bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4142: Capacity building in cancer management in Africa: Envisioning a future from past challenges
Authors: Williams Christopher K. O.
Published: May 2015

Sub-Saharan African institutions, especially the Uganda Cancer Institute in Kampala, Uganda, led in the development of chemotherapy (CMT) for lymphoma subtypes between 1950 and 1980. Recent WHO emphasis on global non-communicable diseases indicates a need for regional HC paradigm shift in a region long inundated with communicable diseases. Expected barriers in capacity building in medical oncology there are illustrated with challenges of experimental management of Burkitt's lymphoma (BL) at the University College Hospital, Ibadan, Nigeria (UCHIN), where from 1/1984 to 12/1985, a study of tolerability and practicability of high dose cytosine arabinoside (HDAC) CMT was initiated. Included were children (chd) with a diagnosis of BL Ziegler's Stage C or D with or without CNS involvement (CNS±), and life expectancy of at least one month, whose parents/guardians were willing to give oral consent. 60 chd were to be assigned randomly to either the standard treatment (RII) or the investigational (RI) protocol. RI was: Cyclophosphamide (CTX) 1000mg/m2 IV day 1, Vincristine (VCR) 2.0mg/m2 IV day 1, cytosine arabinoside (AC) 50mg/m2 q12hr x 6 doses in cycles 1 and 4, and 1000mg/m2 q12hr x 4 doses and 50mg/m2 q12hr x 2 doses for cycles 2 and 3 cycles q14days x 4cycles. R II was: CTX 1000mg/m2 IV day 1, VCR 2.0mg/m2 IV day 1, AC 50mg/m2 q12hr x 6 doses q14days x 4 cycles. AC 50mg/m2 was given intrathecally days 1 and 5 of each cycle. See Table for results. *MDI: Mean dose intensity. HDAC based CMT was well tolerated with more effective control of systemic and CNS disease compared to conventional CMT. Challenges encountered included ethical issues of medical research in the midst of socio-economic deprivation, technical and manpower inadequacies, unreliable drug supply leading to CMT modifications, communication, lack of compliance and unreliable accessibility to follow-up. Persistence of these problems after >2 decades signals a need for cultural change at all community levels: government, HC administration and among categories of providers.

Table of resultsR-IR-IIp-VALUEDEMOGRAPHY#RANDOMIZED14 (30)16 (30)M/F10/410/6AGE9.5±3.58.5±2.5>0.5STAGEC56D-CNS+46D-CNS-43MDI OF AGENTSVCR0.350.520.09CTX382.6466.40.16IV-AC936.0139.50.001IT-AC33.942.00.034OUTCOMES#EVALUATED1012CR9/95/12PR0/95/12NR0/92/12OS (%)59200.21

Citation Format: Christopher K. O. Williams. Capacity building in cancer management in Africa: Envisioning a future from past challenges. [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 4142. doi:10.1158/1538-7445.AM2014-4142
Abstract 4144: Genetic and epidemiology characterization of head and neck cancers by targeted sequencing
Authors: Perdomo Sandra , Reis Luciana , Anantharaman Devasena , Mckay James , Brennan Paul
Published: May 2015

Oral and pharyngeal cancer, grouped together, is the sixth most common cancer in the world. The annual estimated incidence is around 275,000 for oral and 130,300 for pharyngeal cancers excluding nasopharynx, two-thirds of these cases occurring in developing countries.

The principal objective of this work was to investigate the somatic genetic changes that influence the risk of head and neck cancer occurrence and outcome, and how they interact with environmental and host factors: HPV infection, alcohol and Smoking.

We selected 205 paired samples diagnosed as head and neck SCC included in two multicenter studies in Europe and Brazil: ARCAGE, a multi center case- control study, conducted between 2002-2005 involving 10 countries across Europe and the Gencapo case- control study in the state of Sao Paulo from 2001 to 2010.

Targeted sequencing was performed independently on both germline DNA and the tumor material using the PGM™ System at an average depth of 250X.Sequencing included the entire coding region of 5 of the most frequently mutated genes in Head and Neck cancer: TP53, NOTCH1, CDKN2A, CASP8, and PTEN. HPV status was achieved by capsid protein serology and DNA genotyping. Statistical tests were carried out in the R statistical programming environment or using STATA statistic software. Kaplan-Meier analysis was used to determine overall survival.

Statistically significant differences in exposure status were found between both series of patients with more prevalent cases of former and current both smokers and alcohol drinkers in Brazil(p=0.001). 76% and 63% of the patients in each series had at least 1 mutation and there were no significant differences in the percentage of mutations found. Most of the mutations were found in TP53 (60%) and NOTCH1 (18%). Smoking status was significantly associated to TP53 mutations (p=0.015). Positive serology for HPV16 E6 oncoprotein was associated to Oropharyngeal tumors all of which lack TP53 mutations.

When comparing the survival of patients according to the mutational profile we found a reduction in overall survival for those patients carrying mutations in TP53 (p=0.002) and CDKN2A (p=0.001).

Combined molecular profiling and exposure data can be a resource to assess the role of lifestyle habits on prognosis, and will help to identify early markers of survival for head and neck cancer patients.

