bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 282: FGF receptor signaling accelerates Wnt-1 mammary tumorigenesis and enhances translation of Wnt/β-catenin target oncogenes
Authors: Pond Adam C. , Herschkowitz Jason I. , Hilsenbeck Susan , Creighton Chad , Lloyd Richard E. , Rosen Jeffrey M.
Published: February 2011

The fibroblast growth factor pathway is known to cooperate with the Wnt/B-catenin pathway in mouse mammary tumorigenesis, and both of these pathways have been implicated in the etiology of human breast cancer. Despite this evidence, little is known about the molecular mechanism contributing to FGF/Wnt pathway cooperation. To investigate the mechanisms involved in this cooperativity, we used genetically engineered mice expressing a drug-inducible model for FGF Receptor signaling (iFGFR) crossed with the well-characterized MMTV-Wnt-1 mouse model. In these bigenic mice, iFGFR1 activation resulted in a dramatic enhancement of mammary tumorigenesis. Tumor microarray analysis did not reveal transcriptional enhancement of Wnt/B-catenin targets, but instead identified a protein translational gene signature that also correlated with elevated FGFR1 and FGFR2 expression in several human breast cancer data sets. Additionally, iFGFR1 activation resulted in enhanced polysome recruitment and a marked increase in protein expression of several different Wnt/B-catenin target oncogenes. Rapid FGFR1-induced ERK activation and phosphorylation of key translation regulators was observed both in vivo in the transgenic mouse model, and in a human breast cancer cell line treated with exogenous FGF. These studies suggest that translational regulation is a key rate-limiting step required for oncogenic cooperativity between the Wnt and FGF pathways. These results not only demonstrate the oncogenic potential of FGFR1 signaling, but also highlight a possible mode of cooperation between FGF and Wnt signaling, involving synergism between two fundamental levels of gene regulation, transcription and translation. FGFRs, provide drugable targets for adjuvant therapy and several known FGFR inhibitors are currently in clinical trials. Additionally, key downstream regulators of translation initiation may also serve as potential therapeutic targets for breast cancers with enhanced FGF signaling.

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 282.
Abstract 2822: Dietary factors and risk of chronic lymphocytic leukemia and small lymphocytic leukemia: A population-based prospective study
Authors: Tsai Huei-Ting , Cross Amanda J. , Graubard Barry I. , Oken Martin , Caporaso Neil E.
Published: February 2011

Background: Chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL) is the most common leukemia in the western hemisphere. Age (advanced), race (Caucasian>Asian) and gender (male) are established risk factors and familial and migration studies strongly support a genetic component. No unequivocal extrinsic environmental risk factors have been reproducibly identified. Using prospective data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, we assessed the effect of diet on CLL/SLL risk.

Methods: Usual dietary intake was assessed in both the intervention and control arms of the trial using a food-frequency questionnaire. We compared distributions of energy-adjusted food intake by CLL/SLL status using Wilcoxon-Rank tests. We categorized dietary intake by quartiles and computed p-values to assess trend effects in ordinal covariates. We used Cox proportional hazards regression, with age as the underlying time metric, to estimate relative risks (RR) and 95% confidence intervals (CIs).

Results: Among 90,414 healthy participants in the PLCO trial, we identified 229 incident cases of CLL/SLL (median age of diagnosis was 71 years; 58% of cases were male) during up to 10 years of follow-up (median: 7 years). Comparing the highest to the lowest quartile of intake, we found no associations for red meat (OR=0.71, 95% CI= 0.47, 1.08), white meat (OR=1.28, 95%.C.I.= 0.87, 1.88),vegetables (OR=1.06, 95% CI= 0.70, 1.61), fruit (OR=0.99, 95% CI= 0.65, 1.51), fiber (OR=1.26, 95% CI= 0.84, 1.90) or fat (OR=0.98, 95% CI= 0.66, 1.46). When we assessed body mass index (BMI), we observed a suggestive increased risk of CLL/SLL, although the effects did not reach statistical significance (OR=1.19, 95% CI= 0.86, 1.64 for pre-obese (2530), compared to normal weight (18.5<BMI ≤25).

Conclusions: We found no associations between diet and CLL/SLL. The observed tendency for an increase in BMI to be associated with CLL/SLL risk requires further follow-up.

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 2822.
Abstract 2826: Carbohydrate intake, glycemic load, and glycemic index and prostate cancer risk
Authors: Williams Christina D. , Whitley Brian , Hoyo Cathrine , Grant Delores , Iraggi Jared , Newman Kathryn , Gerber Leah , Taylor Loretta , Freedland Stephen
Published: February 2011

