bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 562: Alterations in chromatin remodeling pathways as a predictive biomarker of cisplatin therapy in non-small cell lung cancer
Authors: Hlavin Bell Erica , Chakraborty Arup Ratan , Mo Xiaokui Molly , Carbone David , Chakravarti Arnab
Published: August 2015

BRG1 (SMARCA4) and BRM (SMARCA2) are two important catalytic (ATPase) components of the mammalian chromatin remodeling complex SWI/SNF. Alterations of these components have been implicated in many cancers including lung, prostate, pancreatic, breast, and colon. Several studies have reported that both BRG1 and BRM actively participate in DNA damage repair by inducing phosphorylation of γ-H2AX, stimulating nucleotide excision repair, and also regulating interstand cross-link repair. BRG1 is frequently deleted in many primary tumors and lung cancer cell lines. Therefore, we hypothesized that reduced DNA repair capacity due to loss of BRG1 may enhance the sensitivity to DNA-damaging agents and may serve as predictive biomarkers of sensitivity for these agents. The purpose of this study was to evaluate the association between BRG1 and/or BRM alterations and the outcome of platinum-based chemoradiation in resected non-small cell lung cancer (NSCLC). Using the gene profiling of the patient tumor samples from the North American Intergroup phase III trial of adjuvant cisplatin plus vinorelbine (JBR.10), we found that patients with low BRG1 (SMARCA4) or low BRM (SMARCA2) had significantly longer overall survival (OS) if they had adjuvant chemotherapy (both p<0.05, vs no-adjuvant treatment patients). Interestingly, no significant differences in the OS were observed with high SMARCA4 or high SMARCA2 expression. Collectively, this study suggests that reduced expression of SMARCA4 and SMARCA2 may serve as putative predictive biomarkers of cisplatin therapy and warrants further investigation.

This study was supported by funds from the Lung Cancer Research Foundation (to EB), the Paul P. Carbone Memorial Foundation (to EB), The Ohio State University Comprehensive Cancer Center (to AC); NIH/NCI 1U10CA180850-01(to AC); NIH/NCI 1RC2CA148190 (to AC); NIH/NCI 2K12CA133250-06 (to AC); NIH/NCI/CTEP 1R01CA169368 (to AC); NIH/NCI 1R01CA11522358 (to AC), and RTOG (to AC).

Citation Format: Erica Hlavin Bell, Arup Ratan Chakraborty, Xiaokui Molly Mo, David Carbone, Arnab Chakravarti. Alterations in chromatin remodeling pathways as a predictive biomarker of cisplatin therapy in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2015-562
Abstract 564: The expression of fetal oncogene 5T4 in CTCs obtained from NSCLC patients is discordant with the expression measured in the primary tumor
Authors: Pirie-Shepherd Steven R. , Deng Shibing , Golas Jonathon , Vizcarra Pamela , Tucker Eric , Marrinuci Dena , Gerber Hans-Peter , Powell Eric L.
Published: August 2015

The fetal oncogene 5T4 is a cell surface protein, with over-expression observed in a variety of cancers as compared to normal adult tissue. Recent studies have shown that expression of 5T4 appears to be associated with the undifferentiated state and the epithelial-mesenchymal transition (EMT), and thus has been associated with a more invasive phenotype. We have developed assays to measure the expression of the fetal oncogene, 5T4, in both the primary tumor compartment and in the circulating tumor cell compartment. These assays were then used to investigate 5T4 expression in a small cohort of patients with NSCLC. We obtained matched primary tumor and blood samples, with the blood being obtained prior to resection of the primary tumor. The expression of 5T4 was found to be robust and measurable in both the primary and circulating tumor compartments. We observed expression of 5T4 in both adenocarcinoma and squamous cell carcinoma, in all stages and grades of tumor, with no specific correlation between expression and stage, grade or pathology. We further observed robust enumeration of CTCs in NSCLC samples. The expression of 5T4 was heterogeneous in the CTC compartment with no correlation to grade, stage or pathology. Finally, we observed no concordance between 5T4 expression in the primary tumor and the circulating tumor cell compartment. We discuss the current utility of target expression in predicting response to targeted therapy in the context of antibody based therapy, and the role that CTCs may have in the clinic.

Citation Format: Steven R. Pirie-Shepherd, Shibing Deng, Jonathon Golas, Pamela Vizcarra, Eric Tucker, Dena Marrinuci, Hans-Peter Gerber, Eric L. Powell. The expression of fetal oncogene 5T4 in CTCs obtained from NSCLC patients is discordant with the expression measured in the primary tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 564. doi:10.1158/1538-7445.AM2015-564
Abstract 57: Substrates of protein kinase C drive cell rac1-dependent motility
Authors: Rotenberg Susan A. , Zhao Xin , De Shatarupa
Published: August 2015

This laboratory has identified and/or characterized substrates of PKC that upon phosphorylation give rise to motility, an aspect of metastasis. By use of the traceable kinase method, we discovered that alpha-tubulin and Cdc42 effector protein-4 (CEP4) are PKC substrates. Phosphorylation of alpha-tubulin stimulates its incorporation into microtubules (MTs), consequently increasing the stability and prolonged growth of MTs and leading to the activation of the small GTPase Rac1. CEP4 undergoes phosphorylation by PKC that results in its release from Cdc42, whereupon CEP4 binds a guanine nucleotide exchange factor (GEF) that in turn activates Rac1 GTPase. These results imply that Rac1 acts as a node in pathways driven by phosphorylated PKC substrates. Since translocation of IQGAP to the membrane is known to be promoted by Rac1, a role is explored in non-transformed human MCF-10A cells that express a specific phospho-mimetic mutant substrate. In addition, the phospho-mimetic mutant for each substrate expressed in human metastatic MDA-MB-231 cells produces different morphologies in 3-D growth assays. This research is being supported by NIH CA125632.