Citation Format: Sandra Perdomo, Luciana Reis, Devasena Anantharaman, James Mckay, Paul Brennan. Genetic and epidemiology characterization of head and neck cancers by targeted 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 4144. doi:10.1158/1538-7445.AM2014-4144
Abstract 4146: Polymorphisms of GSTT1, APE1 and MUTYh gene and the risk of oral squamous cell carcinoma
Authors: Lai Chih-Hsiung , Chiu Li-Ling , Chien Huei-Tzu , Liou Saou-Hsing , Huang Shiang-Fu , Chen I-How , Liao Chun-Ta , Hsieh Ling-Ling
Published: May 2015

In Taiwan, oral cancer (including sub-sites in the oral cavity, oropharynx and hypopharynx) is the fourth most common cancer in men. According to the cancer registry report from the Ministry of Health and Welfare of the Executive Yuan, the annual age-adjusted incidence for oral cancer in males has shown a 1.55-fold increase in the past decade. Cigarette smoking, areca quid (AQ) chewing and alcohol drinking have been unveiled as the major risk factors. Previous studies have implicated that oxidative stress generated from cigarette smoking, AQ chewing and alcohol drinking contributed to oral cancer development. It is well known that GSTM1 and GSTT1 are involved in the detoxification of oxidative free radicals and nearly all oxidative DNA lesions are repaired via the DNA base excision repair (BER) pathway. To investigate the role of GSTM1, GSTT1 and BER genes (including OGG1, APE1, MUTYh, WRN and XRCC1) involved in OSCC risk in Taiwan, a comprehensive study on evaluation of polymorphisms of above genes was carried out in 1139 OSCC male cases and 1470 general males. A significant effect of AQ chewing or AQ chewing combined with cigarette smoking or alcohol drinking on the risk of OSCC was observed. GSTT1 null genotype was significantly associated with an increased risk of OSCC (odds ratio (OR), 2.10; 95% confidence interval (CI), 1.64-2.68, p = 0.000000003). After adjustment for cigarette smoking, AQ chewing and alcohol drinking, GSTT1 null-type variant was still significantly associated with an increased risk of OSCC (OR= 2.00; 95% CI, 1.42-2.81, p = 0.00007), while GSTM1 was not associated with OSCC risk. Polymorphisms of OGG1 Ser326Cys, APE1 Asp148Glu, APE1 T-656G, MUTYh Gln324His, WRN Cys1367Arg, and XRCC1 Arg399Gln were not associated with OSCC risk in general. However, stratification analysis indicated that polymorphisms of APE1 Asp148Glu and MUTYh Gln324His were associated with OSCC risk in individuals with cigarette smoking combined with AQ chewing. Furthermore, those individuals with either APE1 148 Asp/Asp or MUTYh 324 His/His genotype had an increased OSCC risks when compared to those with APE1 148 Glu and MUTYh 324 Gln allele (OR = 1.48; 95% CI, 1.13-1.95, p = 0.005). In conclusion, our results demonstrated that polymorphisms of genes involved in detoxification and BER of oxidative stress could influence the OSCC risk especially for those have history of cigarette smoking and AQ chewing.

Citation Format: Chih-Hsiung Lai, Li-Ling Chiu, Huei-Tzu Chien, Saou-Hsing Liou, Shiang-Fu Huang, I-How Chen, Chun-Ta Liao, Ling-Ling Hsieh. Polymorphisms of GSTT1, APE1 and MUTYh gene and the risk of oral squamous cell carcinoma. [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 4146. doi:10.1158/1538-7445.AM2014-4146
Abstract 4150: Nicotine dependence impacts the relationship between genetic variants and risk of lung adenocarcinoma
Authors: Tseng Tung-Sung , Park Jong Y. , Zabaleta Jovanny , Moody-Thomas Sarah , Sothern Melinda S. , Chen Ted , Lin Hui-Yi
Published: May 2015

Lung cancer, the leading cause of cancer death, accounted for 27% of cancer deaths for Americans in 2013. Despite its negative impact on public health, effective early detection tools for lung cancer are still under development. Several genetic variations associated with lung cancer risk and smoking behavior have been identified in some genome-wide association studies. It is unclear, however, if the gene variants affect lung cancer risk directly or indirectly through nicotine dependence. In an attempt to elucidate the relationships between lung cancer, genetic variants and smoking, we applied mediation analysis to quantify the impact of nicotine dependence. We evaluated 37 single nucleotide polymorphisms (SNPs) in nine candidate genes (TERT, CLPTM1L, CHRNB3, CHRNA6, CHRNA5/A3/B4, CYP1A1, and TP53), previously reported to be associated with lung cancer risk or with smoking behavior. A total of 661 lung adenocarcinoma (ADC) cases and 1,347 controls with a smoking history obtained from the Environment and Genetics in Lung Cancer Etiology (EAGLE) case-control study were included in the study. Results show that nicotine dependence is a mediator of the association between lung ADC and gene variations of CHRNA3 and CHRNB4 and accounts for approximately 20% of this relationship. The association between two CHRNA3 SNPs (rs1051730 and rs12914385) and risk for lung ADC reached a genome-wide significance (p-value=1.9x10-10 and 1.1x10-10, respectively). Also, these two SNPs had the most significant indirect effect on lung ADC risk through nicotine dependence (p=7x10-5 and 3x10-4). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had a significant direct association on lung ADC without an indirect effect through nicotine dependence. In addition, rs6474414 in CHRNB3 and rs4646421 in CYP1A1, were associated with nicotine dependence but not directly with lung ADC risk. Our findings provide valuable information for understanding the pathogenesis and for developing potentially effective screening tools for lung ADC. These identified SNPs may improve prediction accuracy of lung ADC at earlier stages, which is essential to enhancing survival rates. Translating these findings into public health practice may lead to tailored and customized smoking cessation interventions for Individuals with genetic variants, which have both direct and indirect effect through nicotine dependence on lung ADC.

