bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2781: Expression patterns of the ERBB2 gene and its splice variant in mammary tissues and their associations with breast risk and survival
Authors: Ye Chuanzhong , Shu Xiao-Ou , Wen Wanqing , Qu Shimian , Courtney Regina , Gao Yu-Tang , Zheng Wei , Cai Qiuyin
Published: February 2011

Alternative splicing generates different transcripts from the same precursor mRNA. ERBB2 proto-oncogene is involved in the growth, invasion, and prognosis of breast cancer. The ERBB2-sp is a splice variant of ERBB2 that lacks the intracellular and transmembrane domains, which may alter the function of the ERBB2 gene. We hypothesize that the ERBB2-sp and the wild type ERBB2 gene may play a different role in the development and prognosis of breast cancer, and thus compared ERBB2 and ERBB2-sp mRNA expression in tumor tissue and adjacent non-tumor tissue in both breast cancer patients and benign breast disease (BBD) patients. Included in the study were 515 patients diagnosed with breast cancer and 206 patients diagnosed with BBD. These women were recruited as part of the Shanghai Breast Cancer Study and they provided samples of tumor tissue and adjacent non-tumor tissue to the study. Tumor tissues from patients with breast cancer had substantially higher levels of ERBB2 expression than those from patients with BBD (81vs 37, P < 0.0001). On the other hand, adjacent non-tumor tissues from patients with breast cancer had substantially lower levels of ERBB2 expression than those from patients with BBD (20 vs 34, p=0.0254). In breast cancer cases, ERBB2 expression in tumor tissue was significantly higher than that in their paired adjacent non-tumor tissue (p=0.0028). No significant difference of ERBB-sp expression levels was found in any of the following comparisons, tumor tissues or adjacent normal tissues between breast cancer patients and BBD controls as well as between the tumor tissues and adjacent normal tissues in both breast cancer and BBD patients. In the comparison of tumor tissues between breast cancer patients and BBD controls, the ratio of ERBB2 to ERBB2-sp expression levels (ERBB2 /ERBB2-sp index) in tumor tissue was associated with a significantly increased breast cancer risk in a linear manner, with adjusted odds ratios (95% CI) increased from 1.00 (reference) to 1.33 (0.84-2.13), 1.82 (1.13-2.94), and 2.63(1.55-4.43) (P for trend <0.001) from the lowest to the highest quintiles of expression groups. However, there were no apparent associations of expressions of ERBB2 and ERBB2-sp, or ERBB2/ERBB2-sp index in cancer tissue with either overall survival or disease-free survival. Our findings suggest that the expression of ERBB2 and its splice variant ERBB2-sp may play a different role in the development, but not prognosis, 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 2781.
Abstract 2782: Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer
Authors: Tamimi Rulla M. , Wang Yihong , Collins Laura C. , Hu Rong , Schnitt Stuart J. , Colditz Graham A. , Connolly James L.
Published: February 2011

The growth hormone and insulin-like growth factor (IGF) axis plays an essential role in the growth and development of the mammary gland. More recently it has become evident that IGF1 and IGF1 receptor (IGF1R) may play a role in the early transformation of mammary cells. Using a nested case-control design, we examined the association between IGF1R expression in normal breast tissue from benign biopsies and subsequent risk of breast cancer within the Nurses' Health Study. We constructed tissue microarrays (TMAs) containing normal terminal ductal lobular units (TDLUs) from benign breast biopsies. Immunostains for IGF1R were performed on sections cut from the TMAs. A total of 312 women had both normal TDLUs included in the TMAs and evaluable IGF1R staining; 75 subsequently developed breast cancer (cases) and 237 did not (controls). The epithelial cells in the normal TDLUs were scored for both cytoplasmic and membranous staining for IGF1R. Membranous IGF1R expression in normal TDLU epithelial cells was inversely associated with subsequent breast cancer risk (OR= 0.49; 95%CI 0.26-0.93) independent of type of benign breast disease (BBD). In contrast, the presence of cytoplasmic IGF1R expression was positively associated with subsequent risk of breast cancer (OR=2.88, 95% CI 1.60-5.19). Women in which TDLU epithelial cells showed little or no membrane expression of IGF1R but high levels of cytoplasmic IGF1R were at the highest breast cancer risk and were 15 times more likely to develop subsequent breast cancer when compared with women who had little or no membranous or cytoplasmic IGF1R expression in their TDLU epithelium (OR=15.1, 95% CI 3.2-70.2). It has been demonstrated that stimulation of cells with IGF1 results in altered localization of IGF1R expression. Upon stimulation, IGF1R levels on the cell membrane decrease while internalized levels increase. Studies of other receptor tyrosine kinases indicate that chronic stimulation by the ligand results in increased internalization of the receptor. In this study, IGF1R expression patterns in the epithelial cells of normal TDLUs were associated with an increased risk of subsequent breast cancer. The results of this study support the hypothesis that the IGF1 pathway plays an important role in the early development of breast cancer and suggest that there may be opportunities for breast cancer chemoprevention.