Citation Format: Susan A. Rotenberg, Xin Zhao, Shatarupa De. Substrates of protein kinase C drive cell rac1-dependent motility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 57. doi:10.1158/1538-7445.AM2015-57
Abstract 574: CD133 and LGR5 characterize stem-cell like subtype of colorectal cancer
Authors: Stanisavljevic Luka , Myklebust Mette Pernille , Dahl Olav
Published: August 2015

Background: Colorectal cancer (CRC) has recently been divided into six subtypes with cluster mRNA expression analysis. The subtype characterized as stem-like subtype exhibit the highest degree of stemness with poorest prognosis. Prominin-1 (CD133) and leucine-rich-repeat-containing G protein-coupled receptor (LGR5) mark cancer stem cells. High CD133 expression is associated with higher rate of metastases and disease progression. In mouse models, tumor cells expressing CD133 are enriched in chemotherapeutic-resistant colorectal cancer. LGR5+ cells characterize fast-cycling columnar-based stem cells of colon which are instrumental in neoplasia formation. Further, the LGR5+ cells are associated with metastasis formation.

Material and methods: A prospective randomized multicenter randomized trial in Norway recruited from December 1992 to October 1996. 412 colorectal cancer patients stage II and III were treated with surgery alone or 5-fluoruracil (5-FU) and levamisole (Lev) after surgical resection. The patients were followed up by routine clinical examination until five years after surgery. We constructed tissue microarrays from 409 patient samples. CD133 protein expression was assessed by mouse anti-CD133 ([clone AC133], Miltenyi Biotec, Bergisch Gladbach, Germany) at a dilution 1:10. LGR5 mRNA expression was assessed by RNAscope 2.0 HD Detection Kit-Brown (Advanced Cell Diagnostics, Hayward, CA, USA).

Results: Colon cancer stage III patients negative for CD133 had better five-year disease-free survival (DFS) when they received 5-FU/Lev (P = .016). In contrast, the patients did not respond to adjuvant therapy when CD133 was expressed (P = .500). LGR5 was a prognostic marker for colon cancer stage II (P = .045). In colon stage III, mRNA expression of LGR5 was associated with better DFS (P = .046) and patients with positive LGR5 responded to chemotherapy (P = .025). In stage II, LGR5 mRNA expression was associated with lower tumor diameter (P = .005), while in stage III there was no statistically significant association.

In conclusion, CD133 expression was associated with chemotherapy resistance in the colon stage III cohort. LGR5 was associated with a metastatic phenotype in CRC stage II and colon cancer stage III. In addition, LGR5 expression predicted response to chemotherapy in colon cancer stage III.

Citation Format: Luka Stanisavljevic, Mette Pernille Myklebust, Olav Dahl. CD133 and LGR5 characterize stem-cell like subtype of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 574. doi:10.1158/1538-7445.AM2015-574
Abstract 575: Identification of response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors
Authors: Strosberg Jonathan , Cives Mauro , Brelsford Marjorie , Black Michael , Meeker Alan , Ghayouri Masoumeh
Published: August 2015

Capecitabine and temozolomide are active in the treatment of metastatic pNETs, with response rates ranging from 30% to 70%. Several small retrospective series have suggested that MGMT deficiency may predict response to temozolomide, however expression of MGMT has not been validated as a predictive biomarker. Cytotoxic chemotherapy is thought to be most active in aggressive tumors, however the ki-67 index has not been formally evaluated as a predictive factor. It is unclear whether chromosomal instability (which correlates with alternate lengthening of telomeres) predicts response. 144 patients with pNET who underwent treatment with cape/tem were retrospectively evaluated for radiographic response. The predictive role of ki-67% and MGMT by IHC as well as ALT activation by FISH was assessed on up to 59 evaluable archival specimens. Frequently altered genes in pNETs were also sequenced and their status was correlated to the radiographic response. The ORR was 63%. Response to treatment was significantly higher in tumors with ki-67>5% (n = 28) as compared to tumors with ki-67≤5% (n = 31) (ORR: 64% vs 29%; p = 0.006). MGMT status (p = 0.358) and ALT pathway activation (p = 0.174) were not predictive of response. pNETs with ki-67 >5% are more likely to respond to cape/tem. MGMT status appears to have no correlation with response.