Citation Format: Tung-Sung Tseng, Jong Y. Park, Jovanny Zabaleta, Sarah Moody-Thomas, Melinda S. Sothern, Ted Chen, Hui-Yi Lin. Nicotine dependence impacts the relationship between genetic variants and risk of lung adenocarcinoma. [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 4150. doi:10.1158/1538-7445.AM2014-4150
Abstract 4153: Global African ancestry is not associated with lung cancer survival
Authors: Iverson Carissa C. , Fletcher Sarah , Blume Jeffery , Dilks Holli , Chen Heidi , Deppen Stephen A. , Bush William S. , Crawford Dana C. , Blot William J. , Grogan Eric L. , Aldrich Melinda C.
Published: May 2015

Lung cancer is the leading cause of cancer-related mortality among men and women in the United States, accounting for 27% of all cancer-related deaths. Blacks experience poorer 5-year survival compared to whites. We hypothesized that individuals with higher global African ancestry have poorer survival compared to individuals with lower global African ancestry. We identified incident non-small cell lung cancer cases in the Southern Community Cohort Study (SCCS), a prospective study of low-income adults recruited from across the Southeast region of the United States. Individuals who donated a biospecimen were genotyped using the Illumina Human Exome BeadChip, which contains a panel of ancestry informative markers (AIMs). After standard quality control, 398 individuals (262 self-reported black and 134 self-reported white) remained for analysis. Global ancestry was estimated from 2,604 AIMs using the software program ADMIXTURE. Self-reported blacks had a median global African ancestry of 88.12%, while the median global African ancestry in self-reported whites was less than 0.01%. We estimated hazard ratios and 95% confidence intervals using Cox proportional hazard models adjusted for age, sex, body mass index (BMI), cigarettes per day, disease stage, treatment, insurance coverage, family history of lung cancer and recruitment site. BMI, age, cigarettes per day and global African ancestry were modeled using restricted cubic splines. We estimated time dependent area under the curve (AUC) for our main effects model and a main effects model with interactions, both with and without genetic ancestry. We found that the main effects model had an average AUC of 0.81. When global African ancestry was excluded, the AUC was minimally reduced to 0.80. When interactions were added to the main effects model, the AUC increased to 0.88. Removal of global ancestry from the interactions model reduced the AUC to 0.84. In the main effects model, the two most predictive variables were stage and treatment with X2 values of 36.13 (degrees of freedom, df=2) and 15.47 (df=4), respectively. While we conclude that global African ancestry has little effect on overall survival, a relationship between global African ancestry and stage or treatment remains to be investigated.

Citation Format: Carissa C. Iverson, Sarah Fletcher, Jeffery Blume, Holli Dilks, Heidi Chen, Stephen A. Deppen, William S. Bush, Dana C. Crawford, William J. Blot, Eric L. Grogan, Melinda C. Aldrich. Global African ancestry is not associated with lung cancer survival. [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 4153. doi:10.1158/1538-7445.AM2014-4153
Abstract 4155: Genome-wide association study of survival in early stage non-small cell lung cancer
Authors: Ma Hongxia , Jin Guangfu , Hu Zhibin , Shen Hongbing
Published: May 2015

Lung cancer, especially non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths all over the world. Studies have indicated that molecular biomarkers including genetic variants may provide additional values for the targeted treatments and clinical outcomes of NSCLC patients. In this study, we evaluated the associations between genome-wide genetic variants and the survival of NSCLC in a cohort of 365 early-stage NSCLC patients with surgery, and replicated sixteen promising loci in another independent cohort with 327 early-stage NSCLC patients in Chinese population. The results showed that rs10023113 in CAMK2D was consistently associated with survival of early-stage NSCLC in the GWAS scan and the replication cohort [GWAS scan: hazard ratio (HR) = 2.84; 95% confidence interval (CI) = 1.90-4.23, P = 1.29×10-6; replication cohort: HR = 2.19, 95% CI = 1.15-4.21, P = 1.80×10-2]. When combining all the patients, the results showed that the variant allele of rs10023113 was significantly associated with poor prognosis of NSCLC with P value reaching 3.40×10-7 (HR = 2.30, 95% CI = 1.67-3.17). These findings suggest that CAMK2D rs10023113 may be a potentially prognostic marker for overall survival of early-stage NSCLC patients in Chinese population.

