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  • Online Resource  (13)
  • American Association for Cancer Research (AACR)  (13)
  • 2010-2014  (13)
  • 2014  (13)
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  • Online Resource  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 2010-2014  (13)
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  • 2014  (13)
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  • 1
    Online Resource
    Online Resource
    Abstract 1379: Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1379-1379
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1379-1379
    Abstract: Glioblastoma (GBM) is the most common and most aggressive brain tumor in adults. Its frequent recurrence after resection and dismal prognosis are thought to be due to a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy. In this study, we performed an in depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary GBM tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified two groups hyper- and hypomethylated of genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also be found in primary GBM-derived xenograft tumors suggesting that they were not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM, and PENK. The comparison between the NSC line and the normal brain tissue sample leads to the identification of a group of NSC-specific differentially methylated regions (nsDMRs). Cluster analysis using nsDMRs revealed the presence of stem cell-specific DNA methylation signatures in both primary GBM and GSC lines. Higher expression of genes associated with stem cell-specific DNA methylation signatures such as DNMT3A, STAT5A, CSTB, PMEPA1 and G6PD in GBM patients was found to be associated with poor patient survival. The results from this study demonstrate the utility of using cancer stem cell models for advancing understanding of the pathobiology of gliomas. Citation Format: Eun Joon Lee, Prakash Rath, Jimei Liu, Dungsheng Ryu, Alan Free, Lirong Pei, Douglas C Anthony, Suash Sharma, Mark D Kirk, John J. Laterra, Duck Hwan Ryu, Jeong-Hyeon Choi, Huidong Shi, Douglas C. Miller, N. Scott Litofsky, Qi Feng. Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells. [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 1379. doi:10.1158/1538-7445.AM2014-1379
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1379
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 4 ( 2014-04-01), p. 658-669
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 4 ( 2014-04-01), p. 658-669
    Abstract: Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P & lt; 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P & lt; 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P & lt; 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-13-0340
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
    Online Resource
    Online Resource
    PIK3CA, BRAF , and PTEN Status and Benefit from Cetuximab in the Treatment of Advanced Colorectal Cancer—Results from NCIC CTG/AGITG CO.17
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 3 ( 2014-02-01), p. 744-753
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 3 ( 2014-02-01), p. 744-753
    Abstract: Purpose: Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. Experimental Design: Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment–biomarker interaction. Results: A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). Conclusions: In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size. Clin Cancer Res; 20(3); 744–53. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0606
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    VEGF/VEGFR-2 Upregulates EZH2 Expression in Lung Adenocarcinoma Cells and EZH2 Depletion Enhances the Response to Platinum-Based and VEGFR-2–Targeted Therapy
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 14 ( 2014-07-15), p. 3849-3861
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 14 ( 2014-07-15), p. 3849-3861
    Abstract: Purpose: To investigate the mechanisms of regulation and role associated with enhancer of zeste homolog 2 (EZH2) expression in lung cancer cells. Experimental Design: We investigated the mechanisms of EZH2 expression associated with the VEGF/VEGFR-2 pathway. Furthermore, we sought to determine the role of EZH2 in response of lung adenocarcinoma to platinum-based chemotherapy, as well as the effect of EZH2 depletion on VEGFR-2–targeted therapy in lung adenocarcinoma cell lines. In addition, we characterized EZH2 expression in lung adenocarcinoma specimens and correlated it with patients' clinical characteristics. Results: In this study, we demonstrate that VEGF/VEGFR-2 activation induces expression of EZH2 through the upregulation of E2F3 and hypoxia-inducible factor-1α (HIF1α), and downregulated expression of miR-101. EZH2 depletion by treatment with 3-deazaneplanocin A and knockdown by siRNA decreased the expression of EZH2 and H3K27me3, increased PARP-C level, reduced cell proliferation and migration, and increased sensitivity of the cells to treatment with cisplatin and carboplatin. In addition, high EZH2 expression was associated with poor overall survival in patients who received platinum-based adjuvant therapy, but not in patients who did not receive this therapy. Furthermore, we demonstrated for the first time that the inhibition of EZH2 greatly increased the sensitivity of lung adenocarcinoma cells to the anti–VEGFR-2 drug AZD2171. Conclusion: Our results suggest that the VEGF/VEGFR-2 pathway plays a role in regulation of EZH2 expression via E2F3, HIF1α, and miR-101. EZH2 depletion decreases the malignant potential of lung adenocarcinoma and sensitivity of the cells to both platinum-based and VEGFR-2–targeted therapy. Clin Cancer Res; 20(14); 3849–61. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-1916