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 2782.
Abstract 2788: Serum steroid hormone levels and risk of lung adenocarcinoma among postmenopausal women in Taiwan
Authors: Li Yao-Jen , Yang Shi-Yi , Chen Chuen-Fei , Liao Kuo-Meng , Chen Chien-Jen
Published: February 2011

Study goal: Lung cancer is the leading cause of death among women worldwide, ande adenocarcinoma is the most common histological subtype among non-smoking women. Among non-smoking population, the lung cancer incidence is higher than men. Previous studies have shown that hormone related factors, such us menstrual cycle, hormonal replacement therapy are associated with female lung cancer. Hormone related factors may play a role in lung cancer. Therefore, we hypothesized that hormone levels in serum among postmenopausal women may associated with lung adenocarcinoma.

Material and methods: This was a case-control study. The study participants came from a medical center which located on Taichung Taiwan, 9 serum steroid hormone markers were determined for 81 women with lung adenocarcinoma and 114 unrelated cancer-free women who were frequently matched by age and sample collecting time from age of menopause. All subjects were postmenopausal and without using hormone replacement therapies. Unconditional logistic regression analysis was used to calculate the odds ratio (OR) and its 95% confidence interval (95% CI) for each hormone markers. Potential confounding factors, such us BMI, age at menarche, parity, and age at enrollment were take into regression models.

Results: Compared to lowest tertile groups of hormone levels, the highest tertile groups of progesterone (OR, 0.34; 0.2-0.7), testosterone (OR, 0.37; 0.2-0.8), Free testosterone (OR, 0.40; 0.2-0.9), Androstenedione (OR, 0.29; 0.1-0.7), sex hormone-binding globulin (OR, 0.47; 0.2-1.0) were associated a decrease risk of lung adenocarcinoma among postmenopausal women after adjusted for age at enrollment, BMI. On the other side, serum estradiol (OR, 0.59; 0.3-1.3) and dehydroepiandrosterone sulfate (OR, 0.49; 0.2-1.0) levels showed non-significant decrease risk to female lung adenocarcinoma among postmenopausal subjects.

Conclusions: The serum sex steroid hormone levels among postmenopausal women may influence the risk to lung adenocarcinoma in Taiwan. Prospective designs will be necessary to clarify the association between serum hormone levels and risk of female lung adenocarcnoma.

Key word: serum, sex steroid hormone, post-menopause, lung adenocarcinoma.

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 2788.
Abstract 279: Increased Met receptor activation mediates enhanced cell invasion upon mutant p53 expression in esophageal squamous cell carcinoma
Authors: Grugan Katharine D. , Miller Charles G. , Michaylira Carmen Z. , Klein-Szanto Andres J. , Nakagawa Hiro , Rustgi Anil K.
Published: February 2011

Esophageal squamous cell carcinoma (ESCC), a type of squamous cell cancer, is one of the most aggressive forms of human cancer with poor prognosis due to late diagnosis and metastasis. Common genomic alterations in ESCC include p53 mutations and overexpression of oncogenes such as cyclin D1, EGFR, and Met. Using an invasive primary esophageal epithelial cell model system genetically transformed by the overexpression of EGFR and p53R175H, we find novel evidence of cross-talk between p53R175H and the Met receptor tyrosine kinase. Increased Met receptor activation is observed upon expression of p53R175H and is further enhanced upon subsequent overexpression of EGFR. Increased Met activation is observed also in a number of human ESCC cells lines that harbor either p53 genetic mutations or are p53 null. Met phosphorylation can be inhibited using two small molecule compounds (CP31398 and 5-iminodaunorubicin) that have been demonstrated previously to activate wild-type p53 signaling through distinct mechanisms, thereby providing further evidence to a link between these two pathways. Both CP31398 and 5-iminodaunorubicin blocked invasion of the genetically transformed primary esophageal epithelial cells (EPC-hTERT-EGFR-p53R175H) suggesting that the mechanism of increased invasiveness upon EGFR and p53R175H expression may be mediated by Met activation. In aggregate, mutant p53 and Met appear to cooperate to foster tumor invasion and this novel linkage has not been reported previously. These results provide further implications to the use of combinatorial therapeutics directed at Met and mutant p53 in ESCC and other squamous cell cancers.