Background: The typical U.S. diet is characterized by high carbohydrate intake, and dietary carbohydrates can modulate insulin sensitivity depending on their glycemic effect. Glycemic load and glycemic index, which represent the quality and quantity of carbohydrate foods, and prostate cancer risk are poorly characterized. Objective: To examine the association between dietary carbohydrate intake, glycemic load, and glycemic index and risk of prostate cancer, and determine if these associations differ between Whites and Blacks. Methods: We analyzed data from an ongoing case-control study of White (N=109) and Black (N=143) veterans at the Durham VA Medical Center. Cases were 65 men with biopsy-confirmed prostate cancer. There were two groups of controls: biopsy-negative controls (N=89) and healthy (i.e. no biopsy indication) controls (N=98). All men had a PSA test done in the year prior to enrolling in the study. Demographic and lifestyle risk factors were collected using self-administered questionnaires. Diet information was obtained using the Harvard food frequency questionnaire. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for prostate cancer risk were obtained using logistic regression analyses adjusted for age, race, and total energy. Results: Mean carbohydrate intake, glycemic load, and glycemic index were similar among cases and both groups of controls (all p-values >0.05). We did not observe any statistically significant risk estimates for high (≥median) carbohydrate intake, glycemic load, or glycemic index. Compared to healthy controls, the ORs for prostate cancer risk associated with high carbohydrate intake, glycemic load, and glycemic index were 0.66 (95% CI 0.34-1.30), 0.57 (95% CI 0.22-1.49), and 1.18 (95% CI 0.61-2.02) respectively. Corresponding ORs when compared to biopsy-negative controls were 0.88 (95% CI 0.46-1.70), 0.69 (95% CI 0.29-1.64), and 0.83 (95% CI 0.43-1.59), respectively. The associations between carbohydrate intake, glycemic load, or glycemic index and risk of low-grade (gleason score <7) as well as high-grade (gleason score ≥7) prostate cancer relative to healthy controls were null for all analyses. There was no evidence of effect modification by race in our analyses. Additional adjustment for fiber intake did not appreciably alter any of the ORs. Conclusion: Our findings in a small case-control study do not suggest that a high carbohydrate intake and/or high glycemic load increase the risk of prostate 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 2826.
Abstract 2830: Energy balance and breast cancer risk among sisters pairs in the Breast Cancer Family Registry Study
Authors: Zhang Fang Fang , John Esther M. , West Dee W. , Knight Julia , Andrulis Irene , Buys Saundra , Daly Mary , Stearman Beth , Kaur Manleen , Vishwanatha Jamboor , Morabia Alfredo , Terry Mary Beth
Published: February 2011

Animal models have shown strong evidence that energy restriction inhibits mammary tumor development. Nevertheless, epidemiologic studies in humans generally do not support an association between energy intake and breast cancer risk. Failure to take into consideration the integrated effect of energy intake, physical activity and body size may obscure the true effect of energy intake on breast cancer risk. We analyzed the combined effects of energy intake, body size and physical activity on the risk of breast cancer among 4,564 women diagnosed with breast cancer between 1995 and 2006 and 3,411 of their unaffected sisters enrolled in the Breast Cancer Family Registry. Dietary data were collected using the food frequency questionnaire developed for the Hawaii-Los Angeles Multiethnic Cohort. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We observed an overall 50% increased risk of breast cancer among women in the highest quartile of energy intake compared to those in the lowest quartile (OR=1.5, 95% CI: 1.1-2.2, ptrend < 0.01). The association with energy intake was limited to women with lower levels of strenuous physical activity (OR=1.9, 95% CI: 1.3-2.9 for < 1.75 hours/week during the past three years), and was stronger among women with higher body mass index (BMI) (OR=2.2, 95% CI: 0.6-7.7 for BMI ≥ 30; OR=1.5, 95% CI: 0.6-3.7 for BMI 25-29; OR=1.3, 95% CI: 0.7-2.5 for BMI < 25 kg/m2). Our results suggest that higher total energy intake in adulthood is associated with a 50% increase in breast cancer risk compared to sisters with lower energy intake in adulthood; these associations are stronger among less active and obese women.

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 2830.
Abstract 2831: Ornithine decarboxylase polymorphisms and risk of colorectal adenoma
Authors: Barry Elizabeth L. , Mott Leila A. , Sandler Robert S. , Ahnen Dennis J. , Baron John A.
Published: February 2011

Introduction: In a recent randomized trial the combination of difluoromethylornithine (DFMO) and the NSAID sulindac was remarkably effective in reducing the risk of colorectal adenoma recurrence. DFMO is a specific inhibitor of ornithine decarboxylase (ODC), which catalyzes the first step in polyamine synthesis. ODC and polyamines, which regulate cell growth and survival, have long been associated with colon carcinogenesis. In previous studies a SNP in the ODC promoter region was associated with risk of adenoma and response to aspirin treatment. The objective of this research was to perform a more comprehensive investigation of the association of adenoma risk with common genetic variation across the entire ODC gene, including potential upstream and downstream regulatory regions.

Methods: We investigated the association between genetic variation in the ODC gene and risk of adenoma recurrence among a cohort of 920 participants in the Aspirin/Folate Polyp Prevention Study. Using the Sequenom platform, we genotyped 29 SNPs within a 23kb region. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs) adjusted for age and gender. Interactions terms were used to test whether ODC genotype modified the protective effect of aspirin treatment.

