bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4444: BRCA1 Circos: A visualization tool for BRCA1 missense variants
Authors: Jhuraney Ankita , Velkova Aneliya , Vallée Maxime P. , Carvalho Renato S. , Tavtigian Sean V. , Monteiro Alvaro N. 
Published: August 2012

Abstract
Germline mutations in BRCA1 have been associated with a significantly increased risk of developing breast and ovarian cancers. A large number of variants have been identified in BRCA1 and are reported as pathogenic, non-pathogenic, or as variants of uncertain significance (VUS). Test results reporting pathogenic or non-pathogenic variants can be used by physicians and genetic counselors to help patients in making important clinical decisions. Around 10-15% of the reported BRCA1 and BRCA2 variants are clearly pathogenic and 5% of these reported variants are VUS. Results reporting a VUS can cause anxiety and make it difficult to advise the patient on further clinical intervention to reduce their risk of developing the disease. Many of these VUSs are non-synonymous single amino acid changes leading to missense changes. A number of previous studies have focused on assessing the functional impact of these changes on the BRCA1 protein. BRCA1 is a gene product with pleiotropic functions and therefore, different functional assays are used in these studies to analyze the variant's impact on function. However, information on the functional impact of VUS is currently not consolidated and collecting available information on missense variants depends on multiple database searches and literature review. Moreover, methods to incorporate functional data into multifactorial models have recently been developed highlighting the need for a common resource to facilitate analysis. Realizing the need for a resource that facilitates the global visualization and analysis of these variants we have developed a visualization tool for multidimensional data using Circos (http://circos.ca) to aggregate the data from all published studies that have assessed these missense variants. Circos plots have been used in the literature to represent genomic data and we have used the same concept to illustrate variants in BRCA1. We have included ∼700 variants for which we have 30 different functional experiments from various studies assessing over 150 missense variants. Results are color coded to uniformly depict various degrees of functional impact on the BRCA1 protein function so that information for any variant can be obtained in a snapshot without having to perform extensive literature searches. Therefore, we believe clinical geneticists and genetic counselors can use this research tool as a quick reference to analyze all the missense variants that have been identified along with associated information to characterize them when faced with the challenge of advising a patient with these types of VUSs.
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 4444. doi:1538-7445.AM2012-4444
Abstract 4448: Fecal miRNA test using microRNA expressions of exfoliated colonocytes for colorectalcancer screening
Authors: Koga Yoshikatsu , Yasunaga Masahiro , Matsumura Yasuhiro 
Published: August 2012

Abstract
Background & Aims: To reduce the mortality rate of several cancers, the development of a screening test is needed. We have been developing new screening methods for colorectal cancer (CRC) by applying molecular biological tools to exfoliated colonocytes. In the last few years especially, we have reported the fecal RNA test including the CRC-related gene expression analysis. Here, we investigated the potential of a fecal miRNA test for the early detection of CRC. Methods: CRC patients (n = 299) and healthy volunteers (n = 116) with no abnormalities detected by screening colonoscopy were enrolled in this case control study. The miRNA expressions in the colonocytes of CRC patients (n = 47) and healthy volunteers (n = 35) were analyzed in the training study and the miRNA expressions in the colonocytes of CRC patients (n = 252) and healthy volunteers (n = 81) were validated in the validation study. First, CRC related oncogenic miRNAs for CRC detection were selected by TaqMan MicroRNA Array v3.0 (corresponded to miRBase release 14). Next, the expressions of the most suitable oncogenic miRNAs were analyzed by quantitative real-time PCR in the training study. Lastly, the sensitivity and specificity of fecal miRNA test was validated by quantitative real-time PCR in the validation study. Results: According to the results of miRNA array, 20 miRNAs were selected as candidate of miRNA analysis. In the training study, significant differences in the relative expression level of miR-17, -18a, -19a, -19b, -20a, -92a, -106a, -135a, -135b, and -146a were observed between the CRC patients and the healthy volunteers (P &lt; 0.01). On the other hand, there was no significant difference in the relative expression level of miR-21, -183, -223, and -454* between the CRC patients and the healthy volunteers (P &gt; 0.1) AUC of ROC curve using miR-17, -18a, -19a, -19b, -20a, -92a, -106a, -135b, and -146a were more than 0.7. The overall sensitivity and specificity in the training study using these miRNAs were 70.2% (33/47) and 74.3% (26/35), respectively. The overall sensitivity and specificity in the validation study were 67.5% (170/252) and 75.3% (61/81), respectively. Conclusions: We selected the suitable miRNAs for CRC detection in exfoliated colonocytes. Fecal miRNA test may be useful for CRC screening.