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 279.
Abstract 2793: Folate, B vitamin and methionine intake and risk of colon cancer in relation to BRAF mutation and CpG Island Methylator Phenotype (CIMP)
Authors: Schernhammer Eva S. , Nosho Katsuhiko , Giovannucci Edward L. , Fuchs Charles S. , Ogino Shuji
Published: February 2011

BACKGROUND AND AIMS: One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of folate or other B vitamins or high alcohol consumption increases colorectal cancer risk. How dietary folate and B vitamins affect the CpG island methylator phenotype (CIMP) and BRAF mutation status in colon cancer remains uncertain.

METHODS: Utilizing 472 colon cancer tissue specimens from a large prospective cohort of women in the Nurses’ Health Study, we sequenced BRAF codon 600 and quantified DNA methylation in eight CpG islands [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], which have been validated as a CIMP marker panel. In addition, we examined 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, WRN). We examined the relationship between intake of folate and other one-carbon nutrients and colon cancer risk, according to BRAF mutation or CIMP status.

RESULTS: We were able to sequence BRAF in 472 incident colon cancers, and determine CIMP status in 462 tumors. Compared with women reporting intake of <200μg of folate per day, the multivariate relative risk (RR) of developing CIMP-low/0 tumors (with <6/8 methylated CIMP-specific markers) was 0.73 (95% confidence interval (CI), 0.53-1.02) for those who took ≥400μg of folate per day. In contrast, total folate intake had no influence on risk for CIMP-high tumors (with ≥6/8 methylated CIMP-specific markers) [multivariate RR, 0.98; 95% CI, 0.54-1.77, comparing ≥400 to <200μg of folate per day]. Vitamin B6 intake did not appear to differentially influence risks for CIMP-high and CIMP-low/0 tumors (Pheterogeneity =0.63). In contrast, a higher methionine intake appeared to lower the risk of CIMP-high cancers (top versus bottom quintile, multivariate RR, 0.68; 95% CI, 0.35-1.31) whereas it had no effect on CIMP-low/0 tumors (multivariate RR, 1.04; 95% CI, 0.71-1.52; Pheterogeneity =0.007). Using the 16-marker CIMP panel did not substantially alter our results. Folate, B vitamin or methionine intake did not differentially affect colon cancer risk by BRAF status.

CONCLUSIONS: Lower levels of folate and vitamin B6 intake were associated with increased risk of CIMP-low/0 colon tumors, whereas higher levels of methionine intake appeared to lower the risk of CIMP-high tumors. These nutrients did not appear to affect BRAF mutation status. Our data support epigenetic alterations as potential mechanisms through which one-carbon nutrients exert their influence on colon carcinogenesis.

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 2793.
Abstract 2797: Measurement of GST-P1 methylation in body fluids and prostate cancer diagnosis: a meta-analysis
Authors: Wu Tianying , Giovannucci Edward , Welge Jeff , Mallick Palash , LeMasters Grace , Tang Wan-yee , Ho Shuk-Mei
Published: February 2011

Prostate-specific antigen (PSA) screening significantly increases the early diagnosis of prostate cancer; however, the specificity of PSA screening is fairly low (20%), leading to many unnecessary biopsies and overtreatment. Hence, the identification of a circulating biomarker with high specificity to complement the traditional PSA test is greatly needed. CpG island promoter hypermethylation may be one of the earliest somatic genome alterations in the development of several types of cancers. Studies have shown that glutathione-s-transferase-π (GST-P1) promoter hypermethylation is the most common somatic genome alteration during prostate cancer development. We have retrieved 22 studies that measured GST-P1 in plasma, urine, buffy coat, ejaculate, or whole blood. In our random effect model, the pooled specificity of measurement of GST-P1 hypermethylation was 89% (95%CI, 71-95%), indicating that GST-P1 has a much stronger specificity than the PSA test. When we stratify the studies by biospecimen type and PCR method, high specificity remains within each stratum. Unlike the PSA test, the pooled sensitivity of the GST-P1 methylation test was 47% (95%CI, 33-61%), relatively low. However, low sensitivity does not downgrade its potential application as a complement to the PSA test, which has a high sensitivity but a poor specificity. Moreover, we have found that the likelihood of GST-P1 methylation tends to increase with prostate cancer pathological stage (stages 3-4 versus 1-2), with an odds ratio of 1.21 (95%CI, 0.99-1.48). However, due to limited sample size (10 studies), this did not reach statistical significance. The current study has several advantages. This is the first study to systemically review GST-P1 methylation as measured in body fluids, and to compare the specificity of GST-P1 to the traditional PSA test; second, this review has rigorously examined specificity by excluding healthy controls, who cannot represent individuals with elevated PSA levels or urological symptoms.

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 2797.
Abstract 2798: VDR gene polymorphism and risk of prostate cancer in African-American
Authors: Daremipouran Mohammad , Beyene Desta , Nouraie Seyed-Mehdi , Kanaan Yasmine
Published: February 2011

Background: Genetics and epidemiological studies have shown that genes and environment interaction play strong roles in prostate cancer etiology. We have already shown that higher UV exposure, higher serum vitamin D, and lower skin pigmentation inversely associated with the risk of prostate cancer in African-American.