Results: As gene frequencies for 26 of the 29 SNPs varied significantly by race/ethnicity, analyses were limited to whites only (86%). There were 7 SNPs associated with increased risk and 3 with decreased risk of adenoma recurrence (see table). In addition, at least three SNPs without any main effect modified the effect of aspirin treatment: rs1405948 (P for interaction=0.048), rs28362422 (P=0.043), and rs4669584 (P=0.050).

Conclusion: Our findings suggest that common genetic variation throughout the ODC gene and adjacent regulatory regions influence risk of adenoma recurrence as well as efficacy of aspirin treatment.Association of ODC polymorphisms with adenoma riskSNPRR95% CIP-valueModelMAFLocationrs23575511.231.06-1.440.008dominant0.345′ flankingrs23026141.371.08-1.740.009dominant0.04exon 2rs37526611.351.06-1.720.017dominant0.04intron 5rs10495001.381.08-1.750.009dominant0.04exon 12rs8181620.700.52-0.940.019recessive0.303′ flankingrs109296691.251.06-1.480.009dominant0.113′ flankingrs24634630.760.62-0.930.009recessive0.443′ flankingrs24304201.251.08-1.460.004dominant0.323′ flankingrs116949111.341.13-1.590.001dominant0.113′ flankingrs130009160.770.63-0.040.009recessive0.453′ flanking

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 2831.
Abstract 2838: p53-R72P single nucleotide polymorphism is not associated with cancer risk, histopathologic features or clinical outcome in renal cell carcinoma in Caucasians
Authors: Hammerschmied Christine G. , Stoehr Robert , Walter Bernhard , Junker Kerstin , Moch Holger , Hinze Raoul , Hofstaedter Ferdinand , Hartmann Arndt
Published: February 2011

Aims:

At codon 72, the human p53 gene contains a single nucleotide polymorphism (SNP), where the sequence can either read CGC, which encodes the amino acid arginine (R), or CCC which codes for proline (P). This SNP, p53-R72P, was found to affect numerous carcinogenesis related cell functions, like apoptosis, cell cycle progression, DNA repair, growth arrest and transcriptional activation. P53-R72 was found to be more effective at protecting stressed cells from neoplastic development. Significant associations of this variant to cancer development were found in various cell types, e.g. breast, gastric and lung cancer. No data are available for renal cell carcinoma (RCC).

Methods:

DNA extracted from formalin-fixed, paraffin-embedded normal tissue of 334 caucasian renal tumor patients (among them 157 affected by clear cell, 54 by papillary, 70 by chromophobe carcinoma and 41 by benign oncocytoma) and 196 controls was examined by restriction fragment length polymorphism (RFLP) using primers for PCR and the restriction enzyme BSTUI. After digestion, the length of the resulting bands was estimated by gel electrophoresis. Genotype distribution of both groups was compared by two sided exact Chi2 test. We also tested for associations of any genotype to histologic subtype, stage, nuclear grade, age at diagnosis, tumor-related survival and gender. Survival analysis was performed using log rank statistics. For examination of the potential influence of the presence or absence of the C allele, analyses were repeated with a combined C/C+CG group vs. G/G.

Results:

Genotype distribution of RCC or benign oncocytoma carriers and controls did not differ significantly, and there was no correlation of genotype and age of onset. We did not observe a significant acceleration of a certain genotype relative to gender, age group, subtype, stage or nuclear grade. Both tumor-related survival and progression free survival were not affected by genotype. Similar results were obtained when the two C allele carrying groups were pooled for analysis.

Conclusions:

The p53 R72P polymorphism does not seem to affect the risk of developing RCC or benign oncocytoma, the course of the disease, or histopathologic features in Caucasians.

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 2838.
Abstract 2839: Effects of CDKN2A genetic polymorphisms on DNA methylation in head and neck cancer
Authors: Rios Leslimar , Aquino-Lopez Arianexys , Velez Germán L. , Rivera-Pena Bianca , Baez Adriana
Published: February 2011

Gene polymorphism has been found to be associated with the susceptibility to cancer or its severity as exemplified in the CDKN2A gene. CDKN2A regulates G1 arrest and plays an important role in head and neck cancer (HNSCC) carcinogenesis. Deregulated tumor expression of CDKN2A has previously been described in association with HNSCC clinical progression. Aberrant methylation of CDKN2A is common gene silencing mechanism in HNSCC. CDKN2A is polymorphic, with variant alleles G/A442, C/T 540, and C/G 500 associated with cancer. Previously we have shown that in the Puerto Rican population the G/A 442, GG variant is associated with an increased head and neck cancer risk (OR, 4.09). In the present study, we examined the CDKN2A G/A442, C/T 540 and C/G 500 polymorphisms using PCR-RFLP and the pattern of methylation of the CDKN2A gene by methylation-specific PCR or Methylight assay in 152 HNSCC. The allelic frequencies were compared to a control group of 69 age - matched healthy blood donors. CpG island methylation for CDKN2A was found in 45% HNSCCs. The G/A 442, GG variant was more common in tumors of the larynx (63%). A significant correlation between CDKN2A G/A442 and head and neck cancer was indicated (r = 0.24, P = 0.02). We found no association between CDKN2A gene hypermethylation and CDKN2A C/T 540 and C/G 500 polymorphisms, However, we confirmed that individuals carrying the AG variant in G/A 442 gene had a higher frequency of hypermethylation in HNSCCs. Our results suggest that G/A 442 polymorphisms of CDKN2A gene may affect the methylation status. Functional and bioinformatic studies to clarify these results are underway.