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
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    Abstract 201: The combination treatment of TNF-α and poly (dA:dT) preactivated hMSCs with doxorubicin enhances antitumorigenic activity
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 201-201
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 201-201
    Abstract: Our recent study showed that human mesenchymal stem/stromal cells (hMSCs) were activated to express TRAIL by exposure to TNF-α. These TRAIL expressing hMSCs effectively induced apoptosis in MDA-MB-231 (MDA) cells in vitro and in vivo. TRAIL was further up-regulated by RNA released by dead MDA cells in a TLR3-dependent manner. Here, we show that the further increase of TRAIL in hMSCs was also mediated by feed-forward stimulation of AIM2 or IFIH1 by DNA and RNA released from dead MDA cells. Poly(dA:dT), a synthetic ligand for AIM2, most effectively activated hMSCs to express TRAIL and increased the killing efficacy of hMSCs in MDA cells compared to TNF-α or poly(I:C), a synthetic ligand for TLR3 or IFIH1. Furthermore, weekly infusions of hMSCs pre-activated with TNF-α and poly(dA:dT) effectively inhibited the progression of lung tumor formation in mice, compared to TNF-α pre-activated hMSCs. Such anti-tumorigenic effect of hMSCs upon activation with TNF-α and poly(dA:dT) was enhanced when combined with chemotherapeutic drug, doxorubicin and thereby, this combination treatment significantly reduced the size of tumor burden in mice compared to TNF-α pre-activated hMSC treatment. These results suggest that treatment of pre-activated hMSCs combined with doxorubicin enhances their tumor-suppressive properties and may provide a potential novel therapy for cancer treatment. Citation Format: Nara Yoon, Min Sung Park, Grant Peltier, John C. Reneau, Darwin J. Prockop, Darwin J. Prockop, Ryang Hwa Lee. The combination treatment of TNF-α and poly (dA:dT) preactivated hMSCs with doxorubicin enhances antitumorigenic activity. [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 201. doi:10.1158/1538-7445.AM2014-201
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-201
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 6
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    Online Resource
    Abstract 1274: Alcohol and lung cancer risk: a pooled analysis using International Lung Cancer Consortium studies
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1274-1274
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1274-1274
    Abstract: Background: Alcohol consumption is known to be associated with risk of developing several cancers. It is unclear, however, whether alcohol consumption is a risk factor for lung cancer. The relationship between lung cancer and alcohol consumption is likely to be confounded by smoking. To minimize potential confounding by tobacco consumption, we conducted a pooled analysis to examine the association of alcohol consumption with lung cancer risk in a large sample of never-smokers. Methods: We pooled data from 22 case-control and cohort studies from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. We examined the association of average lifetime alcohol consumption (expressed as average grams per day intake) with lung cancer risk in never smokers using logistic regression to model categories of alcohol consumption (0 & lt;5g per day, 5 & lt;10g per day, 10 & lt;20g per day, 20 & lt;30g per day, 30 & lt;45g per day, 45+ g per day). To investigate the shape of the dose response relationship, we applied restricted cubic spline models to examine the association for lung cancer risk overall and by histological subtype. Additional analyses examined wine, beer and liquor consumption in relation to risk, with mutual adjustment for each alcoholic beverage. All analyses were adjusted for age, sex, education, ethnicity and study. Results: A total of 2548 never-smoking cases and 9362 never-smoking controls were included in the analysis. The results showed lower risk among consumers of alcohol with strongest evidence found for moderate drinkers relative to non-drinkers with ORs of 0.80 (95% CI 0.70-0.90) and 0.82 (95% CI 0.69-0.99) for & lt;5grams and 5-10 grams of alcohol per day respectively. Non-linear restricted cubic splines showed reduced lung cancer risk among moderate drinkers relative to non-drinkers with risk increasing towards the null as consumption increased. Similar results were seen for adenocarcinoma and squamous cell carcinoma. Associations with lung cancer differed for wine and beer consumption. Reduced risk was observed for wine drinking particularly at low levels of drinking, OR of 0.80 (95% CI=0.69-0.94) for & lt;5g per day. Risk for beer consumption increased from close to null among occasional drinkers to 1.54 (95% CI 0.90-2.65) among consumers of 20-30g of alcohol per day (test for trend P=0.09). Conclusions: These results indicate an inverse association