bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5590: Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations
Authors: Hsiao Susan , Gonzalez Anne Koehne de , Mansukhani Mahesh M. , Fine Robert L. , Remotti Helen E. 
Published: May 2015

Abstract
Background: BRCA1 and BRCA2 are tumor suppressor genes which play a role in the repair of DNA double stranded breaks and the maintenance of genomic stability. Inherited BRCA mutations increase the risk of development of pancreatic cancer. In sporadic tumors BRCA mutations occur late in pancreatic tumorigenesis. Few studies to date have examined molecular heterogeneity within pancreatic tumors with respect to founder and progressor mutations. This is the first study to examine heterogeneity of mutations in pancreatic carcinomas associated with germline BRCA mutations.
Design: Cases of pancreatic tumors arising in four patients with previously confirmed germline BRCA1 or BRCA2 mutations were identified from our case files. Representative sections of formalin-fixed, paraffin embedded tissue from surgical resection specimens were reviewed and 3 sections of tumor from different geographic regions and 1 section of non-tumor tissue were selected for molecular analysis for each case. Samples were manually macrodissected and genomic DNA was isolated. Genomic DNA was used for target capture and amplification of 212 amplicons targeting mutational hotspots in 48 genes using the TruSeq Amplicon Cancer Panel. Next generation sequencing was performed on the MiSeq Benchtop Sequencer and analyzed with NextGENe software.
Results: In all cases concordant results were observed in all three tumor samples, with no evidence of intratumoral heterogeneity for the genes tested. In one patient with a BRCA1 germline mutation, TP53 and SMAD4 mutations were identified. In two patients with germline BRCA2 mutations, two additional driver mutations were identified involving KRAS, TP53, or SMAD4. In one case with BRCA2 germline mutation, no additional mutations were identified.
Conclusion: Pancreatic tumors arising in the background of germline BRCA mutations had between 1-3 driver mutations per tumor, which is consistent with the reported numbers of driver mutations in sporadically arising pancreatic tumors. No mutual exclusivity among the mutated genes was observed. Mutations observed include KRAS codon 12 mutation, TP53 mutation (within the DNA binding domain), and SMAD4 mutation. Taken together, these results suggest that pancreatic tumors occurring in BRCA patients show similar mutational profiles of key oncogenes and tumor suppressor genes as seen in sporadic tumors with little heterogeneity with respect to these driver mutations.
Citation Format: Susan Hsiao, Anne Koehne de Gonzalez, Mahesh M. Mansukhani, Robert L. Fine, Helen E. Remotti. Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5590. doi:10.1158/1538-7445.AM2014-5590
Abstract 5599: Serum biomarkers reflecting specific tumor tissue remodeling is a valuable diagnostic tool for lung cancer
Authors: Willumsen Nicholas , Bager Cecilie L. , Leeming Diana J. , Smith Victoria , Christiansen Claus , Karsdal Morten A. , Dornan David , Bay-Jensen Anne-Christine 
Published: May 2015

Abstract
Background: The extracellular matrix (ECM) that integrates and surrounds malignant tumors consists of several proteins, amongst other type I collagen and elastin. These structural proteins, as well as intermediate filament (IMF) proteins like vimentin, are remodeled and dysregulated as part of malignant changes. We investigated whether serum biomarkers reflecting ECM and IMF remodeling/dysregulation could be used to differentiate lung cancer patients from healthy controls, other lung pathologies, and other cancer types.
Methods: Levels of matrix metalloproteinase (MMP) generated fragments of type I collagen (C1M), of elastin (ELM) and of citrullinated vimentin (VICM) were measured in serum from patients with lung cancer (n=40), gastrointestinal cancer (n=25), prostate cancer (n=14), malignant melanoma (n=7), chronic obstructive pulmonary disease (COPD) (n=13), and idiopathic pulmonary fibrosis (IPF) (n=10), as well as in age-matched controls (n=33). The area under the receiver operating characteristics (AUROC) was calculated for the biomarkers and a diagnostic decision tree was generated from specific cut-off values.