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 2839.
Abstract 2840: A functional nonsynonymous single nucleotide polymorphism in the migration and invasion inhibitory protein (MIIP) gene confers differential risk of breast cancer
Authors: Chen Kexin , Song Fangfang , Ji Ping , Zheng Hong , Song Fengju , Wang Yingmei , Hao Xishan , Wei Qingyi , Zhang Wei
Published: February 2011

The migration and invasion inhibitory protein (MIIP) gene encodes an inhibitor of cancer cell migration and invasion. Our previous studies using the colony formation assay have demonstrated that MIIP also inhibits tumorigenesis in breast cancer cells. Therefore, we hypothesized that genetic variations in MIIP may affect breast cancer development and prognosis. In this case-control study, we genotyped the MIIP single nucleotide polymorphism (SNP) rs2295283 (codon 167, A>G, K>E) from 1524 breast cancer patients and 1592 age-matched controls for its association with breast cancer risk. The SNP analysis was next performed on a validation set (736 cases and 760 controls). Colony formation and cell migration assays were then conducted to functionally interrogate the difference between the A and G variants. Compared with the AA genotype in both the test and validation sets, the combined AG+GG genotypes (167E) were associated with a significantly lower risk of breast cancer. Among the test set, the protective effect of the AG+GG genotypes was more evident among participants with a family history of cancer. Further case series analysis revealed that the GG genotype was less susceptible to breast cancer with tumor size >2 cm and late clinical stage (II+III+IV). Colony formation assays showed that MIIP 167E (the G variant) was a more potent inhibitor of colony formation but not cell migration. These results suggest that MIIP K167E SNP may be a genetic predictor of breast cancer development and prognosis, as supported by differential abilities of the two isoforms in inhibiting breast cancer colony formation in vitro.

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 2840.
Abstract 2843: Caspase-8 gene SNPs in prostate cancer susceptibility: a replication study
Authors: Parry Marina , Elliott Graeme , Abo Ryan , Camp Nicola J. , Neal David E. , Donovan Jenny L. , Hamdy Freddie C. , Cox Angela
Published: February 2011

Introduction

A single nucleotide polymorphism (SNP) in the caspase-8 gene, (CASP8 D302H), has been reported to be involved in susceptibility to breast and pancreatic cancer, melanoma and glioma, but not colorectal or ovarian cancer. We previously have used a tagging-SNP approach to test the hypothesis that this SNP, or other variants in CASP8, were associated with prostate cancer, in 1009 cases, 987 men with normal serum prostate specific antigen (PSA) levels and 961 men with low serum PSA (<0.5ng/ml). These subjects were drawn from those participating in the UK ProtecT (Prostate Testing for Cancer and Treatment) trial. Of the 15 tagging SNPs in caspase-8 that were genotyped, 7 showed some evidence of association with prostate cancer (P<0.05). The aim of the present study was to attempt to replicate these results in an independent set of case and control subjects.

Methods

A further independent sample of men from the ProtecT trial formed the replication cohort for this study. Blood DNA samples were available for 1262 men with prostate cancer, 1258 men with normal serum PSA, and 609 men with low serum PSA. SNP genotyping was carried out by 5-prime nuclease PCR (TaqmanTM, Applied Biosystems). The association with prostate cancer was tested using logistic regression, controlling for sample set.

Results

Two SNPs with duplicate concordance rates of less than 98% were not included in the analysis. Genotype call rates for the remaining 5 SNPs were all greater than 95%, and genotype frequencies in control subjects were consistent with those expected under Hardy-Weinberg equilibrium. None of the 5 SNPs yielded significant evidence of association in the replication cohort, although some odds ratios were consistent between the two data sets. We combined the data from the test and replication cohorts to evaluate the overall evidence for association. The rare alleles of rs3769826 and rs6723097 conferred a reduced risk of prostate cancer with per-allele odds ratios (95% confidence interval) [OR(95%CI)] of 0.90 (0.82-0.98) and 0.88 (0.80-0.96), and P=0.013 and P=0.004 respectively. In addition, the deletion allele of the promoter indel rs3834129 conferred an increased risk of prostate cancer, with OR (95%CI) of 1.15 (1.05-1.27), P=0.003. While these results await further replication, it is interesting to note that the rare alleles of rs3769826 and rs6723097 are carried on European haplotypes that are associated with increased risk of breast cancer, suggesting the possibility of a different mode of action of caspase-8 in the two tumour types.

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 2843.
Abstract 2846: SNPs in apoptosis and cell cycle control related genes and brain tumor risk among children in Korea
Authors: Jeon Sujee , Han Sohee , Lee Kyoung-Mu , Park Ae Kyung , Ahn Hyo Seop , Shin Hee Young , Kang Hyoung Jin , Koo Hong Hoe , Seo Jong Jin , Choi Ji Eun , Kim Ho , Kang Daehee
Published: February 2011

Objective

In a hospital-based case-control study in Korea, we evaluated the association between polymorphisms in genes involved in apoptosis and cell cycle control and brain tumor risk among children.

