bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 102: Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men's Health Study.
Authors: Wu Jie , Cai Qiuyin , Li Honglan , Cai Hui , Gao Jing , Yang Gong , Zheng Wei , Xiang Yong-Bing , Shu Xiao-ou
Published: August 2014

Chronic inflammation has been implicated in the pathogenesis of colorectal cancer. C-reactive protein (CRP), a biomarker of systemic inflammation, has been investigated in various populations for its association with colorectal cancer risk, but results have been inconsistent. We examined pre-diagnostic circulating levels of CRP with colorectal cancer risk among 288 colorectal cancer cases and 576 frequency-matched controls nested within the Shanghai Men's Health Study (2002-2006), a population-based cohort study of 61,483 men. Baseline plasma CRP levels were 47% higher among men who subsequently developed colorectal cancer than among those who remained free of the disease (1.12 μg/ml vs. 0.76 μg/ml; P<0.001). Multivariate analyses showed a dose-dependent relationship between CRP and colorectal cancer risk (P-trend=0.001); men in the highest tertile with CRP >1.19 μg/ml had 1.88-fold (95%CI: 1.24-2.86) increased odds of developing colorectal cancer compared with men in the lowest tertile with CRP <0.45 μg/ml. The association was observed for both colon and rectal cancers, became stronger after excluding subjects who took any antibiotics during past 7 days, and was restricted to cancer cases diagnosed within 4 years of blood collection (ORs for the highest tertile being 3.28 (95%CI: 1.28-8.37), 3.68 (95%CI: 1.62-8.38), and 1.05 (95%CI: 056-1.97), respectively for cases diagnosed within 2, 2-4 and 4 years after blood draw). The findings from our study suggest that circulating CRP level is positively associated with colorectal cancer risk in Chinese men, and this association, at least in part, is explained by inflammation related to cancerous or precancerous processes.

Citation Format: Jie Wu, Qiuyin Cai, Honglan Li, Hui Cai, Jing Gao, Gong Yang, Wei Zheng, Yong-Bing Xiang, Xiao-ou Shu. Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men's Health Study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 102. doi:10.1158/1538-7445.AM2013-102
Abstract 1049: PIM2 inhibitor as a targeted therapy for the treatment of multiple myeloma patients with specific genetic signatures.
Authors: Baldino Carmen M. , Caserta Justin , Dumas Stephane , Flanders Yvonne , Nair Jayakumar , Lee Kelvin P.
Published: August 2014

Jasco Pharmaceuticals has developed a novel and selective pan-PIM inhibitor (JP_11646) that has demonstrated biochemical IC50s of 24, 0.5 and 1 nM for PIM1, PIM2 and PIM3 respectively. Jasco also developed an engineered cell line to measure PIM2 transphosphorylation by over-expressing human PIM2 in human HEK293 cells together with human BAD as the substrate. The cell based assay measures the phosphorylation levels of BAD at Ser112 attributed solely to PIM2. JP_11646 exhibited a 590 nM IC50 in this cell based PIM2 assay confirming the MOA. JP_11646 increases apoptosis and decreases cell viability in multiple myeloma cell lines with the t(14;16) and t(4;14) translocations, which are known markers for poor prognosis. JP_11646 is orally bioavailable and has demonstrated in vivo efficacy, inhibiting tumor growth by >80% in a MM1.S tumor xenograft study. These data provide solid rationale for further development of JP_11646 as a targeted therapy for specific population of multiple myeloma patients that exhibit these genetic markers.

Citation Format: Carmen M. Baldino, Justin Caserta, Stephane Dumas, Yvonne Flanders, Jayakumar Nair, Kelvin P. Lee. PIM2 inhibitor as a targeted therapy for the treatment of multiple myeloma patients with specific genetic signatures. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1049. doi:10.1158/1538-7445.AM2013-1049
Abstract 105: Serum retinol and risk of head and neck cancer.
Authors: Chang Jeffrey S. , Hsiao Jenn-Ren , Ou Chun-Yen , Wong Tung-Yiu , Tsai Sen-Tien , Lo Hung-I , Huang Cheng-Chih , Lee Wei-Ting , Chen Ken-Chung , Huang Jehn-Shyun , Wang Yi-Hui , Weng Ya-Ling , Yang Han-Chien
Published: August 2014

Background: Head and neck cancer (HNC), including cancer of the oral cavity, pharynx, and larynx, is one of the leading cancers in the world. The known risk factors, including alcohol, betel quid, and cigarette, account for the majority of the HNC cases. However, the biological mechanisms regarding the carcinogenic effects of these agents in the development of HNC are not completely understood. Retinoic acid is involved in cell growth, differentiation, and apoptosis, which when dysregulated may lead to the development of cancer. Studies have shown that alcohol, betel quid, and cigarette can affect either the metabolism or the function of retinoic acid pathway. The current analysis evaluated the association between serum retinol and HNC risk and assessed whether this association can be modified by alcohol, betel quid, or cigarette.