Citation Format: Hongxia Ma, Guangfu Jin, Zhibin Hu, Hongbing Shen. Genome-wide association study of survival in early stage non-small cell 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 4155. doi:10.1158/1538-7445.AM2014-4155
Abstract 4163: Chemokine and cytokine levels among lung cancer cases responsive to HPV antigen stimulation
Authors: Scheurer Michael E. , Amirian E Susan , Porter Paul , Corry David B.
Published: May 2015

Purpose: Human papillomavirus (HPV), the causative agent for anogenital and certain head and neck cancers, has been detected in lung tumors, but its role as an etiologic agent for lung cancer remains controversial. The lung is often subjected to exogenous inflammatory insults, and patients with chronic lung inflammation have an increased risk for cancer. In addition to the genomic instability that can be caused by HPV oncoproteins, the immunomodulatory impacts of HPV infection may foster a pro-inflammatory state that increases lung cancer risk. We sought to identify such immunomodulatory effects by examining the differences in lymphocyte and cytokine/chemokine profiles between lung cancer cases and HPV-vaccinated healthy controls.

Methods: Peripheral blood mononuclear cells were isolated from 22 newly diagnosed lung cancer cases and 11 healthy controls who had prior exposure to HPV antigens (immunized with Gardasil). Cells were enumerated via a hemacytometer, and were exposed to media alone or to 3 doses of Gardasil for 20 hours as an HPV challenge. Interleukin (IL-) 4, IFN-γ, and IL-17A secreting cells were then quantified using enzyme linked immunocell spot (ELISpot) analysis. Individuals were categorized as HPV-responsive if the HPV challenge resulted in an increase in at least 2 types of secreting cells, compared to media-exposed cells. The Milliplex human cytokine detection kit was used to assess circulating levels of 38 key cytokines in the plasma of cases and controls. Cytokine levels among HPV-responsive and HPV-non-responsive cases were compared. Survival analysis was also conducted.

Results: All 11 HPV-vaccinated controls demonstrated an increase in cells secreting IFN-γ and IL-4. Of the 22 cases, 13 (59%) were classified as HPV-responsive, with 2 cases displaying an increase in IFN-γ and IL-4 secreting cells upon HPV challenge. Levels of TGF-α, IL-10, IL-3, IL-5, and IL-7 were significantly higher among HPV-responsive compared to non-responsive cases. Significant survival differences were also observed by HPV-responsiveness and cytokine levels.

Conclusions: HPV clearly has substantial effects on the host's systemic immune response. Our study may explain whether and how the pathogenic process differs between HPV-infected and -uninfected lung tumors.

Citation Format: Michael E. Scheurer, E Susan Amirian, Paul Porter, David B. Corry. Chemokine and cytokine levels among lung cancer cases responsive to HPV antigen stimulation. [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 4163. doi:10.1158/1538-7445.AM2014-4163
Abstract 417: DNA methylation changes in Lynch syndrome and FAP-associated colorectal tumorigenesis
Authors: Valo Satu , Kaur Sippy , Ristimäki Ari , Renkonen-Sinisalo Laura , Järvinen Heikki , Mecklin Jukka-Pekka , Nyström Minna , Peltomäki Päivi
Published: May 2015

Colorectal cancer (CRC) develops via multiple steps which involve genetic changes, such as mutations in growth-regulatory genes, and epigenetic alterations, such as CpG island hypermethylation. These changes accumulate over time in the normal tissue, for example due to many environmental factors such as diet, and may result in pre-cancerous field defects. Genes having high level of methylation in peritumoral tissues could be used as biomarkers for colorectal carcinogenesis.

The most common familial cancer susceptibility syndromes are familial adenomatous polyposis (FAP), caused by inherited mutations in the APC tumor suppressor gene, and Lynch syndrome (LS), associated with inherited defects of the DNA mismatch repair (MMR) genes which together with other genetic and epigenetic changes are known to accelerate tumorigenesis. This investigation was designed to define how CpG island methylation of CRC risk genes varies in pre-cancerous and cancerous lesions, adjacent normal mucosa and distinct normal mucosa from genetically predisposed individuals.

Colonic mucosa biopsies from different colorectal regions were gathered from 40 Finnish LS mutation carriers and 23 FAP patients during regular surveillance. In addition with normal mucosa biopsies, all adenoma and carcinoma findings from these individuals together with matching normals were gathered and analyzed. Patient information was obtained from the nation-wide registry. CpG island methylation was studied with the methylation-specific multiplex ligation-dependent probe amplification test (MS-MLPA) which detects CpG methylation of selected genes. Immunohistochemistry was used to detect MMR protein expression in neoplastic lesions.

Of 16 CRC risk genes tested so far 9 show increased methylation in polyps/adenomas/carcinomas. Mean methylation values increase along with age in both syndromes, with polyps from LS showing the highest proportional increase relative to normal tissues. The results offer new insights to the molecular mechanisms through which DNA methylation can affect colorectal carcinogenesis in LS and FAP mutation carriers.