Methods

Incident brain tumor cases (n=70) and non-cancer controls (n=254) were recruited from three teaching hospitals in Seoul between May 2003 and August 2006. Information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Tagging single-nucleotide polymorphisms (SNPs) were selected using a pairwise linkage-disequilibrium (LD) based algorithm (n=304) were genotyped for 43 cases and 153 controls in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) for SNP genotypes were estimated using unconditional logistic regression adjusted for age and birth weight. The false discovery rate (FDR) was estimated to evaluate the probability of false positive associations; we considered FDR <0.2 as noteworthy.

Results

Eleven tag SNPs in six genes, AICDA, LMO2, MYC, BCL2, BCL2A1, and CASP7 were significantly associated with childhood brain tumor (Ptrend<0.05). Two SNPs (rs12306110 and rs3794318) in AICDA gene, encoding activation-induced cytidine deaminase, remained significant after adjusting of multiple tests. These SNPs were in tight LD. The most significant association with childhood brain tumor risk was for the rs12306110 (OR, 0.24; 95% CI, 0.11-0.51).

ConclusionOur results suggest that genetic polymorphisms in AICDA may be associated with the risk of brain tumor in childhood.

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 2846.
Abstract 2848: The DEC1 promoter polymorphism −249 T>C reduces the risk of squamous cell carcinoma of the head and neck
Authors: Huang Yu-Jing , Niu Jiangong , Wang Li-E , Liu Zhensheng , Sturgis Erich M. , Wei Qingyi
Published: February 2011

The human DEC1 (deleted in esophageal cancer 1) gene is located on chromosome 9q, a region frequently deleted in various types of human cancers, including squamous cell carcinomas of the head and neck (SCCHN). Previous studies have shown that DEC1 expression was greatly reduced or absent in esophageal cancer, and its tumor suppressive ability was observed in both in vitro and in vivo assays. Therefore, we hypothesized that DEC1 might also play roles in the etiology of SCCHN. To assess the association between DEC1 polymorphisms and SCCHN risk, two independent promoter SNPs, −1628 G>C (rs1591420) and −606 T>C (rs4978620), the latter being in complete linkage disequilibrium with both −249 T>C (rs2012775) and −122 (rs2012566), were genotyped in 1,111 non-Hispanic whites SCCHN patients and 1,130 age-and sex-matched cancer-free controls recruited at The University of Texas M. D. Anderson Cancer Center. The joint effect of DEC1 SNPs and the TP53 tumor suppressor gene codon 72 (Arg72Pro, rs1042522) polymorphism, which has been suggested to be associated with susceptibility to tobacco-related cancers, was also assessed. After adjustment for age, sex, and smoking and drinking status, a significantly protective effect on SCCHN risk was observed for the −606 T>C (rs4978620) CC homozygotes (adjusted OR = 0.72, 95% CI= 0.52-0.98), compared with those carrying the −606 TT genotype. Stratification analyses showed that a decrease risk associated with the −606 CC genotype remained significant in the subgroups of never smokers, never drinkers, younger subjects (≤55 yr), patients with oropharyngeal cancer, and in the presence of the TP53Arg/Arg (rs1042522) genotype. By an in silico analysis, we identified that the −249 T>C SNP would gain a transcription factor binding site. Indeed, further functional analysis showed that the T to C allelic change at the −249 site significantly enhanced transcriptional activity of the DEC1 promoter and the DNA-protein binding activity, supporting a tumor suppressor role of DEC1 in SCCHN. We conclude that the DEC1 promoter −249 T>C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic whites. The association with oropharyngeal cancer among never smokers and never drinkers and with TP53 Arg/Arg genotype suggests that this polymorphism could modulate the human papillomavirus-induced carcinogenic process. (Supported by NIH grants R01CA131274 and R01ES011740)

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 2848.
Abstract 2849: A functional promoter variant (rs2075533 C>T) in TNFSF8 involved in apoptosis contributes to decreased risk of lung cancer — a finding from Texas lung cancer genome-wide association study
Authors: Wei Sheng , Niu Jiangong , Zhao Hui , Liu Zhensheng , Wang Li-E , Han Younghun , Amos Christopher I. , Spitz Margaret R. , Wei Qingyi
Published: February 2011