between moderate drinking and lung cancer risk relative to never drinkers. However, the inverse association was restricted to wine consumption, not consumption of beer. Lifestyle differences between consumers of beer and wine may play a role in differing patterns of risk found by alcohol type. Citation Format: Gordon Fehringer, Darren Brenner, Zuo-Feng Zhang, Yuan-Chin Amy Lee, Keitaro Matsuo, Isabelle Stucker, Paolo Vineis, Paolo Boffetta, Paul Brennan, Maria T. Landi, Hal Morgenstern, Curtis C. Harris, Qing Lan, Yun-Chul Hong, Jack Siemiatycki, John R. McLaughlin, Philip Lazarus, Joshua Muscat, Ann G. Schwartz, Juan M. Barros Dios, Alberto R. Raviña, Gad Rennert, David C. Christiani, Adonina Tardon, Loic Le Marchand, Irene Orlow, Eric J. Duell, Angeline S. Andrew, Hermann Brenner, Dario Consonni, Ann Olsson, Kurt Straif, Rayjean J. Hung. Alcohol and lung cancer risk: a pooled analysis using International Lung Cancer Consortium studies. [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 1274. doi:10.1158/1538-7445.AM2014-1274
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1274
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 7
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    Phase II Study of Cetuximab in Combination with Cisplatin and Radiation in Unresectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: Eastern Cooperative Oncology Group Trial E3303
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 19 ( 2014-10-01), p. 5041-5051
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 19 ( 2014-10-01), p. 5041-5051
    Abstract: Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination. Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival. Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively). Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-0051
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    Abstract 4127: A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways Study
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4127-4127
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4127-4127
    Abstract: Background: With over 2.8 million breast cancer survivors in the U.S. today, there is increasing interest and need to identify factors associated with recurrence and survival. The Pathways Study was designed to examine the effects of lifestyle (e.g., diet, physical activity, complementary and alternative medicine [CAM]), psychosocial (e.g., quality of life), molecular and genetic, medical care, and contextual (e.g., social and built environment characteristics) factors on breast cancer prognosis. Methods: Women newly-diagnosed with invasive breast cancer were identified daily from Kaiser Permanente Northern California (KPNC) electronic pathology records from January 2006 to April 2013; KPNC is a large, integrated health care organization. Eligibility included age at diagnosis of at least 21 y, no previous history of invasive cancer, and English, Spanish or Chinese-speaking. Women were enrolled during an in-person baseline interview that took place on average two months post-diagnosis, with collection of blood and saliva specimens. Active follow-up to update lifestyle and other factors and ascertain outcomes occurs periodically. Outcomes are also identified using KPNC electronic databases and confirmed via medical record review. Results: The final study cohort consists of 4,505 women, with blood and saliva collected from 90% and 95% of participants, respectively. The cohort has substantial racial/ethnic diversity: 64.2% White, 12.4% Hispanic, 12.8% Asian, 7.9% African American, 2.7% other. The mean age at diagnosis was 59.6 y (range: 23.6-94.8 y). Educational attainment is high, with 84.1% of the cohort having at least some college education. Most women were diagnosed with AJCC Stage I (54.0%) or II (34.6%) cancers, and receptor status was positive for estrogen in 83% of women, progesterone in 63.4%, and Her2 in 12.3%. As of December 1, 2013, 307 recurrences and 327 deaths have been confirmed, with 490 experiencing either. Initial age-adjusted results with proportional hazards regression demonstrate poorer disease-free survival (DFS) among African Americans (hazard ratio [HR]=1.84, 95% confidence interval [CI] ,1.39-2.45) and better DFS among Asians (HR=0.70, 95% CI, 0.49, 1.00) compared to Whites. Greater stage at diagnosis, increasing age, and negative ER status are also associated with poorer DFS. Discussion: The Pathways Study is a rich, unique resource collecting data on multiple factors that may influence breast cancer prognosis, including lifestyle, molecular, medical, and contextual factors. To date, 14 papers have been published on topics ranging from CAM use, quality of life, and physical activity during treatment, to tumor DNA methylation profiles and correlates of breast cancer molecular subtypes. With continued follow-up, it promises to provide findings on factors influencing prognosis to help guide breast cancer care. Citation Format: Lawrence H. Kushi, Marilyn L. Kwan, Isaac J. Ergas, Cecile A. Laurent, Julie R. Munneke, Janise M. Roh, Heather Greenlee, Chi-Chen Hong, Theresa H. Keegan, Dawn L. Hershman, Susan E. Kutner, Marion M. Lee, Jeanne Mandelblatt, Alfred I. Neugut, Peggy Reynolds, Salma Shariff-Marco, Li Tang, Song Yao, Janice Barlow, Scarlett Lin Gomez, John K. Wiencke, Christine B. Ambrosone. A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways Study. [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 4127. doi:10.1158/1538-7445.AM2014-4127