Methods: In order to explore the relationship between Vitamin D receptor (VDR) polymorphisms and prostate cancer risk in African American men; 91 affected African American men with histologically diagnosed adenocarcinoma of the prostate, PSA of > 2.5 ng/ml and a positive digital rectal exam have been recruited. Ninety-one age and ethnicity matched controls have been also recruited.

Genomic DNA was extracted from blood sample of each case and control subjects.

Nine primers were designed for amplification of 9 different axons in VDR gene. DNA fragments from all samples were amplified using PCR reaction. In order to investigate the existence of heteroduplex, PCR products denatured and using denaturing high performance liquid chromatography (DHPLC) technique heteroduplex analysis on the Wave system was performed. Those samples demonstrating heteroduplex peaks were sequenced using an ABI 377 DNA sequencer.

Results: Seven polymorphisms in VDR sequence were confirmed after sequencing. SNPs 132G>A, 332 G>A, 83 G>A, invs9-286C>T, 122 A>G, and invs10-49G>T are located in non-coding region. 209 T>C SNP is located in coding region. However this SNP is anonymous as previously reported. 332G>A, 83G>A, and invs9-286C>T SNPs showed strong negative association with prostate cancer risk (p< 0.05). 132G>A, 209T/C, and IVS10-49G>T showed direct association with risk of prostate cancer but statistically is not significant.

Using Binary Logistic Regression Model confirmed that 332G>A, 83G>A, and invs9-286C>T SNPs are good predictor of protection against prostate cancer. Whereas having SNP 209T>C is strong indicator of risk of prostate cancer.

Conclusion: It is possible that genetic variants may mediate prostate cancer risk via a mechanism involving availability of 1, 25(OH)2 D. Vitamin D protects against risk of prostate cancer. UV exposure, good vitamin D diet, and lighter skin along with advantageous VDR polymorphism as modulators of vitamin D can improve this protection.

We are in the process of assessment of analysis the interaction between other genes involved in vitamin D metabolism and environmental factors.

Our results require further corroboration in large statistically powerful sample collections.

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 2798.
Abstract 280: Met (the HGF receptor) localizes to the nucleus in wound healing
Authors: Bordeaux Jennifer , Hanna Jason A. , Agarwal Seema , Rimm David L.
Published: February 2011

Background: The hepatocyte growth factor (HGF)/Met signaling pathway has been shown to be important for stimulating cell proliferation, motility, invasion and metastasis. Recent work from our lab has also demonstrated patients with high levels of nuclear Met have a worse prognosis even in lymph node negative breast cancer and has also identified a 60 kDa fragment from the carboxy-terminal domain of Met that localizes to the nucleus.

Methods: We developed a method for quantification of in vitro wounding of epithelial cellular monolayers that we have utilized to further characterize nuclear Met. Nuclear Met was identified by immunofluorescence with the carboxy-terminal Met specific antibody CVD13 (Invitrogen) in H1650, A431 and Caco2 cells. The Met ligand (HGF) was used to stimulate wound healing and the Pfizer Met kinase inhibitor PHA-665752 (PHA) was used to determine the dependence of activated Met for nuclear localization.

Results: As previously observed, stimulating cells with HGF (50 ng/mL) increases overall wound healing and inhibition of Met kinase activity with PHA reduces overall wound healing. Using immunofluorescence we have determined nuclear Met is present at the wound edge of lung (H1650), colon (CaCo2), and skin (A431) cancer cell lines. Additionally, nuclear localization of Met is also observed in H1650 cells by immunofluorescence with a phospho-Met antibody (CST). Nuclear localization of Met is inhibited when cells are pretreated with PHA even in the presence of HGF. However, HGF stimulation alone is not sufficient to induce nuclear Met in the A549 lung cancer cell line. Finally, the 60 kDa Met fragment is absent by Western blot when H1650 cells are grown in serum-starved conditions.

Conclusion: Nuclear Met is observed during the wound healing of cellular monolayers and can be inhibited with Met specific kinase inhibitors. Nuclear Met, as defined by the presence of the 60 kDa fragment, is lost in serum-starved growth conditions. Since, several pharmaceutical companies are currently developing Met-based therapies, the role of Met the nucleus may be important in future targeted cancer 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 280.
Abstract 2825: Red meat and heterocyclic amine intake, metabolic pathway genes, and bladder cancer risk
Authors: Lin Jie , Wang Jianming , Grossman H. Barton , Chen Meng , Dinney Colin P. , Wu Xifeng
Published: February 2011