Citation Format: Jonathan Strosberg, Mauro Cives, Marjorie Brelsford, Michael Black, Alan Meeker, Masoumeh Ghayouri. Identification of response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 575. doi:10.1158/1538-7445.AM2015-575
Abstract 577: The albumin to globulin ratio predicts chemotherapeutic outcomes in patients with unresectable metastatic CRC
Authors: Shibutani Masatsune , Maeda Kiyoshi , Nagahara Hisashi , Ohtani Hiroshi , Iseki Yasuhito , Ikeya Tetsuro , Sugano Kenji , Sakurai Katsunobu , Yamazoe Sadaaki , Kimura Kenjiro , Toyokawa Takahiro , Amano Ryosuke , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Ohira Masaichi , Hirakawa Kosei
Published: August 2015

Background:

Markers of the systemic inflammatory response have been recognized to correlate with prognosis in patients with various types of cancers. The pretreatment albumin to globulin ratio (AGR) has been reported to correlate with the long-term survival in patients with various cancers. However, there are no reports regarding the correlation between the pretreatment AGR and chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. The aim of this study was to evaluate the prognostic significance of the pretreatment AGR in patients with unresectable metastatic colorectal cancer.

Methods:

A total of 66 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled. The AGR was calculated as follows: Albumin/(Total protein - Albumin).

Results:

The median pretreatment AGR was 1.254 (range: 0.849-1.840); we set 1.25 as the cut-off according to this value. Based on the cut-off value of 1.25, 34 patients were classified into the high-AGR group and 32 patients were classified into the low-AGR group. The high-AGR group had a significantly higher chemotherapeutic disease control rate (p = 0.040) and better progression-free survival (p = 0.0171) and overall survival (p = 0.0360) rates than the low-AGR group. Among the clinicopathological factors, the AGR was identified to be the only prognostic factor for progression-free survival (Hazard Ratio: 2.527, 95% Confidence Interval: 1.152-5.545, p = 0.021) and overall survival (Hazard Ratio: 1.946, 95% Confidence Interval: 1.033-3.668, p = 0.039).

Conclusions:

The pretreatment AGR is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Citation Format: Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Hiroshi Ohtani, Yasuhito Iseki, Tetsuro Ikeya, Kenji Sugano, Katsunobu Sakurai, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. The albumin to globulin ratio predicts chemotherapeutic outcomes in patients with unresectable metastatic CRC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 577. doi:10.1158/1538-7445.AM2015-577
Abstract 578: Molecular subgroup analysis of clinical outcomes in a phase 3 study of gemcitabine and oxaliplatin with or without erlotinib in advanced biliary tract cancer
Authors: Kim Seung T. , Park Joon
Published: August 2015

BACKGROUND. We previously reported that the addition of erlotinib to gemcitabine and oxaliplatin (GEMOX) resulted in greater antitumor activity and might be a treatment option for patients with biliary tract cancers. Molecular subgroup analysis of treatment outcomes in patients who had specimens available for analysis was undertaken.

METHODS. EGFR, KRAS, and PIK3CA mutations were evaluated using peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp reactions. Survival and response rates were analyzed according to the mutational status. 64 patients (48.1%) were available for mutational analysis in the chemotherapy alone group and 61 (45.1%) in the chemotherapy plus erlotinib group.

RESULTS. 1.6% (2/116) harboured an EGFR mutation (2 patients; exon 20), 9.6% (12/121) harboured a KRAS mutation (12 patients; exon 2), and 9.6% (12/118) a PIK3CA mutation (10 patients; exon 9 and 2 patients; exon 20). The addition of erlotinib to GEMOX in patients with KRAS wild type disease (n = 109) resulted in significant improvements in overall response compared with GEMOX alone (30.2% vs. 12.5%, P = 0.024). In 95 patients with both wild type KRAS and PIK3CA, there was evidence of a benefit associated with the addition of erlotinib to GEMOX with respect to response rate (RR) as compared with GEMOX alone (P = 0.04).

CONCLUSION. This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in biliary tract cancers (BTCs). Additionally, the mutation status of PIK3CA may be a determinant for adding erlotinib to chemotherapy in KRAS wild type BTCs.

Keywords: KRAS, PIK3CA, Erlotinib

Citation Format: Seung T. Kim, Joon Park. Molecular subgroup analysis of clinical outcomes in a phase 3 study of gemcitabine and oxaliplatin with or without erlotinib in advanced biliary tract cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 578. doi:10.1158/1538-7445.AM2015-578
Abstract 580: hENT1 testing in pancreatic ductal adenocarcinoma: Are we ready yet? A comparative analysis of the murine and the rabbit antibodies
Authors: Cros Jerome , Marechal Raphael , Bachet Jean Baptiste , Laurent-Puig Pierre , Flejou Jean Francois , Demetter Pieter , Svrcek Magali
Published: August 2015

Introduction

Human equilibrative nucleoside transporter 1 (hENT1) level of expression in pancreatic adenocarcinoma (PAC) may predict survival in gemcitabine-treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2), which is not commercially available. Another antibody, rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PAC. This raises the question of the equivalence of the antibodies.