Although genome-wide association studies (GWASs) of lung cancer have identified several significant variants associated with risk of lung cancer, few variants in known biological pathways involved in the etiology of lung cancer have been yet implicated. In this study, we further explored the variants in the extrinsic apoptosis pathway, a fundamental pathway in lung cancer etiology, in 1,154 lung cancer cases and 1,137 cancer-free controls, all being ever-smokers, from the Texas lung cancer (TLC) GWAS (using the Illumina Human370 chip, in which 611 tagSNPs in 41 genes in the apoptosis extrinsic pathway were included. An association analysis using Plink1.06 showed that 10 of these 611 SNPs were associated with risk of lung cancer with a p value <10−2. Among the tagSNPs with the smallest p values, we selected the TNFSF8 gene for further analysis. To search for the tagged functional SNPs, we applied MACH1.0 to impute 52 additional SNPs in the 48-kb region around TNFSF8 based on the genotypes of 10 tagSNPs from the TLC-GWAS database and the genotypes in the same region from the Hapmap database. With further SNP function prediction analyses using SNPinfo and TFSEARCH bioinformatics software, we found that a SNP, −861 C>T (rs2075533), located in the promoter region of TNFSF8 may be a functional SNP. In subsequent functional validation by the luciferase transfection assay, the T allele of this SNP significantly decreased expression of the luciferase reporter constructs by 5-10 fold in all H1299, Hela and HCT116 cell lines tested, compared with the C allele. Our findings implicated a possible novel role of TNFSF8 in the development of lung cancer. Further investigation is warranted to determine whether TNFSF8 rs2075533 alone or in combination with other SNPs contribute to the risk of lung cancer. (Supported by NIH grants R01CA131274, CA055769, CA127219, and R01ES011740)

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 2849.
Abstract 2853: Genetic variation in IGF1, GHR, and IGFBP1 is associated with colorectal cancer
Authors: LeRoy Elizabeth C. , Jacobs Elizabeth T. , Ashbeck Erin L. , Martínez María Elena , Marchand Loic Le , Lance Peter , Duggan David , Thompson Patricia A.
Published: February 2011

Background

The insulin-like growth factor (IGF-1)/growth hormone (GH) pathway has been implicated in the development of colorectal cancer. Circulating IGF-1 increases cell proliferation and inhibits apoptosis. Genetic variation in the IGF pathway genes has been shown to alter circulating IGF-1 concentrations and has been associated with colorectal cancer. This risk may differ by anatomic location.

Methods

We used a principal components approach to evaluate the relationship between genetic variation in six IGF pathway genes (IGF1, IGF2, IGFBP1, IGFBP3, GHR, and GH1) and colorectal cancer in a family-based case-control study from the Colon Cancer Family Registry (CCFR). Cases were recruited from both high-risk clinics and population-based registries. Controls had no previous diagnosis of colorectal cancer and were full biologic siblings of the cases. Clinic-based (cases = 268, controls = 475) and population-based (cases = 1,802, controls = 2,874) data were analyzed separately and all models were adjusted for age and sex.

Results

There was no overall association between genetic variation in the IGF pathway genes and colorectal cancer. However, when the data were analyzed by colorectal cancer anatomic location, GH1 was associated with distal colon cancer (p=0.05) in the population-based families and IGF1 was associated with rectal cancer (p=0.004) in the clinic-based families. Furthermore, when the data were stratified by MSI-status, IGFBP1 was associated with MSI-low/stable tumors (p=0.017) in the clinic-based families.

Conclusion

In this family-based case-control study, genetic variation in IGF1, GHR, and IGFBP1 was associated with colorectal cancer differentially by anatomic location, population source, and tumor type. The clinic-based data represent families with high genetic risk in contrast to the population-based data which represent families of moderate to average genetic risk. These results replicate prior case-only analyses that suggest IGF1 is a modifier of colorectal cancer risk in high-risk families. Single SNP analyses and exploration of SNP x SNP interactions may further elucidate the significance of IGF pathway genes on colorectal 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 2853.
Abstract 2857: SULT1A1 gene copy number variations and functional polymorphism in relation to breast cancer risk
Authors: Li Guoliang , Ye Chuanzhong , Shu Xiao-Ou , Wen Wanqing , Lu Wei , Zheng Wei , Cai Qiuyin
Published: February 2011

Sulfotransferase (SULT) 1A1 enzyme plays an important role in the detoxification of environmental and dietary procarcinogens as well as the regulation of a number of steroid hormones, including estrogens. SULT1A1 gene is located in the short arm of chromosome 16, which has been shown to contain many repetitive sequences and to be highly duplicated. It has been suggested that SULT1A1 gene displays variations in copy number. In our previous study, a common functional polymorphism rs9282861 (213Arg>His) in SULT1A1 was associated with an elevated risk of breast cancer in postmenopausal Caucasian women. In this study, we evaluated copy number variations and functional polymorphism rs9282861 of SULT1A1 gene in relation to breast cancer risk. Included in the study were 1,989 breast cancer cases and 1,918 controls from the Shanghai Breast Cancer Study II, a population-based, case-control study conducted among Chinese women. SULT1A1 gene copy number was determined by real-time PCR assays and genotyping was conducted using TaqMan assays. One to five copies of the SULT1A1 were observed in our population. Approximately 22.6% of these women were found to have more than 2-copy of the SULT1A1 gene and 1.7% of these women were found to have 1-copy of the gene. No woman was found to have null copy of SULT1A1 gene. No overall association of the SULT1A1 gene copy number variations with breast cancer risk was observed. We found that the A allele (213His) of rs9282861 was associated with a reduced risk of breast cancer risk. Women carrying GA/AA genotypes had an OR of 0.81 (95%CI=0.68-0.97) compared to women carrying GG genotype. The inverse association was constraint in pre-menopausal women with OR of 0.68 (95%CI=0.53-0.87) for women carrying GA/AA genotypes compared to those carrying GG genotype. There is no interaction between SULT1A1 gene copy number variations and polymorphism 213Arg>His in relation to breast cancer risk. Our data suggest that functional 213Arg>His polymorphism of SULT1A1 gene, not SULT1A1 gene copy number change, may play a role in the etiology of 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 2857.
Abstract 2858: Relation of androgen receptor polymorphisms and prostate cancer risk by level of sex steroid hormones
Authors: Sakoda Lori C. , Weiss Noel S. , Barnett Matt , Goodman Gary E. , Chen Chu
Published: February 2011