Results: Circulating levels of C1M and VICM were significantly elevated in lung cancer patients as compared to healthy controls (AUROC=0.98, p&lt;0.0001) and other cancers (AUROC=0.83 p&lt;0.0001). A trend was detected when comparing lung cancer with COPD+IPF. No difference could be seen for ELM. Interestingly, C1M and VICM were able to identify patients with lung cancer with a positive predictive value of 0.9 and an odds ratio of 40 (95% CI=8.7-186, p&lt;0.0001).
Conclusion: This study indentifies biomarkers specifically reflecting ECM and IMF remodeling as applicable for lung cancer patients. We speculate that these markers may aid in diagnosing and characterizing patients with lung cancer.
Citation Format: Nicholas Willumsen, Cecilie L. Bager, Diana J. Leeming, Victoria Smith, Claus Christiansen, Morten A. Karsdal, David Dornan, Anne-Christine Bay-Jensen. Serum biomarkers reflecting specific tumor tissue remodeling is a valuable diagnostic tool for lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5599. doi:10.1158/1538-7445.AM2014-5599
Abstract 5600: Wntless (GPR177) regulates WNT/NF-кB signaling in leukemia cells, and its expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia
Authors: Hsu Shih-Hsien , Wang Li-Ting , Huang Shih-Bo , Chiou Shyh-Shin 
Published: May 2015

Abstract
B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common childhood leukemia, with a cure rate of 80%. Nevertheless, disease relapse is the most important prognostic factor for the disease outcome. We aimed to elucidate the role of Wnt secretion-regulating protein, Wntless (Wls)/GPR177, on disease outcome in pediatric patients with BCP ALL, and assess its pathogenetic role in the regulation of the disease. Wls expression was characterized and correlated with Wnt and NF-κB pathway signaling in the bone marrow leukemia cells isolated from 44 pediatric patients with BCP ALL. The overexpression of Wls was detected in leukemia cells and was significantly correlated with the disease relapse and poor survival in the patients. The high expression of Wls also correlated with the Wnt expression, particularly with the NF-κB signaling activation. The Wnt-activated NF-κB signaling induced by Wls was shown to provide essential proliferation, transformation, and anti-apoptotic activity during leukemogenesis. These results indicated that Wls played an essential role in disease relapse and poor survival in patients with BCP ALL. Therefore, Wls may provide a potential future therapeutic target, particularly for patients who do not respond to existing therapies and suffer relapse.
Citation Format: Shih-Hsien Hsu, Li-Ting Wang, Shih-Bo Huang, Shyh-Shin Chiou. Wntless (GPR177) regulates WNT/NF-кB signaling in leukemia cells, and its expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5600. doi:10.1158/1538-7445.AM2014-5600
Abstract 566: The clinicopathological features and prognostic impact of ALK-positivity in resected gastric or gastro-esophageal cancer patients
Authors: Jeon Hongjae , Kim HyeRyun , Noh Sung Hoon , Chung Hyun Cheol , Rha Sun Young 
Published: May 2015

Abstract
Background: To determine the frequency and prognostic impact of ALK-rearrangements in gastric cancer patients who underwent curative surgical resection with extensive (D2) lymph node dissection.
Patients and methods: We concurrently analyzed the ALK-rearrangements and HER2 overexpression in whole tumor sections of 455 curatively resected gastric cancers. We performed immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), and analyzed the relationship between ALK positivity and clinical survival outcome.