Patients and Methods

Murine (10D7G2) and rabbit (SP120) monoclonal anti-hENT1 antibodies were applied on the same tissue microarrays of resected PAC. Two sets of patients from 2 separate institutions (n = 147 each) were used to compared hENT1 expression with both antibodies on two different immunochemistry automates. An additional amplification technique was performed on the second set. hENT1 expression was scored as previously reported. Results were correlated with overall survival (OS) following gemcitabine treatment.

Results

The rate of “hENT1 high” cases was lower with the SP120 clone (set 1: 7 versus 48%, set 2:11 versus 38%). With the amplification technique, the rate of “hENT1 high” cases was globally similar between both antibodies. However, the concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS with the 10D7G2 antibody (HR = 0.49; 95% CI: 0.24-0.98; P = 0.045) but not with the SP120 (HR = 1.61; 95% CI: 0.80-3.21; P = 0.18).

Conclusion

Our data suggest that the two antibodies are not equivalent. Further studies are ongoing and will be presented at the meeting: 1/ Comparative analysis of the rabbit antibody on a larger series (n = 471) with staining performed by Ventana® (Roche®), 2/ Comparative analysis of 3 additional anti-hENT1 antibody together with mRNA level correlation, 3/ Comparative expression of hENT1 in a series of matched primary tumors-metastases.

Citation Format: Jerome Cros, Raphael Marechal, Jean Baptiste Bachet, Pierre Laurent-Puig, Jean Francois Flejou, Pieter Demetter, Magali Svrcek. hENT1 testing in pancreatic ductal adenocarcinoma: Are we ready yet? A comparative analysis of the murine and the rabbit antibodies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 580. doi:10.1158/1538-7445.AM2015-580
Abstract 584: The DEK oncogene may serve as a predictive plasma biomarker in head and neck cancer patients
Authors: Wise-Draper Trisha , Privette Vinnedge Lisa , Sendilnathan Arun
Published: August 2015

Head and neck cancer (HNC) remains the sixth most common cancer worldwide with almost 50,000 new diagnoses in the US each year. Although, infection with HPV has emerged as a favorable prognostic factor for head and neck squamous cell carcinoma (HNSCC) leading to de-intensifying treatment strategies, no serum biomarkers currently exist to predict tumor response and/or relapse. One candidate serum biomarker is encoded by the human DEK gene. DEK mRNA and protein is highly upregulated in tissue specimens from several tumor types including HNSCC, breast cancer and melanoma and antibodies to DEK are detected in patients with auto-immune disease (juvenile rheumatoid arthritis, systemic lupus erythematous, etc.). Our previous work has demonstrated that DEK is highly and universally expressed in HNSCC tissue specimens regardless of stage or HPV infection. Additionally, in vitro data has suggested that tumor associated macrophages secrete DEK protein leading to the hypothesis that DEK may be present in the serum of cancer patients. In fact, the detection of DEK protein in urine is currently being explored as a diagnostic biomarker for bladder cancer. Here, we sought to determine if secreted DEK protein can be detected in human plasma and if it could be used as a biomarker for HNSCC. Peripheral blood was collected from either patients with newly diagnosed, untreated, HNSCC or age-matched normal healthy controls. Plasma was separated from the samples and subjected to DEK specific ELISA (Cusabio, Wuhan, China). Plasma DEK levels were compared to tumor stage, response to therapy, and overall tumor burden in patients. Preliminary results demonstrate that DEK is indeed present in the plasma of HNSCC patients and we are currently comparing these levels to normal healthy controls. Further analyses are ongoing to determine whether DEK levels predict response to various treatment modalities, correlate with the body's immune response, and whether DEK presence in the serum will predict residual disease and/or early relapse. These data will be important to verify DEK plasma measurements as a clinically useful test and may give insight to future personalized and targeted treatment strategies for HNSCC.

Citation Format: Trisha Wise-Draper, Lisa Privette Vinnedge, Arun Sendilnathan. The DEK oncogene may serve as a predictive plasma biomarker in head and neck cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2015-584
Abstract 588: Search for potential penile cancer biomarkers using frozen tissue proteome profiling by mass spectrometry
Authors: Bulgarelli Adriana , Silva Elisângela de Jesus , Assunção Nilson Antonio , Cunha Isabela Werneck , Zequi Stenio de Cássi , Guimarães Gustavo Cardoso , Soares Fernando Augusto , Vassallo José
Published: August 2015

Penile squamous cell carcinoma (SCC) corresponds to 2.1% of Brazilian men's malignant tumors. In the present study, it was our objective to provide information regarding the differential protein pattern in penile SCC and look for potential prognostic markers. Twenty-four frozen samples, fourteen of penile SCC and ten of normal penile epithelium (NPE) were compared, using two-dimensional gel electrophoresis. A total of 268 spots were identified, 23 were identified only in penile SCC, 207 only in normal tissue and 38 proteins were found differentially expressed between the two groups (p<0.05). Additionally, ongoing experiments for protein identification by Matrix-Assisted Laser Desorption/Ionization - Time of Flight - Mass Spectrometry (MALDI-TOF) have already detected two key proteins with critical role in all aspects of RNA metabolism. The heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) were found expressed only in penile SCC and the RNA helicase DEAD (Asp-Glu-Ala-Asp) box polypeptide 59 (DDX59) were upregulated on tumor samples, which both are associated to tumor aggressiveness. Our data provide a novel proteomic approach to investigate the protein profile of penile SCC and might represent the basis for further studies on the characterization of these proteins, some of which may be of potential clinical value.