Methods: 93 incident cases of HNC and 79 sex- and age- frequency matched controls were recruited from the department of otolaryngology and department of stomatology. Information on the use of alcohol, betel quid, and cigarette was collected by in-person interviews. Serum retinol levels were measured using high performance liquid chromatography. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with serum retinol levels. Additional analyses were performed stratified by alcohol, betel quid, and cigarette.

Results: Compared to controls, HNC cases had a lower level of serum retinol (Median for HNC cases: 811 ug/l vs. median for controls: 901 ug/l, Wilcoxon rank-sum P = 0.04). For every 100 ug/l increase, the risk of HNC was reduced by 8% (OR = 0.92, 95% CI: 0.83-1.02). The OR was 0.5 (95% CI: 0.24-1.06) comparing the highest tertile of serum retinol level to the lowest tertile. A lower HNC risk associated with higher serum retinol levels was observed among never alcohol drinkers (For every 100 ug/l increment, OR = 0.80, 95% CI: 0.66-0.96) but not among regular alcohol drinkers (For every 100 ug/l increment, OR = 0.98, 95% CI: 0.86-1.13).

Conclusion: Higher levels of serum retinol are associated with a reduced risk of HNC. Alcohol consumption obliterates the inverse association between serum retinol and HNC risk, possibly by disrupting the metabolism of retinoic acid pathway.

Citation Format: Jeffrey S. Chang, Jenn-Ren Hsiao, Chun-Yen Ou, Tung-Yiu Wong, Sen-Tien Tsai, Hung-I Lo, Cheng-Chih Huang, Wei-Ting Lee, Ken-Chung Chen, Jehn-Shyun Huang, Yi-Hui Wang, Ya-Ling Weng, Han-Chien Yang. Serum retinol and risk of head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2013-105
Abstract 1064: The combined activation of MET signaling and PKCα is sufficient to induce tumors in mouse skin.
Authors: Cataisson Christophe , Liu Fan , Wright Lisa N. , Zhuang Anne , Merlino Glenn , Yuspa Stuart H.
Published: August 2014

Aberrant activation of MET signaling has been identified in multiple cancers but its relation to cancer-associated inflammation has not been explored. To address this issue in the context of skin carcinogenesis, a double transgenic mouse model (MT1-HGF/ K5-PKCα or DT) was generated. K5-PKCα mice that overexpress PKCα in basal keratinocytes develop a strong neutrophilic cutaneous inflammatory response upon topical TPA (12-tetradecanoylphorbol-13-acetate) application. These mice were crossed with MT1-HGF mice that overexpress HGF under a metallothionein promoter to create MT1-HGF/ K5-PKCα double transgenic (DT) mice and their respective controls. We observed that DT animals were very sensitive to squamous carcinogenesis. Using a low promoting dose of TPA that primarily activates PKCα in K5-PKCα or DT mice yielded an average of 6 tumors per mouse in the DT group; single transgenic K5-PKCα or MT-HGF mice developed an average of 1 tumor while WT developed none at this TPA dose. We hypothesize that in DT mice, keratinocyte-derived HGF synergizes with PKCα to drive tumor promotion and increase tumor growth. Primary keratinocytes derived from MT1-HGF or DT mice display a phenotype reminiscent of EGFR activated cells: increased expression of pro-inflammatory factors, upregulation of Keratin 8 (K8) and downregulation of K1 and K10 mRNAs. Indeed western blot analysis shows that EGFR is transactivated in MT1-HGF and DT keratinocytes and cell proliferation is elevated as well but not in K5-PKCα or WT keratinocytes. The release of CXCL1,a hallmark of RAS transformation, is augmented in RAS-keratinocyte cell culture supernatants with MT1-HGF and DT keratinocytes producing the most in the absence of RAS-transduction. Blockade of EGFR or IL-1 activity can mitigate the HGF-induced RAS-phenotype. K5-PKCα and DT mice exhibit the same acute inflammatory response and regenerative epidermal hyperplasia following low dose TPA treatment. When promoted for 10 weeks with TPA, 100% of DT mice but none of the single transgenic controls developed squamous papillomas in the absence of DMBA-mediated initiation. Our data suggest that the synergistic activity of Met and PKCα can substitute for the lack of RAS mutation during skin carcinogenesis. It remains to be determined if that mechanism could provide an alternate route to transformation in human skin tumors lacking RAS mutations.