Results: Of the 455 tumors that were screened, 38 (8.4%) were ALK+ by IHC, which consisted of 1+ (24, 7.5%), 2+ (3, 0.7%), and 3+ (1, 0.2%), but no cases were confirmed by FISH. ALK+ patients were significantly younger (57 vs. 61 years, P=0.02) and showed similar patterns of ALK+ lung adenocarcinoma. ALK+ patients were significantly more likely to have abundant signet ring cells (defined as ≥ 10% of tumor cells). Moreover, as the ALK intensity (measured by IHC) increased, so did the density of signet ring cell in tumors (Ptrend = 0.02). Also, the disease free survival (DFS) and overall survival (OS) of ALK+ patients in stages were shorter than ALK- patients (DFS: 21.2 vs.100.5 months; P = 0.007, OS: 34.3 months vs. median survival time unattainable; P=0.016)
Conclusions: ALK+ is an independent negative prognostic factor in surgically resected gastric cancers and is associated with signet ring cell histology. Furthermore ALK+ might be a relevant therapeutic target in gastric cancer patients.
Citation Format: Hongjae Jeon, HyeRyun Kim, Sung Hoon Noh, Hyun Cheol Chung, Sun Young Rha. The clinicopathological features and prognostic impact of ALK-positivity in resected gastric or gastro-esophageal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 566. doi:10.1158/1538-7445.AM2014-566
Abstract 57: Blood parameters in renal cell carcinoma patients can have prognostic impact and differ from those of healthy blood donors
Authors: Goebel Steffen , Bluemke-Anbau Karen , Altermann Wolfgang , Bilkenroth Udo , Meye Axel , Fuessel Susanne , Lautenschlaeger Christine , Melchior Andres , Heynemann Hans , Fornara Paolo , Taubert Helge 
Published: May 2015

Abstract
The aim of this study was to evaluate the clinical relevance of blood parameters as circulating tumor cells (CTCs) and HLA subtype in renal cell carcinoma (RCC) patients.
233 peripheral blood samples from 154 RCC patients were tested for the presence of disseminated tumor cells (DTCs) by using the autoMACS technique and immunocytochemical (ICC) staining of cytokeratin. The frequency of CTCs was analyzed statistically and correlated with relevant clinical data. In addition, HLA subtype was analysed for 91 out of the 154 RCC patients and for 203 healthy blood donors. A statistical comparison was performed.
After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. Besides a significant correlation between the detection of CTCs before and after primary tumor resection a significant association with prognosis was found (p &lt; 0.002; X2-test). RCC patients with CK+ CTCs in their peripheral blood had a 5 times increased risk of tumor-related death compared to patients without these cells. In a Kaplan-Meier-Analysis these results were confirmed (p &lt; 0.001). On one hand, RCC patients had less alleles HLA-Cw*07 (p &lt; 0.05; X2-test) and HLA-DRB1*04 (p &lt; 0.05; X2-test) compared to healthy blood donors. On the other hand, RCC patients showed an increased occurrence of the allele HLA-Cw*12 compared to healthy blood donors. However, this difference was not significant.
In summary, for RCC patients the presence of CTCs was associated with a poor overall survival and significantly correlated with an increased risk of tumor-related death. Detection of CK+ CTCs in peripheral blood is a significant and independent prognostic factor for renal cell carcinoma patients. Occurrence of the alleles HLA-Cw*07, and HLA-DRB1*04 was significantly reduced in RCC patients compared to healthy blood donors and may reduce the risk to suffer from a RCC.
Citation Format: Steffen Goebel, Karen Bluemke-Anbau, Wolfgang Altermann, Udo Bilkenroth, Axel Meye, Susanne Fuessel, Christine Lautenschlaeger, Andres Melchior, Hans Heynemann, Paolo Fornara, Helge Taubert. Blood parameters in renal cell carcinoma patients can have prognostic impact and differ from those of healthy blood donors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 57. doi:10.1158/1538-7445.AM2014-57
Abstract 577: Genetic and epigenetic alterations of the WWOX gene in head and neck cancer
Authors: BUYRU NUR , Ekizoglu Seda , Koseoglu Hikmet , Karaman Emin 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease and the 6th most frequent cancer in the world. Despite advances in medical treatment over the past two decades, the overall survival rate for patients with HNSCC remains around 50%. Well known environmental risk factors for developing HNSCC are cigarette smoking, especially in combination with alcohol consumption or tobacco chewing. In addition, many genetic and epigenetic changes are associated with sporadic HNSCC including alterations in the p53, VEGF and cyclin D1genes. Yet the molecular mechanisms of HNSCC carcinogenesis are still undergoing intensive investigation.