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 4448. doi:1538-7445.AM2012-4448
Abstract 4466: Local regulation of steroid hormones in the breast is related to single nucleotide polymorphism of steroid metabolism genes
Authors: Lee Oukseub , Chatterton Robert T. , Shidfar Ali , Heinz Richard , Fought Angela , Denise Scholtens , Khan Seema A. 
Published: August 2012

Abstract
Background: The pattern of steroid hormone levels in nipple aspirate fluid (NAF) significantly differs from systemic levels, but may be a better predictor of breast cancer risk than the systemic environment. We hypothesize that local production and clearance of estrogen precursors or estrogen in the breast is affected by genetic variation in the enzymes involved in steroid transport, biosynthesis, and metabolism, thereby contributing to breast cancer risk. We examined the effect of functional single nucleotide polymorphism (SNP) on the concentrations of the NAF steroid hormones, as compared to serum levels. Methods: NAF was collected from both the contralateral unaffected breast of breast cancer patients and controls (blinded study of 265 women). Selection criteria for SNPs were; 1) known/potential functional significance on activity of the resulting enzyme. 2) Expression in breast tissue. 3) Caucasian population frequency of the minor alleles. gDNA was extracted from the plasma buffy coat by a Qiagen kit, followed by TaqMan genotyping assays (Applied Biosystems). The NAF and serum level of estradiol (E2), estrone (E1), progesterone (P4), testosterone (T), androstenedione (A4), and dehydroepiandrosterone (DHEA) were measured by immunoassay. Hormone levels were compared across genotype groups using the ANCOVA in SAS (age-adjusted significance p &lt; 0.05). Results: (See the Table) Conclusions: There is no data yet to show that NAF hormone content is related to breast cancer risk. This hypothesis will be tested in our on-going study. Locally regulated biosynthesis and clearance of hormones from the breast seems likely. Our data support such a phenomenon, since NAF correlations with functional enzyme SNPs are more frequent than with serum. The significant relationships between SNPs and NAF hormones, not seen with the same serum hormone, support the notion that they are determinants of breast 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 4466. doi:1538-7445.AM2012-4466
Abstract 447: Has the expression of the Wnt-pathway in regard to cMYC and β-Catenin a predicitive influence on the kind of metastasis in colon cancer
Authors: Strohäker Jens , Falch Claudius , Hann-von-Weyhern Claus , Adam Patrick , Königsrainer Alfred , Fend Falko , Brücher Björn LDM 
Published: August 2012

Abstract
Background: cMYC as well as β-Catenin are downstream-targets of the Wnt-pathway and both have an important early function within the carcinogenesis and the progression of colon cancer. Additionally cMYC was found to be associated with a worse prognosis in other neoplasms. The goal of our investigations was the evaluation of the Wnt-pathway on primary non-metastatic colon cancer compared to lymphatic, hepatic and peritoneal metastasis in regard to the expression of cMYC and β-Catenin. Methods: 98 patients with adenocarcinom of the colon and a postoperative pT2/3-status, who underwent surgical resection between 2006 and 2008 at the University of Tübingen had been included within the study collective. 53 patients had no metastasis (control group), while 45 patients revealed primary metastasis: lymphatic metastasis (n=20), hepatic spread (n=20) and multiple metastasize (n=5). cMYC and β-Catenin was coloured on a Tissue-Micro-Array by immunohistochemistry with consecutive semiquantitative analysis. Results: 17 of 98 patients (17%) had been positive for cMYC. 5 out of these 17 (29%) revelaed metastasis. 16 out of the 17 cMYC-positive patients showed a nuclear accumulation of β-Catenin (94%) (p=0.027). 40 out of 81 (49%) cMYC negative patients revealed metastasis. No significant correlation between nuclear positive cMYC and the rate or kind of metastasis was found (p=0.133). In 29 out of 81 cMYC-negative patients (36%) a strong expression of β-Catenin was found. Conclusion: cMYC is well known for a worse prognosis in case of an overexpression in patients suffering from lymphoma. A correlation between the expression of cMYC and the kind of metastasis and / or survival nor prognosis in patients with colon cancer was not able to show (p=0.211). Additonally no correlation between the nuclear exprimed β-Catenin and different ways of metastasis was found (p=0.202).