Citation Format: Christophe Cataisson, Fan Liu, Lisa N. Wright, Anne Zhuang, Glenn Merlino, Stuart H. Yuspa. The combined activation of MET signaling and PKCα is sufficient to induce tumors in mouse skin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1064. doi:10.1158/1538-7445.AM2013-1064
Abstract 1107: β2-integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis.
Authors: Oellerich Thomas , Oellerich Mark , Engelke Michael , Muench Silvia , Mohr Sebastian , Hsiao He-Hsuan , Zhang Jing , Bohnenberger Hanibal , Berg Tobias , Rieger Michael , Wienands Juergen , Bug Gesine , Brandts Christian , Urlaub Henning , Serve Hubert
Published: August 2014

Constitutive activation of certain kinase-dependent signal transduction pathways is critical for the pathogenesis of acute myeloid leukemia (AML). Apart from FLT3-ITD the spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of AML blasts, but the underlying molecular events of Syk signaling have not been investigated so far. Using a phosphoproteomic approach we elucidated the AML-specific phosphorylation state of Syk and found that the kinase is constitutively phosphorylated at all known activation inducing tyrosine residues. Moreover, we have identified the multi-protein complex that is nucleated by constitutively active Syk in AML cells by quantitative proteomic techniques. This complex differs from the B lymphoid Syk interactome regarding several proteins, in particular the

β2-integrin receptor Mac-1 and also the oncogenic transcription factors STAT3 and STAT5. Our functional studies in primary AML cell cultures revealed that tonic signals derived from the integrin-associated Fc-γ chain lead to Syk-dependent activation of STAT3 and STAT5 that in turn induces AML cell proliferation. Moreover, stimulation of Mac-1 intensifies the constitutive Syk-mediated STAT3/5 activation in AML cells, a scenario likely to take place in the bone marrow niche. In accordance with these findings, we observed that β2-integrins including Mac-1 induce proliferation of AML cells in an AML cell/stroma co-culture model. Taken together, we identified an oncogenic integrin/Syk/STAT signaling axis that might serve as a therapeutic target of AML in the future.

Citation Format: Thomas Oellerich, Mark Oellerich, Michael Engelke, Silvia Muench, Sebastian Mohr, He-Hsuan Hsiao, Jing Zhang, Hanibal Bohnenberger, Tobias Berg, Michael Rieger, Juergen Wienands, Gesine Bug, Christian Brandts, Henning Urlaub, Hubert Serve. β2-integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2013-1107
Abstract 1111: Whole genome bisulfite sequencing reveals tissue-specific DNA methylation in a normal mouse.
Authors: Hon Gary C. , Shen Yin , McCleary David F. , Edsall Lee , Kuan Samantha , Ren Bing
Published: August 2014

Epigenetic alteration is a hallmark of cancer. In particular, compared to normal cells, the DNA methylomes of cancer cells often exhibit two contrasting phenomena: 1) hypomethylation of large regions of the genome, notably at regions of late replicating DNA; and 2) hypermethylation of focal sites, frequently at CpG-island containing promoters. While this epigenetic variation between cancer cells and normal counterparts has been well documented, the variation between different normal cell types is still unknown. In an effort to better understand the epigenetic variation of a normal individual, we profiled DNA methylation using whole genome bisulfite sequencing in 16 tissues isolated from an individual mouse. We observed a unique distribution of CpG methylation for each tissue, which cluster based on cell lineage and type. Most somatic tissues exhibit a small but consistent decrease in methylation at late-replicating regions of the genome, suggesting the beginnings of global hypomethylation. Our global analysis identified only one-eighth of the genome as tissue-specific differentially methylated regions. Remarkably, the vast majority of these regions exhibit hallmarks of cis-regulatory activity, including: small size (<500 bp), DNase I hypersensitivity, enhancer chromatin modifications (H3K4me1/H3K27ac), and evolutionary conservation. Our results reveal that most somatic cells are primed for global hypomethylation in regions of the genome that are typically hypomethylated in cancer cells, supporting previous observations that hypomethylation may be an indicator of cell age. In addition, our results in normal tissue suggest that hypomethylation in cancer cells could alter transcriptional regulation through disruption of cis-regulatory activity.

Citation Format: Gary C. Hon, Yin Shen, David F. McCleary, Lee Edsall, Samantha Kuan, Bing Ren. Whole genome bisulfite sequencing reveals tissue-specific DNA methylation in a normal mouse. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1111. doi:10.1158/1538-7445.AM2013-1111
Abstract 1134: RNAi screening of human kinome identified fibroblast growth factor receptor 4 (FGFR4) as potential molecular target in basal-like breast cancers (BLBC).
Authors: Tiong Kai Hung , Tan Boon Shing , Choo Heng Lungh , Radhakrishnan Ammu Kutty , Rosli Rozita , Cheong Soon-Keng , Leong Chee-Onn
Published: August 2014