Note: This abstract was not presented at the meeting.

Citation Format: Adriana Bulgarelli, Elisângela de Jesus Silva, Nilson Antonio Assunção, Isabela Werneck Cunha, Stenio de Cássi Zequi, Gustavo Cardoso Guimarães, Fernando Augusto Soares, José Vassallo. Search for potential penile cancer biomarkers using frozen tissue proteome profiling by mass spectrometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 588. doi:10.1158/1538-7445.AM2015-588
Abstract 592: Prognostic index system based on 20 genes for predicting recurrence of non-muscle invasive bladder cancer
Authors: Kim Jong Hwan , Kim Seon-Kyu , Yun Seok-Joong , Kim Wun-Jae , Kim Seon-Young
Published: August 2015

Backgrounds

There is a crucial need for practical molecular markers of bladder cancer recurrence, despite several molecular signatures for the bladder cancer outcomes have been numerously investigated. Here, we aim to identify a molecular signature consisting of small number of genes to predict disease recurrence in non-muscle invasive bladder cancer (NMIBC) and to assess its usefulness as a practical indicator.

Methods

Trascriptomic profiling was performed using gene expression data from 103 primary NMIBC specimens (Korean cohort) to identify a signature associated with disease recurrence. The prognostic value of the signature was validated in an independent cohort (European cohort, n = 302). Time-dependent receiver operating characteristic (ROC) curves of recurrence using the nearest neighbour estimation method with a cut-off value of 36 months were used to identify a small number of genes that strongly retain prognostic value. A prognostic index (PI) based on the expression data of 20 genes was developed in the Korean cohort and validated in the European cohort. The association between the 20-gene-based PI method and prognosis of NMIBC patients was assessed using Kaplan-Meier plot, the log-rank test, Cox proportional hazards model, and leave-one-out cross validation methods.

Results

The determination of gene expression patterns by transcriptome data analysis identified 822 genes associated with disease recurrence. Of the 822 genes, 20 genes which are highly associated with recurrence free survival were detected by time-dependent ROC curves. The PI was developed by using Cox coefficient values of 20 genes in the Korean cohort and its robustness was validated in the European cohort (log-rank test, P < 0.001). The PI was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and (hazard ratio = 6.082, 95% confidence interval = 3.280 to 11.279, P < 0.001). The subset analysis also revealed that the PI could identify patients who would benefit from intravesical therapy. Finally, gene network analyses and experimental assays indicated that, among the 20 genes, CA9, ARTS-1 and FGF11 could be important mediators for NMIBC recurrence.

Conclusions

The PI system based on 20 genes illustrates a novel diagnostic tool to identify NMIBC patients that have a high risk of recurrence.

Citation Format: Jong Hwan Kim, Seon-Kyu Kim, Seok-Joong Yun, Wun-Jae Kim, Seon-Young Kim. Prognostic index system based on 20 genes for predicting recurrence of non-muscle invasive bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2015-592
Abstract 594: AGT mutations as a prognosis factor in patients with astrocytoma
Authors: Wegman-Ostrosky Talia , Soto-Reyes Ernesto , Vidal-Millan Silvia , Mejia Sonia , Sánchez-Corona José , Herrera Luis A.
Published: August 2015

Background: Astrocytomas are the most common and lethal brain tumors. The median survival of patients is 15 months. The study of genetic alterations may help to understand the mechanisms of development and behavior of the disease and thus understand the risk factors and prognostic factors. AGT gene and its peptide derivatives, are involved in cell proliferation and neoangiogenesis and resistance to apoptosis, hence the pathogenesis of astrocytomas. Objective: To identify somatic and germinal AGT gene variations in from patients with astrocytoma. Material and methods: 155 randomly selected files from patients diagnosed with astrocytoma between 2008-2014 were revised to determined clinical prognosis factor in Mexican population. In 25 patients, the molecular analysis of the whole codification region, 5´UTR and 3´UTR of the gene AGT was done in tumors biopsy and blood. Each amplified region had a depth of minimum 1500x. IonReporter software was utilize to analyze the genetic variants and using Integrative Genomic Viewer we confirmed that each variant had a Phred higher than 25. Genotypic frequencies were compared with HapMapMex. Results The clinical variants associated with prognosis were age (OR 0.01 IC 95% 1.02-1.07, p = 0.000), Grade IV (OR 17.11, IC 95% 1.89-132.13 p = 0.011), location of tumor (OR 1.17, IC 1.2-6.3, p = 0.016), total resection (OR = .186, IC 95% .098-.622, p = 0.003, Karnofsky (OR = .05, IC 95% 0.024-0.24, p = 0.003), motor deficiency (OR = 3.5, IC = 1.1-10.5, p = 0.025). In blood were found 11 genetic variants. rs4049, rs2148582, rs699, rs4762 and rs1926723 were associated with risk of tumor in the codominant model. rs5050 (- A20C) was statistically associated with the prognosis (OR 10.8, IC 1.16-100.51 p = 0.036). These variant it is part of a haplotype related to low expression of angiotensinogen. In biopsies of 2 patients missense mutations were found p.Arg477His in one patient and Gly226Ala -Pro165Ser in another one. Conclusion: In 8% of the tumors samples new somatic mutations were found. The genetic variant rs5050 of AGT is a prognosis biomarker in patients with astrocytoma.