We analyzed the association between meat intake, heterocyclic amines and bladder cancer (BC) risk using data collected in a large case-control study. The study included 884 histologically confirmed BC cases and 878 healthy controls matched to cases by age (± 5 years), gender and ethnicity. Epidemiologic and dietary data were collected using structured questionnaires via an in-person interview. Dietary intake was reported on the National Cancer Institute- Block 135-item food frequency questionnaire (FFQ). Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI). Compared to those in the lowest quartile of total red meat intake, the ORs for the second, third and fourth quartiles of total red meat intake were 1.04 (95% CI: 0.78-1.39), 1.58 (95% CI: 1.19-2.10), and 1.49 (95% CI:1.21-1.99), respectively (P-for trend =0.001). Higher intakes of beef steaks, pork chops and bacon were each associated with increased BC risk in a dose-response pattern. For example, the ORs for the second, third and fourth quartiles of beef steak intake were 1.04 (95% CI: 0.78-1.39), 1.19 (95% CI: 0.89-1.57), and 1.54 (95% CI: 1.17-2.04), respectively (P-for trend =0.001). In addition, high intake of fried chicken and fried fish also conferred significantly increased risk. When assessed in doneness level, compared to the rare done level, intakes of red meat with medium done and well done level were associated with 1.46- fold (95% CI: 1.13-1.89) and 1.94-fold (95% CI: 1.52-2.49) increased risk (P for trend<0.001). Intakes of heterocyclic amine (HCA) were available in a subset of 177 cases and 306 controls. Compared to the first quartile (the lowest quartile of intake), the ORs for the second, third, and fourth quartiles were 1.18 (95% CI: 0.63-2.23), 1.64 (95% CI: 0.89-3.00), and 2.58 (95% CI: 1.43-4.66), respectively (P for trend<0.001). We further assessed joint effects of red meat and genetic variants in the pathways relevant to HCA metabolism. We found that the risk associated with high red meat intake was most significant among subjects carrying high number of unfavorable genotypes in the pathway. Compared with subjects in the lowest quartile of red meat intake and who carried low number of unfavorable genotypes (less than 6), subjects carrying seven or more unfavorable genotypes and whose red meat intake was in the highest quartile were at 4.74-fold increased risk (95% CI=2.78-8.10; P<0.001). These results strongly support that red meat intake and genetic variants in the HCA metabolic pathways jointly influence bladder cancer 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 2825.
Abstract 2832: Genetic variation in TGFB1, TGFBR1, TGFBR2, and prostate cancer risk and recurrence
Authors: Cheng Iona C. , Plummer Sarah , Mefford Joel , Neslund-Dudas Christine , Casey Graham , Rybicki Benjamin , Witte John
Published: February 2011

Background: The transforming growth factor-β (TGF-β) signaling pathway has been reported to play a dual role in prostate carcinogenesis. Initially, TGF-β signaling inhibits tumor growth by its antiproliferative activity, but eventually it promotes tumor development by enhancing tumor cell motility and metastasis. We investigated whether common genetic variation in TGFB1, TGFBR1, and TGFBR2 influences the risk of aggressive prostate cancer and biochemical recurrence.

Methods: Forty-four tag SNPs in TGFB1, TGFBR1, and TGFBR2 were examined in a case-control study of aggressive prostate cancer (501 cases/538 controls) and a follow-up study of biochemical recurrence (824 cases). Aggressive disease was defined as having either having a Gleason score ≥7 or TNM stage ≥ T2c, or PSA at diagnosis >10 ng/ml. Biochemical recurrence was defined as post-treatment prostate specific antigen (PSA) levels >0.3 ng/ml for radical prostatectomy patients or 2 ng/ml increase above the nadir for radiotherpay patients. Odds ratios (OR) and 95% Confidence Intervals (CI) were estimated by unconditional logistic regression to evaluate the association between SNPs and aggressive prostate cancer risk. Hazard ratios (HR) and 95% CI were estimated by Cox proportional hazard regression to examine the association between SNPs and biochemical recurrence.

Results: For risk of aggressive disease, three SNPs were nominally statistically significant (TGFB1-rs4803455; TGFBR1-rs10512263; TGFBR2-rs2276768) with the most compelling polymorphism (TGFBR1-rs10512263) having an OR=1.76; 95% CI: 1.14-2.43 (P = 0.008) per additional minor allele. For risk of biochemical recurrence, seven SNPs were nominally statistical significant (TGFBR1- rs10739778; TGFBR2- rs12493607, rs2082224, rs1346907, rs1431131, rs1835538, rs11129421) with TGFBR2- rs12493607 associated with a HR=1.40; 95% CI: 1.14-1.71; P=0.001 per additional minor allele.

Conclusion: Our study suggests that genetic variation in the TGF-β pathway may be associated with risk of aggressive prostate cancer and biochemical recurrence. Future work will evaluate the cumulative and interactive effects of the associations within this pathway on prostate cancer risk and recurrence.

