bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1642: Rare missense variants in MAP3K14 and ARHGAP27 in men with hereditary prostate cancer
Authors: Ishak Miriam B. , Ray Anna M. , Robbins Christiane M. , Tembe Waibhav D. , Carpten John D. , Lange Ethan M. , Isaacs William B. , Cooney Kathleen A.
Published: August 2012

Background: Linkage studies have consistently identified the 17q21-22 chromosomal region to be important in hereditary prostate cancer, although no known causal variant has yet been identified. Three genes in this region are potential candidates based on known function as well as location in our region of interest. Mitogen-activated protein kinase kinase kinase 14 (MAP3k14) encodes a serine-threonine protein kinase that stimulates NF-κβ activity. The ARHGAP27 gene codes for a Rho-like small GTPase-activating protein and RND2 is part of the Rho GTPase family implicated in endosomal trafficking. Methods: All exons within the 17q21-22 chromosomal region were interrogated in 94 probands from hereditary prostate cancer families and linkage to the 17q21-22 region. Participants were from the University of Michigan Prostate Cancer Genetics Project and Johns Hopkins University. Enrichment was performed using the RainDance Technology following an emulsion PCR protocol. Sequencing was performed on the ABI SOLiD platform. Confirmation of mutation status among family members (both affected and unaffected) was performed using Sanger sequencing. Results: No deleterious truncating mutations were detected in the three candidate genes. Although missense variants were not observed in RND2, five missense variants were identified in the MAP3k14 and ARHGAP27 genes. Four of the five variants are novel (not described in dbSNP) and four out of the five variants are predicted to be damaging on protein function by SIFT and/or PolyPhen. Several of these variants demonstrated evidence of cosegregation within families based on sequencing of family members. Conclusions: We have identified five missense variants in MAP3k14 and ARHGAP27 in men with hereditary prostate cancer. Further research is ongoing in the laboratory to determine the frequency of these variants in a large prostate cancer case-control study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1642. doi:1538-7445.AM2012-1642
Abstract 1645: Genome-wide association studies identify several new loci for human pigmentation traits
Authors: Zhang Mingfeng , Queshi Abrar , Zhang Jiangwen , Liang Liming , Han Jiali
Published: August 2012

Genome-wide association studies (GWASs) have been widely conducted and numerous new loci have been associated with various outcomes. Multiple GWASs have been completed in the Nurses’ Health Study and the Health Professionals Follow-up Study, and we have accrued more than 15,000 individuals with genome-wide genotype data. More recently, with the data released from the 1000 Genomes Project, we have imputed about 10 million SNPs based on the genotyped SNPs and haplotypes from the 1000 Genomes Project. Based on the knowledge that light human pigmentation is a host risk factor for skin cancer development, we conducted the GWASs on pigmentary traits in multiple GWAS datasets in the two cohorts using the newly imputed data. We systematically evaluated the traits of natural hair color (ordinal coding from blonde, light brown, dark brown to black, excluding red hair color), eye colors (blue, green and brown eye colors as co-dominant outcomes), tanning ability (ordinal coding from practically no tan, moderate tan to deep tan) and the number of sunburns (continuous variable). We adjusted for the four largest principal components of genetic variation in the regression model for each component dataset, and performed a meta-analysis to combine the results of all these datasets. No systematic deviation from the expected distribution was detected for any of these pigmentation GWASs. Using a multistage study design, we identified a new region on chromosome 13q22 associated with natural hair color that reached the GWAS significance level. The most significant SNP in this region reached a p-value of 2.4 ×10−14 (p = 5.4×10−9 in the discovery stage and p = 1.2×10−6 in the replication stage). We also newly identified and replicated the association of a SNP on 1q32.3 with brown eye color (p = 7.0×10−8 in the combined set), a SNP on 5p15 with green eye color (p = 9.1×10−7 in the combined set), and a SNP on 11q25 with the number of sunburns (p = 5.6×10−6 in the combined set). Of note, the SNP associated with the number of sunburns was also associated with the expression of a local gene based on the transcript expression profiling data of 87 HapMap CEU cell lines (NCBI GEO database, accession GSE7792). These novel pigmentation SNPs identified by our GWASs are strong candidates to evaluate skin cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1645. doi:1538-7445.AM2012-1645
Abstract 1647: Evaluation of breast cancer susceptibility loci in Chinese women from Singapore
Authors: Chan Maurice , Ji Shen Mo , Liaw Chiew Suan , Yap Yoon Sim , Law Hai Yang , Yoon Chui Sheun , Wong Chow Yin , Ong Kong Wee , Madhukumar Preetha , Wong Nan Soon , Ng Raymond , Yong Wei Sean , Li Hui Hua , Tan Puay Hoon , Ho Gay Hui , Ang Peter , Lee Ann SG
Published: August 2012