Citation Format: Talia Wegman-Ostrosky, Ernesto Soto-Reyes, Silvia Vidal-Millan, Sonia Mejia, José Sánchez-Corona, Luis A. Herrera. AGT mutations as a prognosis factor in patients with astrocytoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2015-594
Abstract 595: Digital PCR validates 8q dosage as prognostic tool in uveal melanoma
Authors: de Lange Mark J. , Versluis Mieke , van Pelt Sake , Ruivenkamp Claudia A.L. , Kroes Wilma G. , Cao Jinfeng , Jager Martine J. , Luyten Gre P.M. , van der Velden Pieter A.
Published: August 2015

Background: Uveal melanoma (UM) development and progression is correlated with specific molecular changes. Recurrent mutations in GNAQ and GNA11 initiate UM development while tumour progression is correlated with monosomy of chromosome 3 and gain of chromosome 8q. Hence, molecular analysis of UM is useful for diagnosis and prognosis. The aim of this study is to evaluate the use of digital PCR (dPCR) for molecular analysis of UM.

Methods: A series of 66 UM was analysed with dPCR for three hotspot mutations in GNAQ/GNA11 with mutation specific probes. The status of chromosomes 3 and 8 were analysed with genomic probes. The results of dPCR analysis were cross-validated with Sanger sequencing, SNP array analysis, and karyotyping.

Results: Using dPCR, we were able to determine the molecular profile of 66 enucleated UM. With digital PCR, GNAQ/GNA11 mutations were detected in 60 of the 66 UM. Sanger sequencing revealed three rare variants, and, combined, these assays revealed GNAQ/GNA11 mutations in 95% of UM. Monosomy 3 was present in 43 and chromosome 8 aberrations in 52 of the 66 UM, with dPCR and SNP results showing an excellent correlation (for monosomy 3 r = 0.921, for 8q gain r = 0.922). Survival analysis showed that increasing 8q copy numbers were positively correlated with metastasis risk.

Conclusion: Molecular analysis with dPCR is fast and sensitive. Just like the recurrent genomic aberrations of chromosome 3 and 8, hotspot mutations in GNAQ and GNA11 are effectively detected in heterogeneous samples. Increased sensitivity contributes to the number of mutations and chromosomal aberrations detected. Moreover, quantification of copy number with dPCR validated 8q dosage as a sensitive prognostic tool in UM, of which implementation in disease prediction models will further improve prognostication.

Citation Format: Mark J. de Lange, Mieke Versluis, Sake van Pelt, Claudia A.L. Ruivenkamp, Wilma G. Kroes, Jinfeng Cao, Martine J. Jager, Gre P.M. Luyten, Pieter A. van der Velden. Digital PCR validates 8q dosage as prognostic tool in uveal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 595. doi:10.1158/1538-7445.AM2015-595
Abstract 60: Genotranscriptomic meta-analysis of centromere protein A (CENPA): An essential role in human cancer progression
Authors: Sun Xia , Qu Sifeng
Published: August 2015

Background: As the cancer hallmark, genetic instability caused by abnormal cell division, is characterized with the gain or loss of entire chromosomes. The specific histone-H3 variant, centromere protein-A (CENPA), plays essential role in regulating kinetochore assembly, centromere activity and chromosome stability during cell division. However, the biological function of CENPA in human cancer remains largely uncharacterized. This study aims to determine the prognostic value of CENPA expression in cancer patients and the potential therapeutic target in cancer treatment via the genotranscriptomic meta-analysis.

Methods: In order to well address the issue, a comprehensive and unbiased genotranscriptomic meta-analysis of CENPA in human cancers was performed with the clinical patient information databases, i.e. COSMIC, Oncomine and cBioPortal.

Results: Based on the analysis, it strongly indicated the widespread cancer promoting role of CENPA. There are no gene fusion, very low point mutation (0.15%) and very rare copy number variation (CNV) gain (0.09%) at the CENPA locus in 15214 patient samples across 33 cancer types. However, transcriptomic analyses indicated high correlation of increased CENPA mRNA levels in various solid cancer tissues compared with normal tissues. Furthermore, the poor clinical outcome among 51 clinical cohorts with different cancer types shows significantly correlation with CENPA up-regulation, especially in breast cancer. More importantly, the CENPA up-regulation is also significantly correlated with the metastasis progression and pathology-assessment in breast cancer patients. The high rank of metastatic related genes correlated with CENPA up-regulation is also confirmed in TCGA breast cancer cohorts.

Conclusions: The current study highly indicates the essential cancer promoting role of CENPA in human cancer and its value as prognostic marker in clinical use. It also provides rationale for further investigation of CENPA as potential therapeutic target in breast cancer treatment.