Citation Format: Satu Valo, Sippy Kaur, Ari Ristimäki, Laura Renkonen-Sinisalo, Heikki Järvinen, Jukka-Pekka Mecklin, Minna Nyström, Päivi Peltomäki. DNA methylation changes in Lynch syndrome and FAP-associated colorectal tumorigenesis. [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 417. doi:10.1158/1538-7445.AM2014-417
Abstract 4173: Discovery at the interface: novel anticancer agents targeting human estrogen receptor/S100 interactions
Authors: Lee David H. , Asare Bethany K. , Hudson Matthew L. , Rajnarayanan Rajendram V.
Published: May 2015

Estrogen-triggered nuclear transcription factor, estrogen receptor (ER) is expressed in about 70% of breast cancer. ER mediates various cellular signaling events including the genomic regulation of target genes that affect reproduction, development, and general metabolism. The antiestrogen tamoxifen is currently administered to patients in order to induce regression of the tumor growth. However, upon continued administration, breast cancer patients develop resistance to tamoxifen. In addition, calcium binding proteins such as, calmodulin (CaM) which are significantly overexpressed in cancer cells, can activate transcription of target genes by directly binding to ER in lieu of estrogen. Calmodulin antagonists (w7 and melatonin) have been shown to significantly inhibit human estrogen receptor alpha (hERalpha) transcriptional activity. In search of a novel anti-cancer agent, we generated a library of interaction profiles of human ER-EF hand protein complexes and identified S100B and S100P (high sequence and structure homology with CaM) as potential targets. Furthermore, S100P is shown to mediate tamoxifen-acquired resistance and cell migration capacity in MCF-7 breast cancer cells. Our objective is to develop peptidomimetics and small molecules to block ER-S100 interactions using an integrated proteomics-assisted drug discovery approach. Briefly, using the fold information and contact regions obtained from the FT-ICR mass spectrometry, 3D structures of ER-S100 protein complexes were reconstructed. These structures of ER best represent the conformational state sensed by the specific interacting partner. ER-S100 complex is distinct from CaM. The lack of the connective peptidic region between the EF hand pairs in S100 attributed to less interaction coverage than CaM. The identified ER conformation-sensing regions of the interacting EF hand proteins were used to develop a library of top peptidomimetics and potential small molecule sensors targeting the interfaces of ER-S100 interactions. We have evaluated their ability to block specific ER-S100 interactions in a high throughput fluorescent polarization based screen, to inhibit cancer cell proliferation and ER-mediated transcription of target genes. We believe that the ensemble of ER-EF hand protein complexes generated by our integrated proteomics-assisted protein interaction profiling will shed light on the lingering issue of hormone independent activation of ER at the molecular level and novel therapeutics targeting ER-S100 interactions.

Citation Format: David H. Lee, Bethany K. Asare, Matthew L. Hudson, Rajendram V. Rajnarayanan. Discovery at the interface: novel anticancer agents targeting human estrogen receptor/S100 interactions. [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 4173. doi:10.1158/1538-7445.AM2014-4173
Abstract 4174: An integrative genomic analysis for clinically relevant cancer genetic aberration and targeted therapeutic prediction
Authors: Lee HoJoon , Ji Hanlee P.
Published: May 2015

While the genomic and genetic basis of many cancers has been partly elucidated, less is known about the identity of specific cancer genes that are associated with clinical parameters such as clinical stage, metastasis, and survival. To address this question, we compiled multiple genomic data types (mutations, copy number alterations, gene expression and methylation status) as well as clinical meta-data for twelve different cancers in the Cancer Genome Atlas Project. We used an elastic-net regularized regression method on the combined genomic data to identify genetic aberrations and their associated cancer genes that are indicators of clinical parameters in each cancer type. To facilitate the identification of clinically actionable genetic aberrations from this cancer genomic data, we utilized genomic and drug response data from the Cancer Cell Line Encyclopedia (CCLE). These expansive data sets of hundreds of cancer cell lines include three genomic data types (mutations, copy number alterations, gene expression) and drug response data. To demonstrate the performance and validity of this approach, we demonstrated that our bioinformatics pipeline successfully identified i) synthetic genes that have their CNVs perfectly associated with stages from a simulated data ii) mutations of TGFBR2, methylation of MLH1 and other driver genes that have genetic changes associated with colorectal cancer (CRC) that demonstrate microsatellite instability CRC from TCGA data, and iii) IDH1 that obtained mutations associated with survival according to glioblastoma (GBM) data. We identify the top ranked genes that delineate key clinical features such as survival analysis or clinical stages for 13 cancers. A fit of the elastic-net regularized regression to more than 200 samples/cancer type and integrative analysis of integrative genomic platforms identified the set of top gene predictors of clinical parameters (TCGA data) and drug response (CCLE data). There are several genes ranked top in multiple cancer types while most of them are unique to a cancer type. These results provide us with new insights into the underlying genetic similarities and differences among 13 cancers; namely, common genetic characteristics that have implications for clinical phenotype. Finally, we are identifying the core set of gene aberrations that are both clinically relevant and drug responsible.

Citation Format: HoJoon Lee, Hanlee P. Ji. An integrative genomic analysis for clinically relevant cancer genetic aberration and targeted therapeutic prediction. [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 4174. doi:10.1158/1538-7445.AM2014-4174
Abstract 4178: Global assessment of the protein tyrosine phosphatome in cancer
Authors: Tonks Nicholas , Lucito Robert
Published: May 2015