Genome-wide association studies (GWAS) have identified several breast cancer susceptibility loci associated with European populations, some of which were also found to be associated with breast cancer among women in China. Women in Singapore are predominantly of Chinese ancestry with an urbanized lifestyle, with breast cancer rates approaching those of the West. To explore the role of these breast cancer susceptibility variants, a Taqman-based microfluidics strategy was established to carry out fast track replication of 22 SNPs for 1,146 cases and 1,534 controls to identify significant risk variants for breast cancer. Interestingly, the most significant SNP [rs2046210; odds ratio (OR), 1.4; 95% confidence interval, 1.2-1.6; P=7x10−6], residing in 6q25.1, had been initially identified in a Chinese population, suggesting a strong and consistent association of this SNP with Chinese ancestry. SNPs in FGFR2 (rs2981579, rs1219648, rs2981582, rs112000014), 8q24 (rs13281615), and MAP3K1 (rs16886165) showed significant associations similar to those observed in women of European ancestry, with ORs ranging from 1.1 to 1.7 (P=5x10−5 to 0.04). Ranking of the SNPs in terms of their ORs for Singaporean Chinese women was compared to that from Western and Chinese studies. The ranking for Singaporean Chinese women resembled, but was not identical to, that of women in China, reflecting the effect of ethnicity. Comprehensive annotation of the genotyping data with associated clinicopathological features enabled the identification of significant SNPs associated with tumour size, lymph node metastasis, and estrogen/progesterone receptor status. Findings from this study implicate 6q25.1 and FGFR2 as the most important susceptibility loci for Asian women of Chinese ancestry and may guide future fine-mapping studies to identify causal variants.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1647. doi:1538-7445.AM2012-1647
Abstract 1648: MICA variation and soluble MICA are possible prognostic biomarkers for HBV-induced hepatocellular carcinoma
Authors: Matsuda Koichi , Kumar Vinod , Nakamura Yusuke
Published: August 2012

Hepatitis B virus (HBV) infection still remains to be one of the dominant risk factor for hepatocellular carcinoma (HCC). Both genetic as well as environmental factors influence the progression of chronic hepatitis B (CHB) to HCC. MHC class I polypeptide-related chain A and B (MICA and MICB) molecules are induced in response to viral infection as well as various stresses. We have recently revealed that SNP in MICA promoter was significantly associated with HCV-induced HCC risk as well as lower sMICA level in serum. To investigate the possible involvement of MICA in hepatocellular carcinogenesis caused by HBV-infection, we analyzed MICA gene polymorphisms and the levels of soluble MICA (sMICA) in HBV-induced HCC patients. The genetic association analysis revealed a nominal association at rs2596542 in which G allele was associated with susceptibility to HBV-induced HCC (P=0.029 with odds ratio of 1.19). We also found a significant elevation of sMICA in HBV-induced HCC cases. Moreover, genotypes at SNP rs2596542 located in the upstream of MICA promoter, was significantly associated with sMICA levels (P = 0.009). Interestingly. HCC patients with high sMICA (> 5 pg/ml) exhibited poor prognosis compared with patients with low sMICA (P = 0.008). Thus, our results highlight the importance of MICA genetic variations and sMICA as predictive biomarkers for HBV-induced HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1648. doi:1538-7445.AM2012-1648
Abstract 1657: Genome-wide association study of lung cancer: Variation in TP63 gene confers the risk of lung adenocarcinoma
Authors: Daigo Yataro , Nakamura Yusuke
Published: August 2012

Lung cancer is the most common cause of death from cancer worldwide, and its incidence is increasing in East Asian and Western countries. Lung cancer comprises various types of histology that are often divided into two main types, non-small cell lung cancer and small cell lung cancer. Each type has different pathophysiological and clinical features, suggesting that their mechanisms of carcinogenesis differ. Adencarcinoma accounts for about 50% of all histological types of lung cancer, and its incidence is increasing in East Asian and Western countries. Because most of the current genome-wide association studies (GWAS) on lung cancer have been conducted in European populations with a full range of different histological types of lung cancer, GWAS that focus on individual histological groups with archived clinicopathological features are required. To identify genetic factors that modify the risk of lung adenocarcinoma, we conducted a genome-wide association study in a Japanese cohort, with replication in two independent studies in Japanese and Korean individuals, in a total of 2,098 lung adenocarcinoma cases and 11,048 controls. The combined analyses identified two susceptibility loci for lung adenocarcinoma: TERT (rs2736100, combined P = 2.91 × 10(-11), odds ratio (OR) = 1.27) and TP63 (rs10937405, combined P = 7.26 × 10(-12), OR = 1.31). When we analyzed the combinational combined effect of TP63 and TERT, we found that these two susceptibility genes showed a synergistic effect on the risk of lung adenocarcinoma (OR = 4.26). Fine mapping and re-sequencing of the region containing TP63 showed that a SNP (rs4488809) in intron 1 of TP63 showed the most significant association. Our results suggest that genetic variation in TP63 may influence susceptibility to lung adenocarcinoma in East Asian populations. Further functional studies are necessary to clarify the mechanisms by which TP63 influences susceptibility to lung adenocarcinoma. We will also report additional studies of TP63 on other ethnic populations as well as other histological types of lung cancer that will provide detailed information on the genetic etiology and heterogeneity of lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1657. doi:1538-7445.AM2012-1657
Abstract 1658: Post-GWAS genetic and functional studies for bladder cancer: An uncommon protective synonymous coding variant within the UGT1A6 gene explains the GWAS signal and affects cellular detoxification
Authors: Tang Wei , Fu Yi-Ping , Figueroa Jonine D. , Malats Nuria , Garcia-Closas Montserrat , Chatterjee Nilanjan , Kogevinas Manolis , Chanock Stephen J. , Silverman Debra T. , Rothman Nathaniel , Prokunina-Olsson Ludmila
Published: August 2012