Global gene expression profiling has uncovered previously unrecognized subsets of human breast cancer, including the so-called "triple-negative" or "basal-like" tumours (BLBC) characterized by estrogen/progesterone receptor negativity, lack of Her-2/Neu amplification and high frequency of p53 mutation. These refractory tumours therefore are insensitive to hormonal therapy or trastuzumab-based therapy, and thus confer a markedly poor prognosis relative to other subtypes. To date, little progress has been made to identify specific molecular pathways associated with these refractory cancers that may be effectively targeted for therapeutic purposes. Using a human kinome RNAi library screen, we show that knock-down of endogenous human FGFR4 (but not FGFR1-3) induces significant tumor-specific cell death in basal-like breast cancer cells. Further analysis reveals that FGFR4 mediates the BLBC cells survival through activation of AKT as knock-down of endogenous FGFR4 in MDA-MB-468 and HCC1937 cells significantly reduced AKT phosphorylation. Consistently, ectopic expression of a constitutively active myristoylated AKT completely abrogates the apoptosis induced by FGFR4 knock-down. Interestingly, both MDA-MB-468 and HCC1937 also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. RNAi-mediated silencing of FGF19 evidently suppresses the growth of these BLBC cells via AKT signalling as marked by diminished AKT phosphorylation following depletion of FGF19. Knockdown of FGF19 in addition triggers ERK1/2 activation to compensate for AKT signalling down-regulation in MDA-MB-468. Together, our results demonstrated the existence of a FGFR4-FGF19 autocrine loop which could potentially be developed as therapeutic target for future treatment of BLBC.

Citation Format: Kai Hung Tiong, Boon Shing Tan, Heng Lungh Choo, Ammu Kutty Radhakrishnan, Rozita Rosli, Soon-Keng Cheong, Chee-Onn Leong. RNAi screening of human kinome identified fibroblast growth factor receptor 4 (FGFR4) as potential molecular target in basal-like breast cancers (BLBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2013-1134
Abstract 1146: STK4 downregulation promotes tumor invasion/migration and is associated with poor prognosis in human colon cancer.
Authors: Lee Yu-Cheng , Yang Chia-Ning , Hsu Tai-I , Lu Pei-Jung
Published: August 2014

Colon cancer has high incidence rate in the world and the early stage of colon cancer can be cured by surgical therapy. However, it remains difficult to predict the prognostic outcome of colon cancer patients. STK4 is considered as a potential tumor suppressor, which plays an important role in Hippo pathway to control the organ size and the inhibition ability of cell-cell contact. The major aim of this study is focused on the investigation of prognostic value of STK4 in colon cancer. By immunohistochemistry assay, we examined the expression of STK4 in 140 pairs normal and tumor colon cancer specimens. The relationship between STK4 expression and clinicopathological factors as well as patient survival were analyzed and the results showed that STK4 was significantly downregulated in tumor tissues compared to their corresponding non-tumor part (P<0.01) and that was significantly associated with tumor size (P=0.003), distal metastasis (P=0.03), disease recurrence and poor survival (P<0.005). Moreover, loss of STK4 expression showed a significant poor outcome in colon cancer patients by univariate and multivariate analysis. These results indicated that there is a positive correlation in STK4 expression and prognosis and survival of colon cancer patients. Loss of STK4 expression displayed poor outcome. The conclusion is that STK4 can be used as a prognostic maker to predict patient survival and play a role in metastasis suppression of colorectal cancer.

Citation Format: Yu-Cheng Lee, Chia-Ning Yang, Tai-I Hsu, Pei-Jung Lu. STK4 downregulation promotes tumor invasion/migration and is associated with poor prognosis in human colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2013-1146
Abstract 1147: Expression of ERO1L gene is poor prognostic factor for gastric cancer.
Authors: Seol So-Young , Lim Jae Yun , Yoon Sun Och , Hong Soon Won , Kim Jong Won , Choi Seung Ho , Cho Jae Yong
Published: August 2014

Gastric cancer is the second cause of cancer-related deaths worldwide. Even though within same stage, gastric cancer patients present diverse clinical manifestations and prognosis. Molecular markers will be important in predicting patients’ outcomes and tailoring personalized treatments according to individual biology. In this study, we analyzed the gene expression profile of human gastric cancer (published on CCR) to identify potential biomarkers. We found that TXN family genes and ERO1L were significantly overexpressed and related to prognosis. We evaluated ERO1L significantly overexpressed in gastric cancer and ERO1L was very highly expressed in hypoxic condition. The other study has identified ERO1L as included in the small group of eight genes predicting poor survival of patients with pulmonary adenocarcinoma. To investigate the function of ERO1L gene in gastric cancer cell line (AGS, MKN1 and NCI-N87), we tested the effect of shRNA inhibition of ERO1L on gastric cancer cells. To determine the biologic role of ERO1L in regulating cancer cell proliferation, stable transfection of shRNA for ERO1L in gastric cancer cells. Our results showed that shERO1L decrease cell proliferation. Furthermore, Knock down expression by shERO1L have effects on regulating gastric cancer cell apoptosis. Next, we tested whether or not the ERO1L gene is involved in progression to metastatic disease in gastric cancer,especially in late tumorigenesis, including migration and invasion. As a results, Knock down expression for ERO1L significantly decreased the migration and invasiveness of gastric cancer cells. In conclusion, our findings show that a prognostic molecular signature that can predict the poor progression of gastric cancer tumors. Furthermore, unequal distribution of expression patterns reflecting activation of ERO1L with different survival rates supports a personalized target therapy in gastric cancer with biomarker gene signature driven patient selection. While further work is needed to elucidate the biological contributions of these markers in. in vivo, the results presented here provide a basis for future investigations of the functional and clinical effect of new target genes in gastric cancer.