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 2832.
Abstract 2834: Genetic variants in TGFβ pathway genes and ovarian cancer risk
Authors: Wu Lei , Lu Karen , Pu Xia , Meyer Larissa , Ye Yuanqing , Wu Xifeng , Liang Dong
Published: February 2011

The transforming growth factor (TGF) β signaling pathway plays a crucial role in cell proliferation, differentiation, apoptosis, extracellular matrix production and other cellular functions. Dysregulation and genetic variations of major genes in this pathway may be involved in the process of carcinogenesis. In this study, 218 single nucleotide polymorphisms (SNPs) in 21 major genes of TGFβ pathway were genotyped in 339 Caucasian ovarian cancer cases and 349 age, gender, and ethnicity matched controls. We analyzed the association between these SNPs and the risk as well as clinical outcomes of ovarian cancer. In the risk analysis, 16 SNPs were found significantly associated with ovarian risk, among these SNPs, a dose-response effect of increased risk for ovarian cancer with increased unfavorable genotype (UFG: defined as the allele related with increased ovarian risk) was observed (P for trend < 0.0001). Compared with individuals carrying ≤ 6 UFGs, subjects carrying ≥ 9 UFGs conferred a 3.7-fold increased risk of ovarian cancer (ORs =3.71, 95%CI=2.52-5.45, P<0.0001). The most significant individual association was found for INHBC: rs2228225. Patients carrying at least one variant allele of this SNP conferred 63% increased risk for ovarian cancer (OR = 1.63, 95%CI= 1.20-2.22, P=0.0018). Potential high-order gene-gene interactions were identified using the classification and regression tree analysis (CART). Eight terminal nodes were identified representing eight groups of patients with different probability for ovarian cancer (ORs ranging from 2.87 to 6.68). In the analysis of clinical outcomes, 13 SNPs were significantly associated with the risk of death. The top two SNPs were from BMP1. Patients carried rare homozygous genotype of either one of the SNP has a nearly two-fold increased risk for death (rs3857979: HR= 1.80, 95%CI= 1.23- 2.65, P=0.0026; rs4075478: HR=1.89, 95%CI=1.22- 2.91, P=0.004). A cumulative effect was also observed (P for trend < 0.0001). The median survival times decreased from 83.3 months for patients with ≤5UFGs to 26.8 months for those with ≥ 9UFGs (log rank P < 0.0001). Survival tree analysis identified eight terminal nodes representing eight groups of patients with different survival probability. Interestingly, the two BPM1 SNPs that were most significant in survival analysis were also significantly associated with poor response for chemotherapy (rs3857979: OR= 1.90, 95%CI= 1.04-3.48, P=0.0375; rs4075478: HR=2.39, 95%CI=1.17-4.86, P=0.0166), indicating that these two SNPs were predictive markers for response. In conclusion, our result demonstrates that genetic variations within TGFβ pathway may have modulate the risk and clinical outcomes of ovarian 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 2834.
Abstract 2836: Association between the hypoxia inducible factor-1α polymorphisms and the tumor size of oral squamous cell carcinoma
Authors: Shieh Tzong-Ming
Published: February 2011

Oral squamous cell carcinoma (OSCC) is a common malignancy. The incidence of OSCC is particularly high in some Asian countries due to the popularity of areca chewing habit. Hypoxia inducible factor-1α (HIF-1α) is up-regulated in hypoxic microenvironment to enhance tumor survival. There are five polymorphisms being identified in exon 12 of HIF-1α including C1772T polymorphism causing P582S, and G1790A polymorphism causing A588T of HIF-1α protein. This study investigated the relationship between these functional polymorphisms and the risk or progression of OSCC. PCR and direct sequencing were utilized to compare genotypic polymorphic and allelic frequency of HIF-1α in 96 normal controls and 305 OSCC patients. No statistically significant difference in C1772T and G1790A genotypes and allelic frequency lying between control and OSCC patients was found. However, multivariate analysis indicated that the A carrier of HIF-1α G1790A in OSCC patients was significantly higher in larger tumor than the contrasting group with an adjusted odd's ratio of 2.92. The findings may suggest a potential of HIF-1α G1790A polymorphism in the growth of OSCC.

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 2836.
Abstract 2837: Diverse associations between ESR1 polymorphisms and breast cancer development and progression
Authors: DING Shian-Ling , Yu Jyh-Cherng , Chen Shou-Tung , Chen Shou-Tung , Hsu Giu-Cheng , Wu Pei-Ei , Shen Chen-Yang
Published: February 2011

Purpose: To test the hypothesis that polymorphisms of ESR1, encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer.

Patients and Methods: A case-control study was performed on 940 patients with incident breast cancer and 1547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNPs) tagging all major polymorphisms of this gene were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility, and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression.