Background: A recent genome-wide association study (GWAS) of bladder cancer identified a single nucleotide polymorphism (SNP), rs11892031, within the UGT1A gene cluster on chromosome 2q37.1, as a novel risk factor. UGT1A locus encodes nine UGT proteins that belong to phase II cellular detoxification system. UGTs are functionally important for detoxification of aromatic amines, which are known risk factors for bladder cancer found in industrial chemicals and tobacco smoke. UGTs are composed of shared exons 2-5 and individual alternative first exons that define enzymatic activity and substrate specificity. Materials and results: We sequenced all nine highly similar alternative first exons of UGT genes in more than 2,000 individuals and identified 27 non-synonymous and 19 synonymous known coding variants, but no novel variants. Imputation based on the GWAS dataset, a combined reference panel of HapMap 3 and 1000 Genomes Projects, and a subset of GWAS samples genotyped for all the identified coding variants, generated data for 1,170 SNPs within the whole UGT region. Of these markers, the strongest association was detected for an uncommon (MAF<0.03) protective genetic variant rs17863783 (OR=0.55, 95%CI=0.44-0.69, p=3.3x10-7 in 4,035 cases and 5, 284 controls; D’=0.96, r2=0.23 with rs11892031). No residual association in this region was detected after adjustment for rs17863783. Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Conclusions: Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease such as bladder cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1658. doi:1538-7445.AM2012-1658
Abstract 1659: Evaluation of microRNA expression profiles and their associations with risk alleles in lymphoblastoid cell lines of familial ovarian cancer
Authors: Shen Jie , Wang Dan , Gregory Steven , Medico Leo , Hu Qiang , Lele Shashikant , Odunsi Kunle , Ambrosone Christine , Liu Song , Zhao Hua
Published: August 2012

Interindividual variations of microRNA expression are likely to influence the expression of microRNA target genes, and therefore, contribute to phenotypic differences in humans, including cancer susceptibility. Whether microRNA expression variation has any role in ovarian cancer development is still unknown. Here we evaluated microRNA expression profiles in lymphoblastoid cell lines (LCLs) from 74 women with familial ovarian cancer and 47 controls. We found that microRNA expression profiles in the LCLs of the cases were significantly different from that in the controls with 91% accuracy by 95 differentially expressed microRNAs. To assess the potential implications of microRNAs in ovarian cancer, we investigated the associations between microRNA expression and ovarian cancer risk alleles discovered from genome wide association studies. We observed 130 significant associations at a permutation level of 0.01. Compared to other risk variants, rs3814113 and rs2072590 had the greatest number of significant associations (68 and 37, respectively). Interestingly, 14 microRNAs which were associated with ovarian cancer risk alleles belong to 5 microRNA clusters. The most notable cluster is the tumorigenic miR-17-92 cluster with 5 microRNAs, all of which are significantly associated with rs3814113. Using pathway analysis, several key biological pathways were significantly overrepresented, such as cellular response to stress (P=2.87x10−06), etc. Our results indicate that microRNA expression profiles in LCLs can serve as potential detection biomarkers for familial ovarian cancer. Further characterization of significant associations between microRNAs and risk alleles could facilitate the understanding of the functions of these GWAS discovered risk alleles in the genetic etiology of ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1659. doi:1538-7445.AM2012-1659
Abstract 166: A novel therapeutic approach for triple negative breast cancer
Authors: Boopalan Thiyagarajan , Arumugam Arunkumar , Suman Suman , Das Trinath P. , Damodaran Chendil , Lakshmanaswamy Rajkumar
Published: August 2012