Citation Format: So-Young Seol, Jae Yun Lim, Sun Och Yoon, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Jae Yong Cho. Expression of ERO1L gene is poor prognostic factor for gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2013-1147
Abstract 1151: Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis.
Authors: Goos Jeroen A C M , Coupé Veerle M H , Diosdado Begoña , Delis-van Diemen Pien M. , Karga Cemile , Beliën Jeroen A.M. , Carvalho Beatriz , van den Tol M. Petrousjka , Verheul Henk M W , Geldof Albert A. , Meijer Gerrit A. , Hoekstra Otto S. , Fijneman Remond J A
Published: August 2014

Introduction: Approximately half of all colorectal cancer (CRC) patients die as a consequence of metastases. Hemihepatectomy, occasionally in combination with radiofrequency ablation (RFA), is the only curative treatment available for patients with CRC liver metastases (CRCLM). Patient eligibility is based on established prognostic clinicopathological variables, however, 70% of patients still die within 5 years indicating that better prognostic markers are needed. Aurora kinase A (AURKA) is a driver of 20q gain-associated tumor progression and is associated with disease recurrence in stage III CRC patients. AIM: This study aimed to investigate the prognostic value of AURKA protein expression in liver metastases of CRC patients who underwent hemihepatectomy with curative intent. Patients and Methods: Tissue microarrays (TMAs) were generated from formalin-fixed paraffin-embedded CRCLM of 507 patients who underwent hemihepatectomy in the Netherlands between 1990 and 2010. Matched primary CRC tissue was collected of 234 patients. TMAs were stained for AURKA by immunohistochemistry, nuclear expression of neoplastic cells was assessed and subsequently associated with patient overall survival (OS) in a training and validation set. Results: High AURKA expression in CRCLM was associated with poor OS in a univariate analysis (HRR 1.68; 95%CI 1.04-2.73; P=0.03) and upon correction for established prognostic clinicopathological variables (HRR 1.77; 95%CI 1.02-3.08; P=0.04). Furthermore, AURKA expression in liver metastases was correlated to its expression in corresponding primary CRC (P=0.0002). Conclusion and Discussion: AURKA protein expression is a molecular biomarker with prognostic value for CRC patients with liver metastasis, independent of established clinicopathological variables. This study opens novel opportunities to investigate AURKA inhibitors for personalized therapy.

Citation Format: Jeroen A C M Goos, Veerle M H Coupé, Begoña Diosdado, Pien M. Delis-van Diemen, Cemile Karga, Jeroen A.M. Beliën, Beatriz Carvalho, M. Petrousjka van den Tol, Henk M W Verheul, Albert A. Geldof, Gerrit A. Meijer, Otto S. Hoekstra, Remond J A Fijneman. Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2013-1151
Abstract 1154: Detection of aberrant methylation of the RASSF1A gene as a biomarker for hepatocellular carcinoma.
Authors: Jain Surbhi , Xie Lijia , Boldbaatar Batbold , Su Ying-Hsiu , Song Wei
Published: August 2014

Hepatocellular carcinoma (HCC) is an aggressive malignancy that is responsible for between 250,000 and 800,000 deaths annually worldwide. HCC has a poor prognosis with a 5-year survival rate of less than 15% mainly due to a lack of early detection. The current biomarker for HCC is the alpha-fetoprotein (AFP), which has a low sensitivity of 40-60%. There is a necessity for non-invasive, convenient, and sensitive methods to detect the cancer in its curative stages to improve prognosis. Previous studies from our laboratory showed that the location of the CpG site methylation studied could impact the marker performance in distinguishing HCC from other liver diseases. The aberrant methylation of the tumor-suppressor RASSF1A gene has been extensively studied as a marker for a variety of cancers, including liver cancer. However, some studies found that the gene was methylated even in non-cancerous liver tissues. Thus, in order to explore the possibility of detecting aberrant methylation of the tumor-suppressor RASSF1A gene as a biomarker for HCC screening, we analyzed the methylation profiles of 57 CpG sites in three regions of the promoter - P1, P2, and E1 - in normal, hepatitic, cirrhotic, adjacent non-HCC, and HCC tissue samples through bisulfite DNA sequencing. We discovered that the P1 region was most specifically methylated to HCC. We then confirmed the findings by developing a methylation specific PCR and analyzing a larger sample size. The data were analyzed and the P1 test was found to have an area under the curve (AUROC) of 0.90, whereas the E1 and P2 tests had AUROC of 0.84 and 0.72, respectively. At a cutoff of 10 copies for our analysis, the P1 MSP gave a sensitivity of 80.8% and specificity of 85.7%. Furthermore, we found that out of 62 AFP-negative samples, mRASSF1A detected 54 (87.1%). By combining AFP and mRASSF1A, 107 of 115 (93.0%) of HCC samples were detected as cancerous. Subsequently, we developed a PCR assay to detect the methylated RASSF1A gene in the urine of patients. This assay was then used to test the urine DNA isolated from patients with hepatitic, cirrhotic, or HCC after which the data were statistically evaluated. The potential of a urine DNA test for HCC screening is discussed.