Results. Three SNPs, located in one cluster in intron 1, were found to be important and the variant alleles showed a significant association with a decreased breast cancer risk and, coincidently, with low ERα expression in tumors. The tumorigenic contribution of these intron-1 SNPs was more obvious in combination with reproductive risk factors (p for interaction<0.05). Interestingly, the same SNPs showed a significant correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the five-year survival rate of all patients, but had opposite effects in ERα-negative and ERα-positive early-stage patients.

Conclusions: Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERα in these two 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 2837.
Abstract 284: FGFR2 is required for growth and survival in a rare subset of FGFR2 amplified colorectal cancer
Authors: Mathur Anjili , Davis Lenora , Bacco Alessandra Di , Gazdar Adi , Lutterbach Bart
Published: February 2011

FGFR2 amplification has been reported in subsets of gastric cancer and breast cancer. We describe FGFR2 amplification in a cell line derived from a colorectal carcinoma arising in a young patient with ulcerative colitis. The cell line has features of endocrine differentiation, representing a rare (< 1%) subset of colorectal cancer. FGFR2 amplification in this cell line results in an overexpressed and highly activated FGFR2 kinase. The FGFR selective inhibitor PD173074 blocked FGFR2 phosphorylation and inhibited Erk, Akt, and S6 ribosomal protein phosphorylation. FGFR2 inhibition resulted in profound cell death as measured by robust accumulation of cells in subG1 by flow cytometry and PARP cleavage by western analysis. A structurally unrelated FGFR2 inhibitor, MK2461, also caused cell death and inhibited downstream signaling pathways. RTK arrays revealed coactivation of EGFR family kinases, and a functional role for these kinases is being investigated. Interestingly, an FGFR2 isoform in this cell line migrated at 160kD, in contrast to the 140kD isoform observed in SNU16 and other cell lines. However, C-terminal FGFR2 antibodies did not react with the 160kD FGFR2 isoform, suggesting that it has a C-terminal deletion similar to the FGFR2 isoform in OCUM2M and KatoIII cell lines. We are currently defining the frequency of FGFR2 overexpression and activation in colon cancer tissue microarrays. The strong growth inhibition and induction of cell death observed in vitro suggests that colorectal cancer tumor cells harboring FGFR2 amplification / activation may show similar response to FGFR inhibitor 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 284.
Abstract 2841: A SNP in the 3′-UTR of the MDMX gene is strongly correlated with decreased overall and disease-free survival in ovarian carcinoma patients in an estrogen-receptor-dependent manner
Authors: Boehnke Anja , Wynendale Jessica , Lambertz Irina , Wolf Anja , Hammer Stefanie , Gradhand Elise , Balschun Katharina , Hauptmann Steffen , Marine Jean-Christophe , Bartel Frank
Published: February 2011

The tumor suppressor p53 is inactivated in the vast majority of cancers, either by mutations of the p53 gene itself or by alterations of p53-regulating factors. The MDM2 homologue, MDMX, is another critical negative regulator of p53. Only a few data exist so far, demonstrating the clinical importance of SNPs in the MDMX gene. The aim of our study was therefore to perform sequencing analyses to identify mutations and/or SNPs in the MDMX gene. A single nucleotide polymorphism (A/C) was identified in the 3′-UTR, 31 bp downstream of the stop codon (SNP34091; rs4245739). In high-grade carcinomas, we found the SNP at a relatively high frequency in the wild-type (A/A) state (62.5%) and in 36% in the heterozygous (A/C) state compared with low-grade carcinomas (45.5%, 45.5%, respectively). The A-allele was associated with increased expression of the full-length MDMX-mRNA. Furthermore, tumors of females who were homozygous for the A-allele showed an increased expression of the MDMX protein. By Cox-regression analysis we found that in estrogen receptor negative tumors the A-allele of SNP34091 was strongly associated with an increased risk of recurrence (RR=8.2; p=0.009) and decreased overall survival time (RR=6.7; p=0.014). According to miRNA-databases the SNP34091 of the MDMX gene is a potential target of miR-191 if the C-allele is present. Therefore, we subsequently analyzed the impact of miR-191 on MDMX expression. We found that mimics of miR-191 resulted in a significantly decrease of MDMX protein levels in C/C ovarian carcinoma cells (Efo-21) but not in cells homozygous for the A-allele (OAW-42). Since MDMX-mRNA levels remained unchanged after transfection, we suggest that miR-191 blocks translation of the MDMX-mRNA and does not lead to its destabilization. These data show that the A-allele increases translation of the MDMX-mRNA which in turn results in a weakened p53-tumor suppressor pathway.