Triple negative breast cancers (TNBCs) are defined as tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (EGFR2). TNBCs account for 15-20% of all breast tumors. These breast tumors are usually aggressive and have a specific molecular profile. Unfortunately, treatment options for TNBCs are limited, leading to a poor prognosis and high mortality rates. Thus, novel therapeutic approaches are needed to treat TNBCs. To date, several molecular targets have been identified (e.g., PARP, EGFR, mTOR, Akt, and BRAC-1). Moreover, many pre-clinical and clinical trials are underway to determine the efficacy of specific inhibitors against these molecular targets, used either alone or in combination with chemotherapeutic agents. So far, these trials have failed to produce significant promising results. Hence, our goal is to identify novel therapeutic agents that specifically target breast tumor cells, especially TNBCs, without causing toxicity to normal cells. Our studies identified nimbolide as a novel therapeutic agent. Nimbolide is a major bioactive compound derived from the Azadirachta indica (Neem) leaves, which is well-known medicinal plant having a wide spectrum of biological activities. In our studies, nimbolide targeted TNBC cells without causing toxicity to normal primary breast epithelial cells. We also explored the molecular mechanism underlying the anti-cancer effect of nimbolide on TNBC cells and found that nimbolide, simultaneously inhibited phosphorylation of Akt mediates pro-survival signaling. In addition, downstream signaling by mTOR and NF-kappa-B was down regulated by nimbolide which resulted in the induction of pJNK and pc-Jun mediated pro-apoptotic signaling and apoptosis in TNBC cells. These changes in the pro and anti-apoptotic molecular circuits also inhibited migration and invasion properties of TNBC cells. Altogether, our results strongly suggest that nimbolide could be a potent compound for the prevention and/or treatment of TNBC. Our ongoing in vivo studies may reveal the in vivo efficacy of nimbolide and toxicity to other organs or cells if any.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 166. doi:1538-7445.AM2012-166
Abstract 1661: Fine-mapping of GWAS variants in BMP4, GREM1, CDH1, and RHPN2 in African American colorectal cancer patients
Authors: Kupfer Sonia , Ludvik Anton E. , Hong Ellie , Hooker Stanley , Kittles Rick , Keku Temitope , Sandler Robert , Ellis Nathan A.
Published: August 2012

Background: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified risk variants in candidate genes involved in TGF-ß signaling including BMP4, GREM1, CDH1, RHPN2 and SMAD7. We previously replicated the association with a 3′-UTR SNP in GREM1 (rs10318) in African Americans but did not find evidence of associations in the other genes. This finding could be explained by different genomic structure in African Americans. Therefore, we sought to fine-map these genes to identify CRC risk variants in African Americans who are at highest risk of CRC in the US. Methods: DNA from cases and controls was obtained from two US institutions. In total, we included DNA from 795 AA cases and 985 AA controls. TagSNPs with minor allele frequencies >5% and pairwise r2 >0.8 were identified in five genes using YRI Hapmap data. A total of 81 SNPs were genotyped in cases and controls using Sequenom MassARRAY. We calculated odds ratios and 95% confidence intervals using logistic regression controlling for ancestry, age, gender and multiple testing in PLINK. Results: Association analysis was completed for four genes: BMP4, GREM1, CDH1 and RHPN2. The top tagSNP associations for each gene are shown in the Table. None of the SNPs were significant after permutation testing. In GREM1, the strongest SNP associations were found at the 3′ end of the gene. In BMP4, we identified two SNPs (rs1957852 and rs7146040) that are in LD with rs4444235 previously identified in a European GWAS. In CDH1, rs12931189 is located in the same LD block as the strongest association signal (rs7199991) in a recent fine-mapping study in Europeans. Finally, we have no evidence for associations in RHPN2 in African Americans. Conclusion: These results provide preliminary evidence of associations in African American colorectal cancer patients in BMP4, GREM1 and CDH1 identified by GWAS in Europeans. Ongoing work is testing associations in SMAD7 and further fine-mapping by imputation and resequencing in these regions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1661. doi:1538-7445.AM2012-1661
Abstract 1665: High resolution genome profile in familial colorectal cases without mutations on mismatch repair genes
Authors: Villacis Rolando AR , Abreu Francine B. , Santos Érika MM , Rossi Benedito M. , Carraro Dirce M. , Kowalski Luiz P. , Rogatto Silvia R.
Published: August 2012