Citation Format: Surbhi Jain, Lijia Xie, Batbold Boldbaatar, Ying-Hsiu Su, Wei Song. Detection of aberrant methylation of the RASSF1A gene as a biomarker for hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1154. doi:10.1158/1538-7445.AM2013-1154
Abstract 1155: Promoter CpG island hypermethylation of Decoy Receptor 1 (DCR1) is associated with poor response to irinotecan in colorectal cancer.
Authors: Bosch Linda JW , Trooskens Geert , Snaebjornsson Petur , Haan Josien C. , Pelosof Lorraine , Koopman Miriam , Tol Jolien , Louwagie Joost , Dehaspe Luc , Ylstra Bauke , Verheul Henk , van Engeland Manon , Nagtegaal Iris D. , Herman James G. , Punt Cornelis JA , van Criekinge Wim , Carvalho Beatriz , Meijer Gerrit A.
Published: August 2014

Background

Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC.

Material and Methods

The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase III CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88).

Results

Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)).

Conclusion

CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy.

Citation Format: Linda JW Bosch, Geert Trooskens, Petur Snaebjornsson, Josien C. Haan, Lorraine Pelosof, Miriam Koopman, Jolien Tol, Joost Louwagie, Luc Dehaspe, Bauke Ylstra, Henk Verheul, Manon van Engeland, Iris D. Nagtegaal, James G. Herman, Cornelis JA Punt, Wim van Criekinge, Beatriz Carvalho, Gerrit A. Meijer. Promoter CpG island hypermethylation of Decoy Receptor 1 (DCR1) is associated with poor response to irinotecan in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1155. doi:10.1158/1538-7445.AM2013-1155
Abstract 1159: Increased ceramide synthase 5 expression is associated with lymphovascular invasion, metastasis and poor survival in colorectal cancer.
Authors: Fitzgerald Seán , Sheehan Katherine M. , O'Grady Anthony , Kenny Dermot , O'Kennedy Richard , Kay Elaine W. , Kijanka Gregor
Published: August 2014

Background: Ceramide synthase 5 (CerS5) is multi-pass transmembrane protein of the endoplasmic reticulum. Functioning as a bona fide (dihydro)ceramide synthase, CerS5 regulates the levels of short ceramide species. Ceramides are bioactive lipids implicated in proliferation, senescence, angiogenesis and death of normal and cancerous cells. We aimed to investigate CerS5 expression in colorectal cancer tissue and to evaluate the prognostic significance of CerS5 in colorectal cancer patients.

Methods: CerS5 expression was analyzed by immunohistochemistry on tissue microarrays constructed from 125 colorectal cancer patients. The associations between CerS5 staining and the clinicopathological factors were examined using the Spearman rank correlation test. Patient survival was examined using the Kaplan-Meier survival analysis and Cox proportional hazard modeling, categorized according to high or low CerS5 staining intensity.

Results: Immunohistological staining revealed an overexpression of membranous CerS5 in 63 out of 125 (50.4%) colorectal carcinomas. CerS5 overexpression significantly correlated with lymphovascular invasion and metastatic disease in matched tumor cases (P = 0.036 & P = 0.037, respectively). Patients with CerS5 overexpressing tumors had a significantly lower overall 5-year survival (OS, P = 0.029) and 5-year recurrence-free survival (RFS, P = 0.047). Cox multivariate analysis showed that the increased CerS5 expression was an independent predictor of OS (hazard ratio (HR) = 1.604; 95% confidence interval (CI) 1.010-2.548, P = 0.045) and RFS (HR = 1.592; CI 1.036-2.447, P = 0.034).

Conclusions: We found an increased expression of ceramide synthase 5 (CerS5) in 50% of investigated colorectal carcinomas, which was associated with lymphovascular invasion, metastasis and poor survival in colorectal cancer patients. Our study identifies CerS5 as a novel independent prognostic biomarker for patients with colorectal cancer.

Citation Format: Seán Fitzgerald, Katherine M. Sheehan, Anthony O'Grady, Dermot Kenny, Richard O'Kennedy, Elaine W. Kay, Gregor Kijanka. Increased ceramide synthase 5 expression is associated with lymphovascular invasion, metastasis and poor survival in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2013-1159
Abstract 1160: Inactivated hippo-pathway as a prognostic biomarker in hepatocellular carcinoma.
Authors: Hayashi Hiromitsu , Kuroki Hideyuki , Yokoyama Naomi , Nakagawa Shigeki , Nitta Hidetoshi , Imai Katsunori , Hashimoto Daisuke , Ikuta Yoshiaki , Chikamoto Akira , Beppu Toru , Baba Hideo
Published: August 2014