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4127
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract 933: Copy number changes are associated with BRAF and NRAS mutations and response to treatment with carboplatin, paclitaxel and sorafenib
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 933-933
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 933-933
    Abstract: Copy number alterations, both gains and losses, have been shown to be involved in melanoma pathogenesis and may provide novel targets for treatment. Previous observations have additionally suggested that specific copy number profiles may be associated with BRAF, NRAS and WT/WT status. The randomized, phase III clinical trial E2603: carboplatin, paclitaxel, +/- sorafenib (CP vs. CPS) offers the largest available collection of tumor samples from patients with well annotated clinical outcome to evaluate these associations. We evaluated copy number variants (CNVs) using array Comparative Genomic Hybridization in melanoma tumor samples from patients treated on this trial. Genomic DNA was hybridized on SurePrint G4 human CGH microarrays 2 x 440 K (Agilent). Copy number gains and losses were ≥ 0.3 or ≤ -0.3 on a log2 scale, respectively (Nexus BioDiscovery, Inc). In 119 melanoma tumor samples, 45% had BRAF mutations, 24% NRAS mutations, and 24% without either (designated WT), CNVs were evaluated in an initial set of 26 genes known to be involved in melanoma pathogenesis. Overall genomic instability, as measured by number of genes with CNVs, was associated with poor ECOG performance status (P=0.007) and marginally significant for more organs with metastatic involvement (P=0.06), and is consistent with other studies suggesting that genomic instability is a predictor of worsened outcome. We further explored the association between copy number and somatic mutation status. Not surprisingly, BRAF gene amplification was observed in 91% of BRAF mutant melanoma tumor samples (P & lt;0.001, as compared to 66% of NRAS/WT samples). The average value of BRAF copy number was higher in tumor samples with BRAF V600K mutations compared to samples with BRAF V600E mutations (1.11 v 0.55, P & lt;0.001). MET, also on chr 7, was found to be amplified in 59% of BRAF mutated melanoma tumor samples. The average value of MET copy number was also higher in BRAF V600K mutant compared to BRAF V600E mutant melanoma (0.53 v 0.27, P=0.04), which may contribute to the differing clinical behaviors of melanomas with the two mutations. Patients with BRAF copy number gain had a trend towards lower overall response rate to either treatment compared to diploid (15.2% v 29.6%, OR=0.37, P=0.08). Patients with NRAS copy number gain receiving CPS had significantly improved overall survival compared to patients receiving CP alone (HR=0.35, P=0.03) in multivariable Cox model. We had previously found a trend suggesting an improved clinical response and PFS in patients with NRAS mutant melanoma treated with CPS as compared to CP. Our present study demonstrates an association between CNVs and treatment response to CP or CPS, as well as an association with somatic mutations. In addition, distinct cooperating genomic events identified in somatic mutation cohorts, such as MET and BRAF V600K gain, may contribute to the pathogenesis of melanoma tumors. Citation Format: Melissa A. Wilson, Fengmin Zhao, Sanika Khare, Richard Letrero, Kurt D'Andrea, David L. Rimm, John M. Kirkwood, Harriet M. Kluger, Sandra J. Lee, Lynn M. Schuchter, Keith T. Flaherty, Katherine L. Nathanson. Copy number changes are associated with BRAF and NRAS mutations and response to treatment with carboplatin, paclitaxel and sorafenib. [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 933. doi:10.1158/1538-7445.AM2014-933
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-933
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Discovery Vol. 4, No. 5 ( 2014-05-01), p. 564-577
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 5 ( 2014-05-01), p. 564-577
    Abstract: In this report, we show that expression of a NUP98–PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell–like expression signature, including Hoxa, Hoxb, and Meis1 genes. The PHF23 plant homeodomain (PHD) motif is known to bind to H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein binds to chromatin at a specific subset of H3K4me3 sites, including at Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD motifs to H3K4me3, rapidly and selectively killed NP23-expressing myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98–JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3. Significance: NP23 and NJL belong to a subset of chromatin-modifying fusion oncoproteins that cause leukemia characterized by overexpression of Hoxa and Meis1 genes. Inhibition of NP23 binding to H3K4me3 at Hoxa and Meis1 loci by disulfiram, a U.S. Food and Drug Administration–approved drug, leads to leukemic cell death, demonstrating the feasibility of targeting this subset of oncoproteins. Cancer Discov; 4(5); 564–77. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 495
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-13-0419
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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