Given that androgens exert their effects on target tissues through androgen receptor (AR) binding, polymorphic variation in the AR gene may influence prostate cancer development. Studies examining the AR CAG and GGC repeat polymorphisms in relation to prostate cancer risk, however, have yielded conflicting results. In a case-control study of prostate cancer nested in the β-carotene and Retinol Efficacy Trial, we previously found suggestive evidence of reduced risk in men with a small number of AR CAG [<22 versus ≥22: odds ratio (OR), 0.89; 95% confidence interval (CI): 0.65-1.23] or GGC [≤17 versus >17: OR, 0.80; 95% CI: 0.57-1.12] repeats. The possibility that these associations are more pronounced in certain subgroups of men, with respect to level of circulating sex steroid hormones, has not yet been examined. In the same population of 300 cases and 300 controls, we now explore whether prostate cancer risk associated with CAG or GGC repeat length may differ by levels of serum testosterone, estradiol, androstenedione, dehydroepiandrosterone sulfate, 3α-androstanediol glucuronide, and sex hormone binding globulin concentrations. To cases diagnosed from 1987-1998 who had blood drawn from 0.5 to 8.5 (mean: 3) years prior, controls who were free of prostate and lung cancer were matched on the basis of age, race, study center, time of blood draw, time from enrollment to blood draw, and year of randomization. We found no trend in prostate cancer risk associated with short (≤17) GGC repeat length across thirds of the distribution of the hormones, except for estradiol. For men in the lowest, middle, and highest third of total estradiol, the ORs (95% CIs) were 1.16 (0.65-2.10), 0.87 (0.50-1.72), and 0.50 (0.27-0.92), respectively (p-interaction=0.14). A similar, but weaker association pattern was noted across thirds of free estradiol. No clear differences in the relation of CAG repeat length and prostate cancer risk across levels of each hormone were found. Since the observed positive results may be due to chance, further investigation is needed to determine whether AR GGC repeat length and circulating sex steroid hormone levels interact to alter 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 2858.
Abstract 286: Expression and role of fibroblast growth factor receptor2 IIIc in human uterine cervical intraepithelial neoplasia (CIN) and invasive cervical cancer
Authors: Kawase Rieko , Ishiwata Toshiyuki , Matsuda Yoko , Onda Munehiko , Teduka Kiyoshi , Kawahara Kiyoko , Takeshita Toshiyuki , Naito Zenya
Published: February 2011

Fibroblast growth factor receptors (FGFR) FGFR1 through FGFR3 possess IIIb and IIIc isoforms as the result of alternative splicing of the immunoglobulin-like domain. The IIIb isoforms are mainly expressed in normal epithelial cells, and IIIc isoforms are expressed in mesenchymal cells. Single nucleotide polymorphisms (SNPs) of the FGFR2 gene are associated with endometrial cancer, and missense mutations or copy number gains of the FGFR2 gene occur in breast cancer. In uterine cervical cancer, FGFR2 IIIb, also known as keratinocyte growth factor receptor (KGFR), was reported to be highly expressed in squamous cell carcinoma (SCC), which accounts for 90% of all cervical cancer patients. However, there has been no report on the expression and roles of FGFR2 IIIc in cervical cancer. In the present study, we determined the expression and roles of FGFR2 IIIc in CIN and cervical SCC. In noncancerous cervical tissues, FGFR2 IIIc immunoreactivity was either not present or very faintly localized in squamous epithelial cells. In CINs 1 and 2, FGFR2 IIIc was localized at the basal to lower two-thirds of squamous epithelium, whereas FGFR2 IIIc was strongly expressed in most of the squamous epithelium, except for the superficial layer in CIN 3. FGFR2 IIIc protein was detected in keratinizing and non-keratinizing types of SCC in all cervical cancer patients examined (8 and 21 cases, respectively). In situ hybridization (ISH) analysis using an FGFR2 IIIc-specific antisense RNA probe showed that the expression patterns of FGFR2 IIIc mRNA are similar to those of FGFR2 IIIc protein in noncancerous and CIN tissues. In addition, FGFR2 IIIc mRNA was strongly expressed in the invasive fronts of cancer cell nests in cancer tissues. Moreover, full-length FGFR2 IIIc cDNA, subcloned to pIRES2-EGFP vector, was stably transfected into CaSki cells, which are derived from a well-differentiated type of SCC. The growth rates of the FGFR2 IIIc-transfected CaSki cells were higher than those of mock cells in vitro. Cell migration assays did not show any differences between FGFR2 IIIc-transfected CaSki cells and mock cells. To assess the effect of FGFR2 IIIc expression on tumorigenicity, the CaSki cells were injected into nude mice. The FGFR2 IIIc-transfected CaSki cells tended to form larger subcutaneous tumors than mock cells in nude mice. These findings suggest that FGFR2 IIIc plays important roles in the carcinogenesis and proliferation of cervical cancer cells. FGFR2 IIIc is considered to be a novel therapeutic target for inhibiting the growth of CIN and cervical 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 286.
Abstract 2874: A γ-tocopherol-rich mixture of tocopherols inhibits chemically induced lung tumorigenesis in A/J mice and xenograft tumor growth
Authors: Lu Gang , Xiao Hang , Li GuangXun , Picinich Sonia C. , Chen Yu-Kuo , Liu Anna , Li Mao-Jung , Loy Shea , Yang Chung S.
Published: February 2011