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 447. doi:1538-7445.AM2012-447
Abstract 4538: Semiquantitative detection of aberrant methylation as a tumor biomarker in the serum and plasma of patients with gastric cancer
Authors: Lee Jae-Hyuk , Kim Jin-Sook , Lee Kyung-Hwa , Lee Ji-Shin , Choi Chan , Juhng Sang-Woo 
Published: August 2012

Abstract
Background: Epigenetic silencing of tumor-related genes, due to CpG island methylation, is considered to be an important mechanism for the development of many tumors, including gastric cancinoma (GC). DNA methylation of multiple CpG sites in promoter regions of several tumor related genes, such as hMLH1, p14, COX2, and APC has been analyzed in GC so for. Circulating tumor DNA in serum/plasma has been demonstrated to reflect the biological characteristics of tumors. Recently, the presence of gene promoter methylation in serum/plasma DNA has also been demonstrated in patients with cancers of lung, head and neck, liver, and breast. So, in the present study, we attempted to determine the feasibility and the clinical correlations of detecting tumor-associated aberrant methylation in the serum/plasma of patients with gastric cancer. Materials and Methods: We examined promoter methylation of 6 genes using methylation-specific PCR (MSP) and methylation-sensitive high-resolution melting (MS-HRM) in paired serum, plasma and tumor samples of 50 gastric cancer patients. The tumor and the paired serum/plasma were investigated for aberrant methylation in BLU, DAPK1, GADD45G, MGMT, p15 and p16. The sensitivity of the HRM analysis was tested by using dilutions of fully methylated DNA into unmethylated DNA. Results: MSP was used to assess gene methylation in tumor samples. Promoter methylation in BLU, DAPK1, GADD45G, MGMT, p15, and p16 were detected in 47%, 37%, 59%, 32%, 14%, and 43% of tumor tissues by MSP. MS-HRM was used to assess gene methylation in serum/plasma samples concurrently. In the serum/plasma of gastric cancer patients, BLU, DAPK1, GADD45G, MGMT, p15, and p16 were methylated at frequencies of 26%, 21%, 23%, 11%, 9%, and 17%, respectively. Nineteen (38%) gastric tumor samples displayed concurrent methylation in three or more tumor genes. Aberrant methylation in one or more genes was found in 74% (37/50) serum samples and 70% (35/50) plasma samples. However, there was not a significant relationship of gene methylation between gastric tumor tissues and serum/plasma samples.Conclusion: These results suggest that aberrant promoter methylation in serum/plasma can be detected in a substantial proportion of gastric cancer patients. Detection of DNA methylation in serum/plasma may be a biomarker for early detection of gastric cancer. MS-HRM is powerful technique for the analysis of promoter methylation. Application of HRM analysis to large amount of clinical samples proves to be a fast and high-throughput way to investigate the epigenetic status of genes.