Colorectal cancer (CRC) represents the fourth leading cause of cancer mortality. Approximately 30% of all CRC cases have a hereditary component, but only 5% are associated with inherited mutations in known genes. The most common hereditary syndrome of CRC is the Lynch syndrome (LS) and is caused by mutations in mismatch repair genes, mainly MLH1 and MSH2. In ∼50% of families classified with the Amsterdam criteria not show germline mutations in mismatch repair genes, suggesting that other genetic factors are associated with predisposition to CRC. In this study, it was evaluated germline copy number alterations (CNAs) in 57 LS patients without pathogenic mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS1 and PMS2), as well as in CHEK2 and TP53, by array comparative genomic hybridization (aCGH) using a platform of 4x180K (Agilent). Genomic data were extracted with Feature Extraction software and analyzed using Nexus 6.0 software, statistical algorithm FASST2 Segmentation and sensitivity threshold of 5.0E-6. The aCGH data showed a total of 361 CNAs (in average, 6.3±3.8 CNA/individual) including 144 gains and 217 genomic losses. After the comparison with a reference dataset obtained from 100 healthy Brazilian individuals (Krepischi et al, 2011; personal communication) and exclusion of the CNAs detected in more than 5% of this reference dataset, it was identified ∼100 rare CNAs. Most of them were detected in only one case, however, six CNAs were common at least in five cases: 1p11.2, 1p36.32, 7p22.3, 8q24.3, 9p11.2 and 18q11.1. The ROCK1 gene, mapped on 18q11.1, was found as involved in nine cases (three losses and six gains). This gene was associated with carcinogenesis and progression of human tumors, including colon cancer (Nakashima et al, Int J Oncol. 36:585, 2010). Amplification on 7p22.3 (5 cases), where is mapped the homeobox gene UNCX, a transcription factor involved in somitogenesis and neurogenesis. Mutations in rare constitutional CNAs may affect genes or major pathways associated with cancer, offering an explanation for families with high cancer risk. In CRC, the large scale analysis of germline CNAs in patients and their relatives can allow the identification of new genes involved in tumor predisposition. Financial support: FAPESP and CNPq

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1665. doi:1538-7445.AM2012-1665
Abstract 1666: Mitochondrial DNA sequence mutations and risk of pancreatic cancer
Authors: Tranah Gregory J. , Lam Ernest T. , Bracci Paige M. , Holly Elizabeth A.
Published: August 2012

Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases=286, controls=283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (p<0.05) with the strongest finding for mt5460g in the ND2 gene (odds ratio (OR)=3.9, 95% confidence interval (CI)=1.5-10; p=0.004) which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32, CI=0.13-0.76; p=0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (p<0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (p=0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1666. doi:1538-7445.AM2012-1666
Abstract 167: Myricetin suppresses UVB-induced photoaging, skin cancer, and angiogenesis by targeting multiple kinases
Authors: Jung Sung Keun , Lee Ki Won , Bode Ann M. , Lee Hyong Joo , Dong Zigang
Published: August 2012

Chronic exposure to solar ultraviolet is a major cause of photoaging and skin carcinogenesis. In the present study, we investigated the effect of myricetin on UVB-induced photoaging, skin cancer, and angiogenesis in JB6 P+ cells and a mouse skin tumorigenesis model. Myricetin inhibited wrinkle formation induced by UVB irradiation (0.18 J/cm2, 3 days/week for 15 weeks) in mouse skin. Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. In vitro and in vivo pull-down and kinase assays revealed that myricetin suppressed Raf activity by binding with Raf. Secondly, myricetin suppressed UVB-induced COX-2 expression and mitogen-activated protein kinases in JB6 P+ cells and mouse skin. Pull-down and kinase assay results showed that myricetin directly inhibited UVB-induced Fyn kinase activity by binding with Fyn in an ATP-competitive manner. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Topical treatment with myricetin suppressed repetitive UVB-induced neovascularization in the SKH-1 hairless mouse skin. The induction of vascular endothelial growth factor, matrix metalloproteinase (MMP)-9 and MMP-13 expression by chronic UVB irradiation was substantially suppressed by myricetin treatment. Immunohistochemical and Western blot analyses revealed that myricetin attenuated UVB-induced hypoxia inducible factor-1alpha expression in mouse skin. In vivo kinase and pull down assay data revealed that myricetin suppressed UVB-induced phosphatidylinositol 3 (PI3)-kinase activity by direct binding with PI3-kinase. Overall, together these results suggest that the anti-photoaging, anti-skin carcinogenesis, and anti-angiogenesis effects of myricetin are due to mainly targeting Raf, Fyn, and PI3-K, respectively.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 167. doi:1538-7445.AM2012-167
Abstract 1674: Two phase study of KCNJ1 polymorphisms, calcium, magnesium and colorectal adenoma risk, results from the Tennessee Colorectal Polyp Study
Authors: Zhu Xiangzhu , Shrubsole Martha J. , Ness Reid M. , Cai Qiuyin , Long Jirong , Chen Zhi , Deng Xinqing , Smalley Walter E. , Edwards Todd , Zheng Wei , Dai Qi
Published: August 2012