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 2841.
Abstract 2844: Association of genetic variants in TNFRSF10B and breast cancer
Authors: Abo Ryan P. , Parry Marina , Rigas Sushila H. , Cox Angela , Camp Nicola J.
Published: February 2011

Susceptibility to non-Mendelian forms of breast cancer likely involves many low penetrance variants from multiple genes. Recent associations between genetic variants in CASP8 and breast cancer suggest that CASP8 is one such gene contributing to breast cancer risk (Cox et al. 2007; Shephard et al. 2009). Here we investigate TNFRSF10B for associations with breast cancer. TNFRSF10B is a death receptor gene whose protein signals via caspase-8 in the extrinsic apoptosis pathway.

We selected 11 tagging-SNPs (tSNPs) to represent the majority of the common genetic variation in the TNFTRSF10B gene. These tSNPs were genotyped on 1,992 independent cases and controls from Sheffield, UK. We performed 11 single marker association analyses and a haplotype-mining analysis using hapConstructor (Abo et al. 2008). HapConstructor implements a stepwise forward-backward procedure to search for haplotypes associated with disease. The algorithm allows for automatic consideration of non-contiguous SNP sets and the construction of numerous different genetic models that consider haplotypes, composite genotypes, and both monotype (chromosome-based) and diplotype (individual-based) tests. Briefly, all single locus tests are performed, then loci that surpass predefined significance thresholds are considered in all two-locus combinations, and so on.

For the single marker association testing, dominant, recessive, and trend tests were performed. For the hapConstructor analysis, monotype haplotype tests and diplotype dominant and recessive tests were considered. HapConstructor is implemented within a Monte Carlo testing framework, with all p-values estimated empirically from 100,000 simulations under the null.

Seven SNPs reached nominal significance in at least one of the association tests performed in the single SNP tests. Five of these were based on a recessive model (most significant single SNP yielded p = 0.002). Using hapConstructor, the most significant finding was a 4-SNP haplotype that was associated with an increase of risk (p=0.0006; OR=1.75). Four haplotypes were also identified that were associated with a decrease in risk and each obtained the same level of significance and risk (p=0.00096; OR=0.35). These results for reduced risk were obtained using the diplotype recessive model, similar to the single SNP findings. These results provide initial evidence that further common genetic variants in genes in the extrinsic apoptosis pathway, beyond CASP8, are involved in breast cancer 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 2844.
Abstract 2861: Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice
Authors: Yasuda Yoichi , Shimizu Masahito , Sakai Hiroyasu , Kubota Masaya , Tanaka Takuji , Moriwaki Hisataka
Published: February 2011

Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in this carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, β-catenin accumulated crypts, by inhibiting their proliferation and surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, TNF-α and leptin. In addition, pitavastatin caused a significant decrease in the expression of TNF-α, IL-6, IL-18 and COX-2 mRNAs on the colonic mucosa of AOM-treated mice. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statin, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals.

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 2861.
Abstract 2868: EGCG inhibits pancreatic cancer growth in xenografts and KrasG12D transgenic mice models
Authors: Marsh Luke , Shankar Sharmila , Srivastava Rakesh K.
Published: February 2011

FoxO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FoxO proteins relies on their ability to control diverse functions such as proliferation, differentiation, DNA repair and apoptosis. Constitutively active AKT and ERK in cancer cells have been shown to phosphorylate FoxO transcription factors (FKHR, FKHRL1 and AFX), which bind to protein 14-3-3 and sequester in the cytoplasm. In the absence of survival signals, FoxO proteins dephosphorylate, translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest and apoptosis. EGCG, a component of green tea, exerts antiproliferative and proapoptotic actions on a number of different cancer cell lines through diverse mechanisms. However, the mechanisms by which EGCG inhibits cell proliferation and induces apoptosis are poorly understood. EGCG inhibited viability and induced apoptosis in human pancreatic cancer cell lines. EGCG induces PTEN expression and inhibits Akt phosphorylation in pancreatic cancer Hs766T, AsPC-1, MIA PaCa-2 and PANC-1 cells. Treatment of PANC-1 cells with EGCG caused a decrease in ERK phosphorylation, and an increase in JNK phosphorylation. Overexpression of FOXO1, FOXO3a, and FOXO4 inhibited cell viability in PANC-1 cells. The inhibitory effects of EGCG on cell viability were further enhanced when cells were transfected with FOXO1, FOXO3a, and FOXO4. EGCG enhances FOXO-DNA binding activity. EGCG-induced FOXO transcriptional activity was further enhanced in the presence of FOXO1-TM, FOXO3a-TM, and FOXO4-TM. Interestingly, EGCG inhibited pancreatic cancer growth in xenograft, orthotopic and KrasG12D transgenic mice models. In conclusion, our data demonstrate that EGCG can inhibit pancreatic cancer growth through multiple mechanisms and thus can be used for the pancreatic cancer prevention.

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 2868.