Receptor tyrosine kinases and non-receptor tyrosine kinases are an important class of molecules controlling a large number of processes from growth to metabolic regulation. These tyrosine kinases have been well studied and scrutinized for their role in these normal processes as well as abnormal processes, such as cancer. Parallel to these kinases are more that 100 tyrosine phosphatases, which also fall into either receptor or non receptor classifications. While some of these phosphatases antagonize the tyrosine kinases others including many of the receptor bound phosphatases are critical in their own right in signaling processes such as pro survival, proliferation, etc. Although tyrosine kinases have been well studied, the study of tyrosine phosphatases has lagged. Numerous tyrosine phosphatases have been identified that are misregulated and important for cancer growth including PTPRD in breast cancer, and PTPRZ1 in small cell lung cancer as well as many others. However there has been no comprehensive study of all PTPs or the protein tyrosine phosphatome (PTPome), to identify which have a role in cancer. We as a cancer community are fortunate to have access to such a wide array of data types from a number of data sources such as TCGA, where we can determine if the PTPs are mis regulated in more than 20 types of cancers. We used TCGA data for all tumor types and subsetted the data to analyze the PTPome for all data types including expression, methylation, copy number and sequence data where available. Thus far we have identified known PTPs involved in a number of cancers, including PTPRD and PTPRZ1, but have also identified a number of PTPs altered in cancers that were less characterized such as the alteration of PTPRD in melanoma which is predominantly by mutations with much fewer deletions. While many of these mutations are missense and are difficult to characterize there are also a number of non-sense mutations, which would severely alter function as well as a number of splice site mutation of which some severely alter function and others are likely to alter function. The identification of this PTP is but one example to demonstrate the richness of this dataset. This analysis has been extremely useful to identify the PTPs that are altered in cancer and these results will be useful to many in the research community that are interested in PTP involvement in cancer but will also be of even greater use to those researchers who have not appreciated the vast importance of these under studied proteins.

Citation Format: Nicholas Tonks, Robert Lucito. Global assessment of the protein tyrosine phosphatome in 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 4178. doi:10.1158/1538-7445.AM2014-4178
Abstract 4180: Clonal evolution of tumor cell population in a patient with repetitively recurrent dermatofibrosarcoma protuberance (DFSP)
Authors: Oh Ensel , Choi Yoon-La , Ha Sang Yun , Lee Eun Hee , Lee Jeeyun , Kim Sung Joo , Kim Yu Jin , Song Ji-Young , Shin Young Kee , Jung Hae Min , Kwon Mi Jeong
Published: May 2015

It has been suggested that most tumors arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. We investigated clonal evolution of tumor cell population with the tissues obtained from a sarcoma patient who experienced recurrence 4 times (in 2007, 2009, 2010, and 2012). Along the repetitive recurrences, we observed that the tumors which showed, initially, benign morphology and behaviors turned to be malignant from the 3rd recurrence. We performed whole exome sequencing to identify somatic mutations occurred in each recurrent tumor, and traced the change of tumor cell population. From the sequencing results, the COL1A1-PDGFB fusion which is a well-known oncogenic driver of DFSP was detected in all of the recurrent tumors, however, there was no other overlap of mutated genes between the 1st recurred tumor and the following ones. It suggests that there were at least two tumor cell populations which evolved independently after acquisition of oncogenic driver mutation, and the initial tumor cells which represented majority of the original tumor were replaced by the other tumor cells which survived from the systemic chemotherapy, and it finally led to a dramatic change in morphology and behavior of the tumor. We expect that the mutated genes in each population would give us a clue to understand the mechanism of malignancy of DFSP.

Citation Format: Ensel Oh, Yoon-La Choi, Sang Yun Ha, Eun Hee Lee, Jeeyun Lee, Sung Joo Kim, Yu Jin Kim, Ji-Young Song, Young Kee Shin, Hae Min Jung, Mi Jeong Kwon. Clonal evolution of tumor cell population in a patient with repetitively recurrent dermatofibrosarcoma protuberance (DFSP). [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 4180. doi:10.1158/1538-7445.AM2014-4180
Abstract 4190: A survey of the most common methods of group randomization and distribution in preclinical in vivo studies
Authors: O'Brien Neil , Kumer Jeffrey L. , Ibsen Eric M.
Published: May 2015

To more closely emulate clinical research methodology and improve clinical relevance, researchers are increasingly utilizing clinically-similar group randomization and distribution methods for oncology studies in animals. One common pre-clinical approach, a random number generator in a spreadsheet, is paradoxically the least clinically-relevant, and subject to manual and transcription errors. This method provides no easy way to exclude animals from distribution based on other qualitative or quantitative data parameters. Due to limitations in spreadsheet software, commercially available pre-clinical trial applications can be used to perform the most recommended randomization and distribution methods based on tumor volume or other parameters: deterministic and matched distribution, pure randomization, stratified sampling randomization and block randomization across multiple numeric parameters. Subjects may be excluded initially based on recorded qualitative observations, and then by acceptable value ranges for numeric parameters. Animals can be randomized iteratively in rolling enrollment studies and previously randomized subjects can be re-randomized into new groups as required on drug-resistance studies. ANOVA results are displayed instantly to ensure similarity between groups. Standardizing randomization and distribution using clinically relevant methods improves the efficiency, clinical relevance, and outcome of animal studies relative to spreadsheet-based methods.

Citation Format: Neil O'Brien, Jeffrey L. Kumer, Eric M. Ibsen. A survey of the most common methods of group randomization and distribution in preclinical in vivo 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 4190. doi:10.1158/1538-7445.AM2014-4190
Abstract 4191: Whole exome sequencing of a case of olfactory neuroblastoma
Authors: Cha SooJin , Lee Se-Hoon , Kim Jong-Il , Shin Jong-Yeon
Published: May 2015

Purpose: Olfactory neuroblastoma (ONB) is an unusual malignancy occurred in sinonasal tract and molecular characteristics were poorly understood. Here we analyzed sequence of a fresh tissue from an olfactory neuroblastoma patient through whole exome sequencing to identify ONB-specific mutations.