Background: Previous studies generated inconsistent results on the associations between intakes of calcium and magnesium with risk of colorectal adenoma and cancer. It is possible that some of the inconsistency is due to a modifying effect by genetic polymorphisms involved in calcium and magnesium homeostasis. The KCNJ1 gene encodes the Inward-rectifier potassium channel (ROMK). ROMK plays an essential role in the homeostasis of potassium, which is critical for the reabsorption of calcium and magnesium. Objectives: We hypothesize that common variants in KCNJ1 may modify the associations between intakes of calcium and/or magnesium and risk of colorectal adenoma risk. Methods: Included were participants of the Tennessee Colorectal Polyp Study (TCPS), a colonoscopy-based case control study conducted in Nashville, TN. In the phase I study, genotyping was performed using the Affymetrix Human Mapping 500K array set in 958 colorectal adenoma cases and 909 controls and 13 tagging single-nucleotide polymorphisms (SNPs) in the KCNJ1 gene were evaluated. SNPs identified as significant in phase I were genotyped in phase II in an independent set (860 cases and 3083 controls). Results: In phase I, 1 tagging SNP was significantly associated with adenoma risk and 8 SNPs were interacted significantly with calcium or magnesium intake in risk of colorectal adenoma. In phase II, only 1 of the 9 SNPs significantly interacted with calcium and magnesium intakes in relation to colorectal adenoma although the genotype per se was not directly associated with the risk. In combined analysis, the p value for the interaction between the SNP and calcium intake was 0.00015 and it remained statistically significant after Bonferroni correction for multiple comparisons. In stratified analyses by levels of calcium and magnesium (above or below RDA levels), we found adenoma risk significantly increased for those who with at least 1 variant allele and whose intake levels of calcium and magnesium were below the RDA levels, with ORs (95% CI) of 1.35 (1.10, 1.67) and 1.43 (1.08, 1.89) respectively, compared to those who did not possess the variant allele. The corresponding ORs (95% CI) increased to 1.84 (1.33, 2.53) and 2.30 (1.53, 3.46), respectively, multiple adenomas versus controls. Conclusions: In this two-stage analysis, we found no overall association of adenoma with KCNJ1 genotype. However, common KCNJ1 variants significantly interacted with intakes of calcium and magnesium in risk of colorectal adenoma, particular for multiple adenomas.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1674. doi:1538-7445.AM2012-1674
Abstract 1681: Genetic ancestry distribution in basal-cell carcinoma cases and controls from Puerto Rico
Authors: Diaz-Zabala Hector , Dutil Julie , Matta Jaime
Published: August 2012

Introduction: The incidence and clinical presentation of Basal-cell carcinoma (BCC) vary among different ethnic subgroups. In the Hispanic population of Puerto Rico, the contribution of genetic ancestral factors in determining BCC risk and its clinical presentation is unknown. Methods: The study population consists of 83 BCC skin cancer cases and 89 controls recruited from a private dermatology practice in Ponce, Puerto Rico. A panel of 106 ancestry informative markers was genotyped using iPLEX Sequenom technology. Individual genetic ancestry was estimated using a maximum likelihood approach. The distribution of genetic ancestry was compared between cases and controls. Results: The distribution of genetic ancestry among the 172 study subjects varied from 0 to 89% African, 11 to 99% European, and 0 to 70% Native American. There was no significant difference in the average European (p= 0.891), African (p= 0.44) and Native American (p= 0.232) ancestry proportions between BCC cases and controls. Conclusions: Global genetic ancestry does not seem to contribute significantly to the risk of BCC in the Puerto Rican population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1681. doi:1538-7445.AM2012-1681
Abstract 1683: ALK F1174L kinase activity as driver of cell proliferation in neuroblastoma cell line models and neuroblastoma tumors
Authors: Hilhorst Riet , Hovestad Liesbeth , de Wijn Rik , Pijnenburg Dirk , Ruijtenbeek Rob , Schramm Alexander , Eggert Angelika , Schulte Johannes H.
Published: August 2012