The WWOX gene is located on a chromosomal fragile site 16q23.2 which spans the common fragile site FRA16D. It has been shown that exposure to environmental carcinogens such as smoking and alcohol consumption increases the potential for chromosomal breakage at the FRA16D site in esophageal and non-small cell lung cancers. On the other hand, genomic abnormalities affecting chromosome 16q are frequently reported in cytogenetic studies of various epithelial tumors, including prostate, breast, ovarian, esophageal, lung, gastric, and hepatocellular carcinomas. However, there is no data in the literature investigating the WWOX gene in the HNSCC. Therefore, the aim of this study was to determine the role of WWOX as a tumor suppressor gene in patients with HNSCC.
For this purpose, tumor and corresponding normal tissue samples obtained from 75 patients with HNSCC were analyzed for mutations in the coding exons and the flanking intronic sequences by direct sequencing of the WWOX gene. mRNA expression levels were also analyzed by quantitative-real time-PCR and correlated with the methylation level of the WWOX gene promoter. The methylation status was determined by methylation-specific PCR(MSP).
mRNA expression levels were significantly lower in tumor tissue than normal tissue (p≤0.001) and this downregulation was associated with hypermethylation of the promoter of the WWOX gene (p≤0.05). We identified 8 different alterations in the coding sequence of the WWOX gene with a frequency varying between 1.56-58.93%. Additionally, 17 different alterations in the noncoding regions were identified in our study group.
Our results indicate that the WWOX gene may play an important role in the development of HNSCC.
Citation Format: NUR BUYRU, Seda Ekizoglu, Hikmet Koseoglu, Emin Karaman. Genetic and epigenetic alterations of the WWOX gene in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 577. doi:10.1158/1538-7445.AM2014-577
Abstract 581: Identification of PCDHB3 as a potential tumor suppressor in colorectal cancer by exome sequencing
Authors: Ye Wen , Liu Ranyi , Wu Jiangxue , Li Yingchang , Huang Wenlin 
Published: May 2015

Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide and is believed to arise from combinations of genetic and epigenetic disorders. However, besides APC, KRAS, and p53, which are highly targeted by somatic mutations, other genes altered in mutations in CRC patients are under interpreted in their effects and relevance with CRC tumorigenesis.
Out of the genes in which we identified 453 nonsynonymous somatic mutations in this exome sequencing study, PCDHB3 was mutated in 30% exome-sequenced cases and was screened in another 104 CRC cases with a 7.02% mutation rate. Meanwhile, PCDHB3 is lowly expressed in 83.7% tumor of CRC patients and CRC cell lines compared to normal controls, which is detected to be caused by loss of heterozygosity and CpG island hypermethylation. In vitro and in vivo experiments revealed that over-expression of wildtype PCDHB3 in DLD1 cells inhibited tumor cell proliferation and migration (56.8% and 47.5% of control), whereas mutant PCDHB3 lacked of the functions. Furthermore, SW480-shRNA cells, which demonstrated a lower level of endogenous PCDHB3, exhibited a larger growth and migration advantage (2.28-fold and 2.26-fold of control).
In summary, our study identified PCDHB3 as a tumor suppressor gene in CRC. Loss of PCDHB3 suppressor function results from uncommon genetic mutations affecting the protein sequence as well as decreased expression of functional protein.