Methods: We examined fresh tumor sample with matched peripheral blood from a patient diagnosed olfactory neuroblastoma. All procedures were approved by IRB in Seoul National University Hospital. He was 30 years old and had chemotherapy, surgery and radiotherapy. He had a recurrent disease with metastasis to bones and lymph nodes, and tumor tissue was obtained from a lymph node. Genomic DNA was isolated from a dissected tissue and whole exome library was constructed using Agilent SureSelectXT Human All Exon V4+UTRs (71Mb). Sequencing was performed by Illumina HiSeq2000 platform with paired-end 101bp reads and sequenced data was aligned to human reference genome g1k v37 using Burrows-Wheeler Aligner (BWA). Then, a series of bioinformatical tools were used such as SAMtools, PICARD, the Genome Analysis Toolkit (GATK) and MuTect to list up potential candidate genes. These genes were filtered out considered as germline variants informed in database like dbSNP, 1000 genome project and exome sequencing project 6500 (esp6500). Final candidate genes were identified by manual curation based on cancer gene classification of public database and publications.

Results: Our approach generated 15Gb and 17Gb of mapped sequence, with 97.91% and 98.43% of the target regions covered at least 10X depth in tumor and normal sample, respectively. After processing and filtering, we identified 8 candidate cancer genes including 5 somatic nucleotide variants (SNVs; CDKN2C, NBPF1, NBPF10, TGFBR2 and TP53) and 3 insertion/deletion mutations (ACVR1B, AR and CARD11). Among SNVs, CDKN2C showed stopgain SNV resulted in truncated mutation and the same mutation in TP53 were recurrently reported in COSMIC database. Cancer gene candidate indel mutations included 2 frameshift insertions (ACVR1B and CARD11) and 1 nonframeshift insertion (AR).

Conclusions: We analyzed a patient of olfactory neuroblastoma using our WES pipeline and several genes were identified to candidate cancer gene mutations which should be validated in large number of samples.

Citation Format: SooJin Cha, Se-Hoon Lee, Jong-Il Kim, Jong-Yeon Shin. Whole exome sequencing of a case of olfactory neuroblastoma. [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 4191. doi:10.1158/1538-7445.AM2014-4191
Abstract 4197: Regulators of p21 transcription in melanoma
Authors: Bøe Sigurd L. , Thingnes Josef , Golmakani Sima Z. , Hovig Eivind
Published: May 2015

p21(CIP1/WAF1) is a cyclin-dependent kinase inhibitor that directly inhibits the activity of cyclin E/CDK2 and cyclin D/CDK4/6 complexes and thereby functions as a regulator of cell cycle progression. The transcriptional regulation of p21 has been reported to be controlled by a large number of genes. However, the importance of each of these genes upon p21 transcriptional expression in melanoma is not fully explored. Here we have measured p21 mRNA levels in a cell panel consisting of 17 cell melanoma lines with various genetic backgrounds, spanning various stages of the disease. A correlation between p21 expression and p53 status in these cell lines demonstrated low p21 expression in p53 mutant cell lines, such as WM1366, MeWo, SKMEL28, WM45.1, WM983 and WM852 compared to cell lines with wild-type p53. With the use of a number of small molecular inhibitors against the MAPK and cAMP pathways to investigate possible changes in the p21 expression levels, we find that p21 expression levels were more sensitive to regulation by inhibitors in the p53 mutant cell lines compared to cell lines with p53 wild-type. Furthermore, we investigated mRNA expression levels of around 20 genes that previously have been reported to be involved in the regulation of p21 expression, and we find that TBX2 and TBX3 mRNA levels showed the strongest correlation with p21 mRNA levels.

Citation Format: Sigurd L. Bøe, Josef Thingnes, Sima Z. Golmakani, Eivind Hovig. Regulators of p21 transcription in melanoma. [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 4197. doi:10.1158/1538-7445.AM2014-4197
Abstract 4198: cAMP signaling in BRAFV600E melanoma
Authors: Rodriguez Carlos I.
Published: May 2015

G-protein coupled receptor (GPCR) signaling, predominantly the cyclic AMP (cAMP) signaling, is crucial for melanocyte proliferation and differentiation. Previous studies have shown a downregulation in cAMP signaling in mutant NRAS melanoma. However, no relationship has been reported about cAMP signaling in mutant BRAF melanoma, which makes up about 60% of all cutaneous melanoma. Here, we studied the role of four main G-protein signaling pathways using reporters for Gαs (cAMP Response Element, CRE), Gαq (inositol triphosphate signaling, NFAT-RE), Gα12 (RhoA signaling, SRF-RE) and Gβγ (MAPK pathway, SRE), in melanoma. Our data show that cAMP signaling is substantially more constitutively active in BRAFV600E mutant melanoma than NRAS mutant melanoma. Moreover, hyperactivation of cAMP signaling decreases proliferation and migration in BRAFV600E. Interestingly, in a melanoma cell line with neither BRAF nor NRAS mutation, cAMP hyperactivation increased proliferation. Furthermore, BRAFV600E inhibition increases constitutive cAMP activity. These results show a possible crosstalk between cAMP signaling and BRAFV600E in melanoma.