Background. Whereas ALK translocations play a role in tumor growth in selected NSCLC cases, mutated forms of ALK have been shown to drive development of neuroblastoma, the most common malignant extracranial tumor of childhood. The mutation F1147L in the oncogene ALK increases the kinase activity, causing deregulated proliferation of sympatho-adrenal progenitor cells. We explored the use of kinase activity measurements to identify ALK activity in cell lysates and patient derived tissue lysates with the aim of identifying biomarkers to trace the activity of ALK in tumors and the effect of ALK inhibitors on these marker signals. Methods. Protein kinase activities were measured on PamChip® peptide microarrays comprising 144 Tyr containing peptide sequences from known human phosphorylation sites. The activity profiling experiments involved recombinant ALK kinase, lysates of cell lines overexpressing ALK and neuroblastoma tumors with elevated ALK F1174L presence. Per microarray analysis 5 ug of total protein was used in the presence of 100 uM ATP. Experiments were performed in the presence and absence of ALK kinase inhibitors crizotinib and NVP-TAE684. Real time kinetics of 144 peptide phosphorylations were measured with a fluorescently labeled antibody. Results. Phosphorylation profiles for neuroblastoma tumors, ALK overexpressing cell lines and recALK were generated. For recALK 48 novel peptide substrates were identified that showed signals depending on both ATP and kinase concentration and inhibition by the ALK inhibitors. In ALK overexpressing cell lines, but not in control cell lysates, signals on many ALK substrate peptides were significantly elevated, and returned to baseline level in the presence of ALK inhibitors. Whereas neuroblastomas with low ALK expression gave similar kinase activity profiles, the tumors harboring the ALK F1174L mutation were different, suggesting a more complex regulation of phosphorylation activity in these tumors. All tumors showed on-chip responses with ALK inhibitor drugs, but to different extent, which could be a basis for response prediction biomarker discovery. Conclusion. ALK activity of recombinant kinases, cell lysates and tumor lysates can be detected on PamChip® peptide microarrays. Based on results with model systems, this method shows promise to identify tumors that express elevated ALK activity and to study response of this class to ALK inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1683. doi:1538-7445.AM2012-1683
Abstract 1684: The potential role of HER3 on HER2-driven biliary carcinogenesis and the possibility for targeted therapy with pertuzumab
Authors: Kawamoto Toru , Onuki Ken-ichiro , Sugiyama Hiroaki , Thomas Melanie , Yamashita-Kashima Yoriko , Shu Sei , Harada Naoki , Fujimoto-Ouchi Kaori , Ariizumi Shun-ichi , Yamamoto Masakazu , Shoda Jun-ichi
Published: August 2012

HER2 has been implicated in biliary carcinogenesis, because gene amplification of HER2 has been observed in 20% of gallbladder carcinoma (GBC) (Kawamoto, et al. GCR 2007). The first-in-class HER2 dimerization inhibitor (HDI) pertuzumab is a humanized monoclonal antibody that binds HER2 at an epitope that prevents HER2 from dimerizing with ligand-activated HER family receptors, In this study, we determined the expression of HER family proteins in GBC, cholangiocellular carcinoma(CC), and examined whether treatment with pertuzumab would affect GBC and CC cell lines. Methods: HER family expression was examined in surgical or biopsied specimens from 47 GBCs and 57 CCs by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Using 6 GBC and 8 CC cell lines, heregulin-stimulated cell proliferation and its inhibition by pertuzumab, were tested in vitro by MTT assay. The phosphorylated HER family proteins and their respective downstream molecules were examined by Western blot analysis. Anti-tumor activity of pertuzumab in vivo was evaluated in the CC cell line KMCH-1 xenograft model with weekly intraperitoneal administration. Results: Over-expression of HER2 or HER3 was observed in 14-34% of all patients (Table 1). Six of 14 cell lines demonstrated over-expression of both HER2 and HER3, and heregulin stimulation increased the proliferation in 3 of them. In the HER2- and HER3- over-expressing KMCH-1, pertuzumab significantly inhibited cell proliferation in a dose-dependent manner. Pertuzumab completely blocked heregulin-induced phosphorylation of HER3. Furthermore, suppression of downstream pathway molecules including pAKT and pS6 were observed. The xenograft model also revealed tumor growth inhibition with pertuzumab. Conclusions: Pertuzumab demonstrated significant antitumor activities in HER2 and HER3 over-expressing cancer cells. Thus, pertuzumab may provide a new therapy option for both HER2- and HER3- positive GBC and CC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1684. doi:1538-7445.AM2012-1684
Abstract 1685: Ginsenoside compound K inhibits colorectal tumorigenesis via multiple pathways including ATM/p53-p21
Authors: Zhang Zhiyu , Du Guang-Jian , Wang Chong-Zhi , Li Zejuan , Yuan Chun-Su
Published: August 2012

To date, colorectal cancer (CRC) remains one of the most prevalent malignancies in the United States. Health benefits derived from medicinal plants have been investigated for years. Ginseng has been shown to induce diverse pharmacological effects mediated predominantly by saponins, a type of ginsenoside contained in ginseng. Compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to inhibit cell growth in a variety of tumors. However, the detailed mechanism, especially the effects of CK on cell cycle regulation in CRC cells, has not been examined. In addition, it is uncertain whether CK can inhibit colorectal tumor growth in vivo. In this study, we observed that CK significantly inhibited the growth of HCT-116 cells in athymic nude mouse xenograft models. Quantitative analysis revealed that CK significantly inhibited xenograft tumor growth from the 3rd week after CK administration (p<0.001); the higher dose (30mg/kg) of CK treatment exhibited a stronger effect than the lower dose (15mg/kg)(p<0.001). Using MTS assay, we showed that CK significantly inhibited the viability of human colorectal cancer cell lines HCT-116, HT-29 and SW480 in a dose- and time-dependent manner(with IC50 at around 10, 25, and 25uM respectively, p<0.01). In a flow cytometry assay, it was shown that CK could significantly induce HCT-116 cell apoptosis and arrest the cell cycle in the G1 phase. By screening with cell cycle and cell signal PCR arrays, some of the most relevant genes(such as CDKs/cyclins, BCL2, E2F4, p21CDKN1A, p15CDKN2B, TP53, etc.) and signal transduction pathways(such as p53, TGF-β, PI3K/AKT, pathways) were shown to be transcriptionally regulated after CK exposure. Western blots showed that the major regulated targets of CK are cyclin dependent inhibitors, including p21, p27, and p15. CK-induced colorectal cancer cell apoptosis and cell cycle arrest were related to the up-regulation of p53/p21, FoxO3a-p27/p15, Smad3, etc and down-regulation of cdc25A, CDK4/6 and cyclin D1/3 as well. Taken together, the results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in colorectal cancer, which suggest that CK could be useful for the prevention or treatment of CRC. Key words: Colorectal cancer, Ginsenoside, xenograft tumor, p53/p21, cell cycle arrest