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 4538. doi:1538-7445.AM2012-4538
Abstract 4548: Prognostic value of occult metastases detected by cytokeratin 20 and mucin 2 mRNA quantification in sentinel lymph nodes from colon cancer patients
Authors: Nordgård Oddmund , Oltedal Satu , Aasprong Ole Gunnar , Søreide Jon Arne , Søreide Kjetil , Tjensvoll Kjersti , Gilje Bjørnar , Heikkilä Reino , Guriby Marianne , Lothe Ragnhild A. , Smaaland Rune , Kørner Hartwig 
Published: August 2012

Abstract
BACKGROUND: Lymph node (LN) metastasis status is among the strongest prognostic factors in colon cancer. Despite this, 20-30% of LN negative patients experience disease recurrence. These patients may have occult LN metastases that are not detected by routine microscopy. The aim of the present study was to investigate the prognostic value of occult metastases detected by cytokeratin 20 (CK20) and mucin 2 (MUC2) mRNA quantification in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. METHODS: Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. The isolated SLNs were examined for the presence of metastases by routine HES staining and quantitative CK20 and MUC2 mRNA measurements. Primary tumor microsatelite instability- (MSI), KRAS and BRAF mutation status were determined for the included patients. Recurrence-free and disease-specific survivals were analyzed by Kaplan-Meier survival estimates and log rank tests. RESULTS: SLNs were identified in 206 (97%) of the 213 included patients. Routine histological analysis of SLNs and other regional lymph nodes revealed LN metastases in 63 patients (pN+), of which 42 (67%) had metastases detected in one or more SLNs (sensitivity 67%, false negative rate 33%). When analyzing the SLNs by CK20 and MUC2 mRNA quantification, occult metastases were suggested in 86 (60%) and 52 (36%) of the 143 otherwise LN negative (pN0) patients, respectively. Survival analysis with a median 3.6 year follow-up revealed a significant prognostic value of MUC2 mRNA quantification in SLNs from all the patients, but not for the pN0 patients. For CK20 mRNA levels in SLNs we observed no statistically significant survival differences. Patient stratification according to primary tumor MSI, KRAS mutation and BRAF mutation status did not reveal any significant survival differences related to the suggested occult SLN metastases, neither. CONCLUSIONS: Occult SLN metastases detected by quantitative CK20 and MUC2 mRNA measurements did not demonstrate any prognostic value in this 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 4548. doi:1538-7445.AM2012-4548
Abstract 4550: NT5E promoter methylation is a favorable breast cancer epigenetic biomarker
Authors: Nigro Cristiana Lo , Monteverde Martino , Lee Sonia , Lattanzio Laura , Syed Nelofer , Garrone Ornella , Merlano Marco , Hatzimichael Eleftheria , Briasoulis Evangelos , Thompson Alastair , Crook Tim 
Published: August 2012

Abstract
Despite the recent introduction of advanced microarray-based gene expression profiling strategies, relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. DNA methylation emerges as a novel source of epigenetic biomarkers that can help improve individualised breast cancer therapy. In the light of existing preclinical and clinical data we studied NT5E (5′-nucleotidase, ecto) expression and NT5E promoter methylation (NPM) in 14 breast cancer cell lines and 259 breast cancer clinical cases. In vitro, NT5E promoter methylation (as determined by MSP and pyrosequencing) was inversely associated with NT5E expression (as determined by qRT-PCR) and azacytidine produced an increase in NT5E mRNA levels in cell lines with methylated the NT5E promoter CpG. In clinical series, patients whose resected primary tumours were found to have NT5E promoter methylation, were less likely to develop metastasis (p=0.003, OR=0.34, 95% CI 0.17-0.69). Moreover in 3 out of 4 paired samples, NT5E promoter was found methylated in primary tumours and demethylated in CNS metastases. Regarding metastatic profile, patients that progressed