Citation Format: Carlos I. Rodriguez. cAMP signaling in BRAFV600E melanoma. [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 4198. doi:10.1158/1538-7445.AM2014-4198
Abstract 4199: Riluzole modulates the production of exosomes in melanoma cells
Authors: Isola Allison L. , Wen Yvonne , Goydos James , Chen Suzie
Published: May 2015

Exosomes are naturally occurring small membrane enclosed microvesicles generated constitutively and released by various cell types and more frequently released by tumor cells. It was postulated that exosomes may facilitate communication within the local microenvironment and the primary tumor, supporting melanoma cell dissemination and early events in metastasis. A gain-of-function mutation of a neuronal receptor, metabotropic glutamate receptor 1 (GRM1), when ectopically expressed in melanocytes, was sufficient to induce in vitro melanocytic transformation and spontaneous malignant melanoma development in vivo in a transgenic mouse model. Normal mouse melanocytes transformed with an expression vector containing GRM1 showed production and secretion of exosomes confirmed by electron microscopy, while the parental normal melanocytes showed no detectable presence of exosomes. In light of this data, It was hypothesized that over-expression of GRM1 in melanoma cells normally expressing a moderate amount of the protein, may promote elevated levels of exosome formation, while inhibitors to the receptor or limiting the levels of available ligand may suppress exosome production. Preliminary results demonstrated the working hypothesis is correct. Our earlier studies showed that inhibitors of the receptor modulated GRM1-mediated signaling events interfere with downstream effectors resulting in a decrease in both cell proliferation in vitro and tumor progression in vivo. It is not known if GRM1 acts directly, via its signaling cascade, or by another route, on exosome production regulation, this will be investigated. In addition to the pharmacological inhibitors we will also use a genetic approach with silencing RNA to modulate GRM1 expression levels.

Citation Format: Allison L. Isola, Yvonne Wen, James Goydos, Suzie Chen. Riluzole modulates the production of exosomes in melanoma 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 4199. doi:10.1158/1538-7445.AM2014-4199
Abstract 42: TRPM7 expression predicts poor prognosis in patients with nasopharyngeal carcinoma and correlates with tumor metastasis
Authors: Chen Jian-Peng , Sun Guiqin , Wang Wei-Bo , Wang Cai-Xia
Published: May 2015

The aim of this study was to investigate prognostic significance of TRPM7 expression in nasopharyngeal carcinoma (NPC) and evaluate the association of TRPM7 with tumor invasion and metastasis. Immunohistochemical staining for TRPM7 was carried out on paraffin-embedded tissue sections from 206 NPC patients. The data was subjected to statistical analysis with respect to clinicopathological variables and survival. Real-time PCR and Western blot were used to assess the expression of TRPM7 in NPC cells. Small interfering RNA and construct transfection were used to knockdown and improve TRPM7 expression in NPC cells. TRPM7 was highly expressed in 102 out of 206 (49.5%) NPC cases. TRPM7 expression was significantly correlated with clinical stage, lymphatic and distant metastasis. The patients who had high TRPM7 expression showed a significantly lower 5 year survival rate than the patients who had low TRPM7 expression. TRPM7 might be an independent prognostic indicator for patient's survival. The cell lines with high metastatic potential expressed more TRPM7 than the cell lines with low metastatic potential. Moreover, the migratory and invasive potential of NPC cells was significantly decreased and increased by TRPM7 knockdown and overexpression. The study indicates that TRPM7 expression is inversely correlated with NPC patient survival and correlated with NPC invasion and metastasis.

Note: This abstract was not presented at the meeting.

Citation Format: Jian-Peng Chen, Guiqin Sun, Wei-Bo Wang, Cai-Xia Wang. TRPM7 expression predicts poor prognosis in patients with nasopharyngeal carcinoma and correlates with tumor metastasis. [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 42. doi:10.1158/1538-7445.AM2014-42
Abstract 4201: Activation of p90 ribosomal S6 kinase (RSK) and downstream targets are directly regulated by S100B protein in malignant melanoma
Authors: Pierce Adam D.
Published: May 2015

S100B is an effective and extensively used prognostic marker for melanoma, with increasing serum levels of S100B being predictive of disease stage, increased recurrence, and low overall patient survival. We have recently identified a mechanism by which S100B alters ERK-RSK signaling to facilitate the progression of melanoma. Elucidation of this novel mechanism will aid the development of new pharmacological drugs to inhibit tumor progression. We have identified and characterized several ERK-RSK downstream targets regulated by S100B expression. These data are consistent with a mechanism in which elevated S100B binds directly to RSK in a calcium-dependent manner to prevent ERK-mediated phosphorylation of RSK. Our structural studies have further elucidated the S100B-RSK interaction as a novel drug target in melanoma cells and we are currently screening compounds for inhibitors of the S100B-RSK interaction.

Citation Format: Adam D. Pierce. Activation of p90 ribosomal S6 kinase (RSK) and downstream targets are directly regulated by S100B protein in malignant melanoma. [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 4201. doi:10.1158/1538-7445.AM2014-4201