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1685. doi:1538-7445.AM2012-1685
Abstract 1686: Identification of potential prostate cancer biomarkers associated with TMPRSS2-ERG fusion and PTEN deletions
Authors: Almami Amal A.
Published: August 2012

Background: ERG gene rearrangements and PTEN genomic deletions have been shown to be associated with specific molecular subtype of prostate cancer (PCA). It has been also suggested that tumors showing those two genetic aberrations are associated with worse prognosis compared to tumors with none of those genetic aberrations. In this study, we investigated gene expression differences between those two classes of tumors to identify potential genetic targets and pathways Material and Methods: 6144 informative genes belonging to 59 HRPCA samples were previously studied using the DASL platform. We used Singular Value Decomposition (SVD), as an effective method for analyzing gene expression data based on their ERG and PTEN status. We used the normal prostate cell line RWPE-1 as well as different prostate cancer cell lines (LNCaP, VCaP, DU145 and PC-3) to validate the results of microarray expression profiling. We screened for the expression of the different proteins by means of real time PCR and western blot studies. Results: MMP1 and LEF1 protein expression was much higher in VCaP cells and almost absent in RWPE-1 cells while MEIS2, CHD5 and Syntenin were expressed differently between cell lines and were not specifically in VCaP which is only cell line that harbor the ERG fusion. Conclusion: In this preliminary study we show that MPP1 and LEF-1 might be associated with the TMPRSS2-ERG fusion since their expression was much higher in VCaP cell line compared to other cell lines. However, further studies are still needed to confirm these results in TMPRSS2-ERG knockdown VCaP cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1686. doi:1538-7445.AM2012-1686
Abstract 1687: Expression of DAB2IP is related with cancer progression and prognosis of gastric cancer
Authors: Wang Xiangyang , Min Jiang , Yao Xingfeng , Zhao Min , Jiang Jianwu , Wang Jingtao , Liu Liang , Zhang Bo , Li Xiaolan , Tao Deding , Wang Jing , Hu Junbo , Hsieh Jer-Tsong , Xie Daxing , Gong Jianping
Published: August 2012

Background: Gastric cancer remains the fourth most common cancer and the second leading cause of cancer-related death worldwide. DAB2IP, a novel member of the Ras GTPase-activating protein family, is down-regulated in various human cancers and functions as a bona fide tumor suppressor in cancer development. In gastric cancer, the expression of DAB2IP and its relation to tumor progression and prognosis has not been investigated. Therefore, we undertook a clinicpathologic study of gastric cancer to investigate the correlation between the expression of DAB2IP and clinical characteristics. Results: Immunohistochemistry was performed in 120 cases of gastric cancer tissues and corresponding adjacent normal mucosas, 36 cases of non-metastatic lymph node and 68 cases of metastatic lymph node. Overall results showed that 69 of 104 gastric cancer tissues expressed low level of DAB2IP, and 94 of 104 adjacent normal mucosas expressed high level of DAB2IP. We also scored the expression level of DAB2IP based on both the intensity of staining and the percentage of positive cell… The expression of DAB2IP in gastric cancer tissues or lymphatic metastatic tissues was clearly lower than that in normal mucosas (p<0.01). DAB2IP expression was obviously decreased in gastric cancer tissues with lymphatic metastasis compared to those without lymphatic metastasis (p<0.01). The expression of DAB2IP was correlated with gender, serosal invasion, lymphatic metastasis, remote metastasis, tumor grade, and carcinoembryonic antigen (CEA) levels (p<0.05). DAB2IP expression appears to be an independent prognostic marker for survival of patients with gastric cancer (p<0.05). Patients with lower expression of DAB2IP had worse overall survival than those with higher expression of DAB2IP (p<0.01). Conclusions: DAB2IP is a potential new marker for predicting the progression and prognosis of gastric cancer. Loss of DAB2IP expression is related with poor overall survival of patients in gastric cancer, indicating its potent role in gastric carcinogensis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1687. doi:1538-7445.AM2012-1687