The contact inhibition of proliferation and cell movement is crucially important in embryonic development, tissue regeneration, and wound healing for the well-controlled organogenesis. The disruption of contact inhibition results in sustained cell proliferation and uncontrolled cell movement, which is a hallmark of solid tumors. Loss of contact inhibition allows cancer cells to facilitate the invasion of neighboring tissues and metastasis to remote organs. The recently identified Hippo signaling pathway has been implicated in contact inhibition of proliferation as well as organ size control. Indeed, the conditional inactivation of hippo-pathway in liver leads to enlarged liver (massive hepatomegaly) and tumorigenesis (Cell, 2007). Clinically, HCC often shows the huge tumor more than size in 10cm, strongly speculating that inactivation of hippo-pathway plays an important role in HCC progression. However, clinical significance of hippo-pathway in HCC is largely unknown. Here, we investigated the clinical significance of inactivated hippo-pathway, which induce overexpressed oncogenes (YAP/TAZ), using resected 80 HCC samples, and suggested the tumoral-high TAZmRNA expression was a worse prognostic biomarker for HCC patients represented by high proliferative activity. The tumor size in High TAZmRNA expression group (n =24) was significantly larger than that in low expression group (n = 56) (P < 0.05). YAP/TAZ protein over-expression in HCC was associated with high proliferative activity by Ki-67 positive cells. The high TAZmRNA expression group showed significantly worsen disease free survival and overall survival compared with that in low expression group (P = 0.01 and 0.02, respectively). Thus, inactivation of Hippo-pathway plays a crucial role in tumor progression by accelerating proliferative activity, and tumoral TAZmRNA expression level may be a useful prognostic biomarker in HCC.

Citation Format: Hiromitsu Hayashi, Hideyuki Kuroki, Naomi Yokoyama, Shigeki Nakagawa, Hidetoshi Nitta, Katsunori Imai, Daisuke Hashimoto, Yoshiaki Ikuta, Akira Chikamoto, Toru Beppu, Hideo Baba. Inactivated hippo-pathway as a prognostic biomarker in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1160. doi:10.1158/1538-7445.AM2013-1160
Abstract 1168: Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis .
Authors: Cho Dong-Hyung , Jo Yoon Kyung , Kim Seung Cheol , Park In Ja , Kim Jin Cheon
Published: August 2014

Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown. To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line - 8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p=0.005) and invasion (p<0.001). Moreover, both 5-year disease free survival and overall survival rates of patients bearing tumors that did not express ATG10 were significantly higher than those of patients bearing ATG10-expressing tumors (p=0.012). Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis indicating that ATG10 may be a potential prognostic maker in colorectal cancer.

Citation Format: Dong-Hyung Cho, Yoon Kyung Jo, Seung Cheol Kim, In Ja Park, Jin Cheon Kim. Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1168. doi:10.1158/1538-7445.AM2013-1168
Abstract 1187: Personalized cancer therapy for ovarian cancer patients.
Authors: Bravo Maria L. , Gonzalez Pamela , Kato Sumie , Garrido Marcelo , Brañes Jorge , Pizarro Javier , Barriga Maria Isabel , Leon Hector , Bustamante Eva , Alonso Catalina , Bravo Erasmo , Celis Miguel Angel , Aguilera Barbara , Barra Alejandro , Barrena Nicanor , Ibañez Carolina , Jimenez Paula , Cuello Mauricio , Owen Gareth
Published: August 2014

Introduction: The treatment of ovarian cancer is consists principally in radical surgery followed by chemotherapy. Patients generally respond well to first line chemotherapy (70%) but consistently relapse within 18 months, with successive rounds of chemotherapy delivering extremely low patient benefit. Despite every cancer being unique, generally all cancer patients are treated by the same chemotherapy regimes. In previous decades an approach has been to use chemosensitivity assays based on cells isolated from solid tumors to predict chemotherapy response. However, it the metastatic cancer cell (not cells in the primary tumor) that is the true target of chemotherapy. In our laboratory we have resurrected the concept of chemosensitivity but focusing exclusively on cells that have escaped the primary tumor and are potentially enriched in stem-cell like properties. Our objective was to isolate potential ovarian metastatic cells from patients and coorelate their in vitro response to the chemotherapy observed in the patient. Materials and methods: Primary cultures of ovarian cancer ascites (peritoneal fluid) were obtained with signed informed consent from a network of Chilean hospitals and potential metastatic cells cultivated. Chemotherapy response was assessed by MTS and data correlated with CA125 levels, imaging and medical criteria. Results: Analysis of 39 ovarian cancer patients with clinical follow-up demonstrated an average progression free survival of 18 months for patients predicted to respond by our assay, but only 2 months in predicted non-responders. The assay corrected identified 5 of the 6 patients who did not respond to first line carboplatin-paclitaxel therapy. Discussion: We demonstrate a clear distinction in time to relapse between patients predicted to respond in our assay as opposed to patients with no predicted clinical response, demonstrating the requirement to take this research to the stage of randomized clinical trials.

