments or hormone refractory. Early results from the first fifteen patients demonstrate the induction of anti-PSA T cells responses in a high percentage of the vaccinated patients and increase in PSADT in more than half of the patients. No serious vaccine-related toxicities have been identified in the patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4750.
Abstract 4751: Peptide vaccine induces apoptosis of antigen-specific CD8+ T cells
Authors: Daisuke Muraoka , Nishikawa Hiroyoshi , Kato Takuma , Wang Linan , Maeda Yuka , Harada Naozumi , Noguchi Takuro , Kawakami Yutaka , Shiku Hiroshi
Published: February 2011

CD8+ cytotoxic T lymphocytes (CTL) play a critical role in anti-tumor immunity. Although multiple trials of cancer vaccines, particularly using short peptides recognized by CD8+ T cells, have resulted in the development of measurable immune responses, only a minority of patients has experienced clinical benefit such as tumor regression. On the other hand, accumulating data show that peptide immunization induces either tolerance or activation of peptide-specific T cells depending on doses, routes and frequency of peptide administration. In some experiments, vaccination with peptides recognized by CD8+ T cells caused enhanced tumor outgrowth associated with peptide-induced tolerance. However, the detailed mechanism(s) involved in this unfavorable immune response by peptide vaccinations has not been determined. In the present study, we analyzed NY-ESO-1 peptide vaccinations using a new tumor model of BALB/c transplanted tumors expressing NY-ESO-1, which is a cancer/testis (CT) antigen discovered by SEREX (serological identification of antigens by recombinant expression cloning) using the serum of an esophageal cancer patient. Whereas peptide immunization with an H2-Dd-restricted CTL epitope derived from NY-ESO-1 (NY-ESO-1 p81-88) induced NY-ESO-181–88-specific CD8+ T cells in draining lymph nodes and spleens, tumor growth was significantly enhanced. Single cell analysis of specific CD8+ T cells revealed that peptide immunization induced apoptosis of > 80% of NY-ESO-181–88-specific CD8+ T cells at tumor sites and repetitive immunization further diminished the number of specific CD8+ T cells. This phenomenon was associated with elevated surface expression of Fas and PD-1. When peptide vaccination was combined with an adjuvant, a TLR9 ligand CpG, the elevated Fas and PD-1 expression and apoptosis induction were not observed, and resulted in strong tumor growth inhibition. These augmented anti-tumor responses were correlated with CpG-induced DC maturation, as CpG-matured DCs, but not immature DCs could reduced Fas and PD-1 expression on the surface of antigen-specific CD8+ T cells. Taken together, selection of appropriate adjuvants is essential for development of effective cancer vaccines, with protection of effector T cells from peptide vaccine-induced apoptosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4751.
Abstract 4753: Anti-tumor effect of dendritic cell-based immunotherapy in combination with chemotherapy in the patients with advanced colorectal cancer
Authors: Akiyama Shinichiro , Tsukada Jun , Tomoda Takeshi , Abe Hiroyuki , Okamoto Masato
Published: February 2011

Background and objective: Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from colorectal cancer-associated antigens in combination with chemotherapy has been evaluated in the patients with advanced, inoperable colorectal cancer.

Patients and Methods: Thirty-two patients with advanced, inoperable colorectal cancer refractory to standard treatment were entered the study. DCs which were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4, were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigens, such as WT1, MUC1. These DCs (1 × 107) were intradermally administered 5 times at 14-day intervals.

Results: Of the 32 patients, complete response (CR) was observed in 0 (0%), partial response (PR) in 7 (21.9%), stable disease (SD) in 12 (37.5%), progressive disease (PD) in 13 (40.6%). Response rate was 21.9%. Tumor control rate was 59.4%. Survival rate, quality of life, performance status were markedly increased. Severe side effects of more than grade 3 which were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed.

Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptides in combination with chemotherapy was safety and effective in the patients with the inoperable colorectal cancer refractory to standard treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4753.