Citation Format: Xia Sun, Sifeng Qu. Genotranscriptomic meta-analysis of centromere protein A (CENPA): An essential role in human cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 60. doi:10.1158/1538-7445.AM2015-60
Abstract 607: Genomic analyses and novel models validate CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans
Authors: Marino-Enriquez Adrian , Eilers Grant , Czaplinski Jeffrey , Mayeda Mark , Tao Derrick , Zhu Meijun , Hornick Jason L. , Sicinska Ewa , Wagner Andrew J. , Fletcher Jonathan A.
Published: August 2015

Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by an infiltrative growth and high rate of local recurrence. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in ∼50% of patients with unresectable or metastatic DFSP. Efficacious medical therapies have not been developed for imatinib-resistant DFSP. To this end, we established the first patient-derived models of imatinib-resistant DFSP.

Cell lines and mouse xenografts were established from DFSP105, an imatinib-resistant fibrosarcomatous DFSP, and were characterized by SNP arrays and sequencing to identify targetable genomic alterations. Findings were validated in vitro and in vivo, and confirmed in a case series including 12 DFSP and 6 fibrosarcomatous DFSP. SNP analysis of DFSP105 revealed a homozygous deletion encompassing CDKN2A. The resultant p16 loss implicated CDK4/6 as a potential therapeutic target in DFSP. In further studies, we demonstrated CDKN2A homozygous deletion in 1 of 12 conventional DFSP vs. 2 of 6 fibrosarcomatous DFSP. In vitro treatment of DFSP105 with two structurally distinct selective CDK4/6 inhibitors, PD-0332991 and LEE011, led to inhibition of RB1 phosphorylation and proliferation (GI50 160 nM and 276 nM, respectively). In vivo treatment of DFSP105 with PD-0332991 (150 mg/kg) inhibited xenograft growth in mice, in comparison with imatinib-treated or untreated tumors.

In conclusion, CDKN2A deletion is a novel mechanism of DFSP genetic progression. CDK4/6 inhibition is a preclinically effective treatment against p16-negative, imatinib-resistant fibrosarcomatous DFSP, and should be evaluated as a therapeutic strategy in patients with imatinib-resistant DFSP.

Citation Format: Adrian Marino-Enriquez, Grant Eilers, Jeffrey Czaplinski, Mark Mayeda, Derrick Tao, Meijun Zhu, Jason L. Hornick, Ewa Sicinska, Andrew J. Wagner, Jonathan A. Fletcher. Genomic analyses and novel models validate CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2015-607
Abstract 613: Copy number variations distinguish lung adenocarcinomas from squamous cell carcinomas
Authors: Song Kai , Zheng Guangqiang , Girard Luc , Wistuba Ignacio I. , Roth Jack A. , Behrens Carmen , Suraokar Milind B. , Minna John D. , Gazdar Adi F.
Published: August 2015

Purpose

To develop a molecular based classification of non-small cell lung carcinomas based on genome wide copy number variations (CNVs).

Background

For a number of clinical and biologic reasons, the accurate classification of non small cell lung carcinoma (NSCLC) into adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is essential. DNA based tests, which are not currently used, are more robust when applied to formalin fixed paraffin embedded tissues.

Materials and Methods

TCGA Dataset: The Cancer Genome Atlas project (TCGA) level 3 CNVs data (Affymetrix Genome-Wide Human SNP Array 6.0) of resected ADC (n = 241) and SCC (n = 210) patients were utilized as a Training set along with 1091 non malignant lung samples.

SPORE Patient Dataset: The UT Lung SPORE cohort consists of 248 resected lung cancers (168 ADC and 74 SCC samples) run with the Agilent 244K Human Genome CGH Microarray.

Molecular signature identification based on the morphologic subclassification of NSCLC: We used statistical algorithms to identify potential CNV biomarkers and combined them with known amplified oncogenes to identify 28 CNV signature genes that were highly correlated with histological classification.

Identification of CNV classifier genes. The CNV signature genes were identified through the following four sequential steps: 1) Paired t-test. 2) Elastic Net. 3) Partial lease squares algorithm. 4) Naive Bayes classifier.

Results:

The 28 gene CNV signature accurately separated squamous cell carcinomas from adenocarcinomas in the Training and Validation sets as well as distinguished tumors from non-malignant tissues (Table 1).

Table 1. The classification results between ADC and SCC

DataSensitivitySpecificityAccuracyADC vs SCCTraining set (TCGA)0.940.870.91Validation set (SPORE)0.870.840.86Tumor vs Non-malignantADC0.910.960.94SCC0.970.980.98

Conclusions: A 28 gene CNV signature distinguished lung adenocarcinomas from squamous cell carcinomas with great accuracy (86-91%) and the lung tumor samples can be distinguished from the non-malignant lung samples with an accuracy of 94-98%.