Funding BMRC CTU06 & FONDECYT 3120003 and 1120292

Citation Format: Maria L. Bravo, Pamela Gonzalez, Sumie Kato, Marcelo Garrido, Jorge Brañes, Javier Pizarro, Maria Isabel Barriga, Hector Leon, Eva Bustamante, Catalina Alonso, Erasmo Bravo, Miguel Angel Celis, Barbara Aguilera, Alejandro Barra, Nicanor Barrena, Carolina Ibañez, Paula Jimenez, Mauricio Cuello, Gareth Owen. Personalized cancer therapy for ovarian cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1187. doi:10.1158/1538-7445.AM2013-1187
Abstract 1190: Gene expression profiling identified FYN as an important gene in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy .
Authors: Elias Roro Daniel , Vever Henriette , Ditzel Henrik
Published: August 2014

To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer we performed microarray profiling and identified 366 genes with altered expression in 4 tamoxifen-resistant (TamRs) vs. the parental tamoxifen-sensitive MCF-7/S0.5 cell lines. Most of these genes were functionally linked to cell growth, proliferation, death and control of gene expression and included FYN, PRKCα, ITPR1, DPYD, DACH1, GBP1 and PRLR. Increased expression of FYN was observed in TamR cells and treatment with FYN-specific interfering RNA or a specific Src family kinase (SFK) inhibitor restored the anti-proliferative effect of tamoxifen in these cells. TamR cells also expressed increased levels of phosphorylated breast cancer antiestrogen resistance protein 1 (pBCAR1), an important downstream SFK substrate in the MAPK pathway. Evaluation of the association of subcellular localization of FYN in cancer tissue and clinical endpoints was made in 2 cohorts of ER+ breast cancer patients, one with advanced disease (N=47) and the other with early breast cancer (N=76). The result showed that plasma membrane-associated FYN expression in the cancer cells strongly correlated with longer progression-free survival compared to FYN expression not associated with the plasma membrane (p<0.0002) in the advanced disease cohort. Similarly, in the early breast cancer patients, plasma membrane associated FYN expression was associated with longer metastasis-free survival (p<0.003) and overall survival (p<0.0005) independent of tumor size, grade and node status. Our results indicate that FYN plays an important role in tamoxifen resistance, and its subcellular location in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.

Citation Format: Daniel Elias Roro, Henriette Vever, Henrik Ditzel. Gene expression profiling identified FYN as an important gene in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2013-1190
Abstract 1195: A molecular characterization of the anaplastic prostate carcinomas.
Authors: Aparicio Ana M. , Maity Sankar , Wang Xuemei , Hoang Anh G. , Efstathiou Eleni , Troncoso Patricia , Logothetis Christopher J.
Published: August 2014

Molecular markers that identify clinically meaningful, biologically based, subsets of PC are lacking. This results in inefficient clinical trial designs and suboptimal therapy selection off-protocol. The androgen receptor (AR)-negative small cell PC (SCPC) is an often-unrecognized morphological variant of the disease found on repeat biopsies during the castrate-resistant (CR) progression of PC. Its presence predicts for a poor response to hormonal therapies, a distinct clinical behavior and a short survival. Characteristic clinical features of SCPC are frequently present in patients with CRPC, constituting a clinical syndrome termed anaplastic PC. We hypothesized that the anaplastic PC share underlying biology with SCPC, irrespective of morphology. Preclinical studies show that SCPC are characterized by loss of tumor suppressors and AR signaling, as well as overexpression of mitotic genes and proneural transcription factors. To test our hypothesis we used immunohistochemistry to analyze the expression of markers in these pathways, in tumor biopsies from chemotherapy-naïve men with anaplastic PC participating in a prospective phase II clinical trial. To date we have analyzed 6 markers in 25 samples (6 with pure or mixed SCPC morphology) from prostate biopsies (n=10), transurethral resections of prostate tumors (n=4), bone marrow or bone biopsies (n=9), lymph node (n=1) or brain (n=1). Results are shown in Table 1.

Table 1. Immunohistochemistry Anaplastic PC % Positive Cells AR RB1 p53 UBE2C Ki67 CYP17A1 0 8 11 11 5 1 0 < or = 10% 3 6 9 9 8 1 > 10% 14 8 5 11 16 24

Of the 17 samples that had ≤10% RB1+ cells, 10 had ≤10% AR+ cells and 9 had >10% UBE2C+ cells. Of the 11 samples that had ≤10% AR+ cells, 10 also had ≤10% RB1+ cells and 6 had >10% UBE2C+ cells. These data support our hypothesis that the anaplastic prostate carcinomas are characterized by loss of tumor suppressors and overexpression of mitotic genes. Updated results in additional samples and of additional markers will be presented.

Citation Format: Ana M. Aparicio, Sankar Maity, Xuemei Wang, Anh G. Hoang, Eleni Efstathiou, Patricia Troncoso, Christopher J. Logothetis. A molecular characterization of the anaplastic prostate carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1195. doi:10.1158/1538-7445.AM2013-1195