The present study investigated the effects of a preparation of a γ-tocopherol (γ-T)-rich mixture of tocopherols (γ-TmT) and its combination with EGCG on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; i.p. injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 μmol each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% γ-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30%, 51% and 60%, respectively; P<0.05). For three groups of mice treated with NNK alone, the γ-TmT diet was given during the initiation stage (Week 0 to 3), the post-initiation stage (Week 3 to 19), or the entire experimental period, and tumor multiplicity was reduced by 17.8%, 19.7%, or 29.3%, respectively (P<0.05). γ-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36% or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary γ-TmT treatment significantly reduced tumor volume and tumor weight by 56% and 47%, respectively (P<0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of γ-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, γ-H2AX and nitrotyrosine in the tumors of the γ-TmT-treated mice. These results demonstrate the inhibitory effect of γ-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of δ-T and γ-T. We further studied the tumor inhibitory effects of a combination of γ-TmT and EGCG in the above mentioned NNK-induced lung tumorigenesis model. The treatment with γ-TmT (0.3%), EGCG (0.4%), and the combination at half doses (0.15% γ-TmT plus 0.2% EGCG) all significantly reduced the tumor multiplicity in the NNK-induced model. In this experiment, we observed by immunohistochemistry that dietary γ-TmT treatment increased the glutathione peroxidase and superoxide dismutase levels, but EGCG treatment had no effect on these two enzymes. The levels of catalase, heme oxigenase-1 and Nrf2 were not changed by either agent (Supported by NIH grants CA122474 and CA 133021).

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 2874.
Abstract 2877: TRAMP-injected mice fed a no-carbohydrate ketogenic diet demonstrate prolonged survival and decreased tumor volumes compared to mice fed western or low-fat diets
Authors: Whitley Brian M. , Masko Elizabeth M. , Thomas Jean A. , Kim Howard S. , Poulton Susan A. , Phillips Tameika E. , Freedland Stephen J.
Published: February 2011

Introduction and Objective: In multiple previous studies, we have shown that mice injected with subcutaneous prostate cancer cells (LNCaP or LAPC-4) and fed a no-carbohydrate ketogenic diet (NCKD, 84% fat, 0% carbohydrate, 16% protein) have significantly decreased tumor volume and significantly prolonged survival, compared to mice fed a western diet (WD, 40% fat, 44% carbohydrate, 16% protein). All previous studies utilized a human prostate cancer cell line, requiring the use of immunodeficient mice. We sought to replicate these previous studies to determine whether diet affected tumor progression and survival in an immunocompetent model.

Methods: In this treatment model, 75 male C57bl/6 mice were initially fed WD ad libitum for a period of 14 days. After this 14 day period, all mice were injected subcutaneously with 2.5×105 TRAMP cells and randomized to one of three diets: WD, NCKD, or low-fat diet (LF, 12% fat, 72% carbohydrate, 16% protein). Mice receiving LF diet were fed ad libitum, and served as the reference group in paired-feeding protocols for mice receiving WD and NCKD. Tumor volumes were assessed twice weekly, and mice were sacrificed when tumor volumes reached 1000mm3. Survival was calculated using a Log-rank test and tumor volumes were compared among dietary groups using Kruskal-Wallis test for significance.

Results: Mice fed a NCKD demonstrated a trend towards decreased tumor volumes compared to mice fed WD and LF. Median tumor volume at study day 66 for mice fed WD, LF, and NCKD were 1091.2 mm3, 1082.9 mm3, and 661.5mm3 respectively. While the tumor volumes were smaller in mice fed NCKD versus LF or WD, these differences did not reach statistical significance (WD vs. NCKD, p=0.06; LF vs. NCKD, p=0.12). There was no significant difference between tumor volumes among mice fed WD compared to LF (p=0.95). Additionally, a trend towards improved survival was seen in mice fed NCKD vs. WD (p=0.09).

Conclusion: This study in an immunocompetent xenograft model supports the findings of multiple previous studies. Mice fed a NCKD demonstrated a trend towards prolonged survival and decreased tumor volume compared to mice fed WD.

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 2877.