Citation Format: Kai Song, Guangqiang Zheng, Luc Girard, Ignacio I. Wistuba, Jack A. Roth, Carmen Behrens, Milind B. Suraokar, John D. Minna, Adi F. Gazdar. Copy number variations distinguish lung adenocarcinomas from squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2015-613
Abstract 614: Clinical implications of NRG1 fusion in invasive mucinous adenocarcinoma of the lung
Authors: Han Ji-Youn , Lee Yeon-Su , Lee Dong Hoon , Hong Dong Wan , Hong Seung Hyun , Hwang Jung-Ah , Lee Byung Il , You Hye Jin , Shin Dong Hoon , Lee Geon Kook
Published: August 2015

Background: We investigated the clinical implications of NRG1 fusion, a newly identified oncogenic rearrangement, in surgically resected invasive mucinous adenocarcinoma (IMA) of the lung.

Patients and Methods: We performed RNA sequencing on 7 lung adenocarcinomas that had no known driver oncogenes and identified a novel fusion, SLC3A2-NRG1 in a case of IMA. The newly detected NRG1 fusion was verified in an IMA cohort of 59 cases using reverse transcription polymerase chain reaction (RT-PCR), direct sequencing and fluorescence in situ hybridization (FISH) analysis. Targeted caner panel sequencing and RT-PCR were performed to identify the possible coexistence of NRG1 fusions and other genetic alterations.

Results: After screening 59 IMA, we found a total of 16 NRG1 fusions (13 SLC3A2-NRG1 and 3 CD74-NRG1). Among the 16 cases with NRG1 fusion, concurrent KRAS codon 12 mutations were found in 10 cases. We also found concurrent NRAS Q61L mutation and EML4-ALK fusion in additional two cases with NRG1 fusion. When comparing survival according to the presence of an NRG1 fusion, patients harboring NRG1 fusion showed inferior overall survival (OS) compared to those without NRG1 fusion (median 51.9 months [mo] vs. not reached [NR], P = 0.019). They also showed a trend toward shorter disease-free survival (DFS) (median 21.9 vs. 79.4 mo, P = 0.113). In the stage I IMA, patients with NRG1 fusion showed significantly inferior OS (median 48.1 mo vs. NR, P = 0.009) and DFS (median 18.9 vs. 91.1 mo, P = 0.013) compared to those without NRG1 fusion.

Conclusion: NRG1 fusion is an important prognostic factor in IMA and should be considered a novel therapeutic target for IMA.

Citation Format: Ji-Youn Han, Yeon-Su Lee, Dong Hoon Lee, Dong Wan Hong, Seung Hyun Hong, Jung-Ah Hwang, Byung Il Lee, Hye Jin You, Dong Hoon Shin, Geon Kook Lee. Clinical implications of NRG1 fusion in invasive mucinous adenocarcinoma of the lung. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 614. doi:10.1158/1538-7445.AM2015-614
Abstract 619: Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients
Authors: Sausen Mark , Phallen Jillian , Adleff Vilmos , Jones Siân , Leary Rebecca J. , Lytle Karli , Parpart-Li Sonya , Murphy Derek , Barrett Michael T. , Linehan David C. , Maitra Anirban , Hruban Ralph , Von Hoff Daniel D. , Johansen Julia S. , Diaz Luis A. , Drebin Jeffrey A. , Velculescu Victor E.
Published: August 2015

Pancreatic adenocarcinoma has the worst overall mortality of any solid tumor, with only 6% of patients surviving after 5 years. To evaluate the clinical implications of genomic alterations in this low cellularity tumor type, we deeply sequenced the genomes of 134 enriched pancreatic adenocarcinomas from patients who underwent potentially curative resections. Given the low neoplastic cellularity of pancreatic cancers, we enriched for neoplastic cells either by macrodissection of primary tumors or by flow-sorting of tumor nuclei, and performed deep sequencing (high coverage) of these enriched samples using next-generation sequencing approaches. We obtained a total of >1Tb of sequence data, resulting in an average coverage within the target regions of >200-fold for each tumor analyzed by whole-exome sequencing and >750-fold for each tumor analyzed by targeted cancer gene sequencing. These approaches allowed us to identify sequence changes, including single base and small insertion or deletion mutations, as well as copy number alterations in >20,000 genes in the whole-exome analyses and in 116 specific genes in the targeted analyses. These analyses revealed that somatic mutation of chromatin remodeling genes were associated with improved progression-free and overall survival. Alterations in genes with potential clinical utility were observed in a majority of cases and included alterations of AKT1, AKT2, BRCA2, ERBB2, KIT, and PIK3CA. Non-invasive liquid biopsy analyses were performed before and after surgery to evaluate the presence of circulating tumor DNA in the plasma of 83 patients. Through these approaches, we were able to diagnose early stage pancreatic tumors in the majority of patients and to detect the presence of circulating tumor DNA prior to clinical relapse. These observations provide genetic markers of clinical outcome in pancreatic cancer and suggest new avenues for personalized therapy.

Citation Format: Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Karli Lytle, Sonya Parpart-Li, Derek Murphy, Michael T. Barrett, David C. Linehan, Anirban Maitra, Ralph Hruban, Daniel D. Von Hoff, Julia S. Johansen, Luis A. Diaz, Jeffrey A. Drebin, Victor E. Velculescu. Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 619. doi:10.1158/1538-7445.AM2015-619