Citation Format: Wen Ye, Ranyi Liu, Jiangxue Wu, Yingchang Li, Wenlin Huang. Identification of PCDHB3 as a potential tumor suppressor in colorectal cancer by exome sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 581. doi:10.1158/1538-7445.AM2014-581
Abstract 586: Prognostic significance of Tip60 expression in human glioma
Authors: Bai Rongpang , Weng Yu , Zhao Zhongsheng , Bai Jin , Chen Guangdi 
Published: May 2015

Abstract
The tumor suppressor Tip60 plays a major role in transcription, DNA damage response, apoptosis, autophagy and cancer development, but its role in glioma is unknown. In this study, we investigated the role of Tip60 in glioma pathogenesis and assessed its prognostic value. Using tissue microarrays consisting of 437 cases of glioma, including 236 cases with low grade (grade I and II) and 201 cases with high grade (grade III and IV), we found that Tip60 expression was significantly reduced in high grade glioma compared to low grade glioma (P = 0.004) although no significant difference in Tip60 expression was found between grade I and II, or grade III and IV glioma (P &gt; 0.05 for either). Kaplan-Meier survival curve analysis showed that reduced Tip60 expression was associated with a poorer five-year overall survival in glioma patients (P = 0.015). Our data indicate that Tip60 may serve as a potential biomarker for glioma patient outcome as well as a potential therapeutic target.
Citation Format: Rongpang Bai, Yu Weng, Zhongsheng Zhao, Jin Bai, Guangdi Chen. Prognostic significance of Tip60 expression in human glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 586. doi:10.1158/1538-7445.AM2014-586
Abstract 588: Lrig1 suppresses breast cancer stem cell expansion and promotes mesenchymal to epithelial transition
Authors: Yokdang Nucharee , Sweeney Colleen 
Published: May 2015

Abstract
Leucine-rich repeats and immunoglobulin-like domains-1 (Lrig1) is known as a negative regulator of oncogenic receptor tyrosine kinases (ErbB, Met and Ret); and low Lrig1 expression correlates with poor patient prognosis in breast cancer. Lrig1 has been found to maintain stem cell quiescence and marks a subset of quiescent intestinal stem cells where its loss leads to heightened ErbB expression and duodenal adenomas. Lrig1 is defined as a tumor suppressor in healthy tissue such as intestine and epidermis where Lrig1 loss leads to stem cell expansion and epidermal hyperplasia. However, the role of Lrig1 in cancer stem cells (CSCs) and as a metastatic suppressor is unknown. Lrig1 expression is lowest in the highly invasive breast cancer subtype MDA-MB-231, and Lrig1 expression is highest in the weakly invasive luminal A breast cancer subtype. In patients, high Lrig1 expression exhibits longer relapse-metastatic free survival suggesting that Lrig1 expression protects against metastatic relapse. We hypothesized that Lrig1 suppresses breast CSC expansion and promotes mesenchymal to epithelial transition. Our results indicated that restoration of Lrig1 in highly aggressive cell lines promoted mesenchymal to epithelial transition (MET) and a loss of invasive morphology in 3D matrigel cell culture. These results demonstrated that Lrig1 suppressed cell proliferation in both 2D and 3D matrigel cultures and suppressed tumorsphere formation 10-fold. Importantly, we have shown that Lrig1 is down-regulated in the hTERT-immortalized mammary epithelial cell line-twist ER, (HMLE-twist ER) which undergoes EMT. When Lrig1 is knocked-down in HMLE-twist ER by shRNA, the results showed that loss of Lrig1 enhanced mesenchymal and stem cell expansion. These observations suggest that Lrig1 may play a role in EMT transition in metastasis, as well as providing a whole new area of therapeutic targets in breast cancer along with an improved basic understanding in cancer stem cell biology.
Note: This abstract was not presented at the meeting.
Citation Format: Nucharee Yokdang, Colleen Sweeney. Lrig1 suppresses breast cancer stem cell expansion and promotes mesenchymal to epithelial transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 588. doi:10.1158/1538-7445.AM2014-588