to non-visceral metastases were more likely to have NT5E promoter methylated in primary tumours as compared to visceral metastatic disease (p=0.01, OR=11.8). NT5E promoter CpG island was densely methylated in 16 of 21 patients who developed non-visceral metastatic disease (76%) and in 6/28 cases (21%) with visceral metastases. In time-dependent endpoints analysis, patients with tumours lacking detectable NT5E methylation had increased risk for shorter DFS (p=0.001, HR 2.7) and OS (p=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in ER negative (p=0.011, HR=3.27, 95% CI 1.31-8.12) and in triple negative cases (p=0.004; HR=6.2, 95% CI 1.9-20). Moreover we observed a strikingly favourable outcome to adjuvant chemotherapy in patients with tumours profiled as NT5E promoter methylated regarding DFS (p=0.0016, HR 5.1, 95% CI 1.8-14.37) and OS (p=0.0005, HR 7.4, 95% CI 2.416 –23.08), which allows speculations that NPM may convey breast cancers more amenable to chemotherapy, possibly though pro-apoptotic mechanism. We suggest that NT5E promoter CpG island methylation may serve as a promising favourable breast cancer epigenetic biomarker. Our results warrant independent confirmation by other groups before considering its investigation as a metastasis predictor in clinical trials of adjuvant breast cancer therapies.
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 4550. doi:1538-7445.AM2012-4550
Abstract 4552: Utilization of pathway activation and somatic mutation analysis in combination in fine needle aspirates to identify candidate drugs for effective treatment of breast cancer
Authors: Lee Tani , Kim Phillip S. , Harvie Gulia , Meyer Gary , Leesman Glen , Langley Emma , Liu Limin , Hoe Hicholas , Princen Fred , Selvaraj Fabiyola , Liu Xinjun , Singh Sharat 
Published: August 2012

Abstract
A critical hurdle in implementing prognostic and predictive biomarkers in clinical trials is our inability to perform an efficient molecular characterization of the limited amounts of available clinical samples. Here we report a comprehensive molecular analysis of fine needle aspirate (FNA) samples collected from metastatic sites of 58 breast cancer (BCA) patients. The analysis included interrogation of key receptor tyrosine kinases and their downstream signaling molecules including HER1, HER2, p95HER2, HER3, cMET, IGF1R, PI3K, Shc, AKT and ERK as well as oncogenic somatic mutational profiling. A multiplexed immunoarray CEER™ (Collaborative Enzyme Enhanced Reactive-immunoassay) platform was utilized to determine the levels of pathway protein expression and phosphorylation. All FNA collections provided sufficient materials for the combined analysis of multiplexed pathway expression/activation and somatic mutation analysis. All the FNA from metastatic sites (mFNA) collected from HER2 positive primary tumors (determined by IHC) were also CEER-HER2 positive. Over-expression of HER2 was found in 10% of mFNAs collected from BCA patients with HER2 negative primary tumors. PIK3CA mutations were found in 20% of the samples in this cohort. Statistically significant higher levels of phosphorylated AKT, ERK (downstream effector targets) as well as HER1, HER2, HER3 and IGF1R (PI3K membrane recruiter proteins) were found in mFNAs with PIK3CA mutations. Subset of PIK3CA wildtype patients also showed robust pathway signature. Hence, evaluation of biomarkers in BCA patients should include both pathway proteins as well as mutation analysis. A comprehensive disease profiling can provide insightful information on efficacy of specific agents on its intended target protein inhibition. As CEER requires minimal amount of specimen, performance of routine pathway profiling can be achieved in clinical settings. A multiplexed pathway analysis can also provide valuable information about potential drug resistance mechanisms. Furthermore, a combined mutational and pathway activation profiling can guide therapeutic strategies in clinical setting.
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 4552. doi:1538-7445.AM2012-4552