bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2517: Ewing sarcoma associated long non-coding RNA determines neural cell fate of the tumors
Authors: Mitra Sheetal A. , Mitra Anirban P. , Buckley Jonathan D. , Triche Timothy J.
Published: July 2016

BACKGROUND: Ewing sarcoma is a highly invasive pediatric bone and soft tissue malignancy with a 20% 5-year survival rate for patients with metastatic disease. 85% of Ewing sarcomas express a chimeric oncogene, mainly EWS-FLI1, which drives the gene expression signature in these tumors. The exact cell of origin for these primitive small round cell tumors is unknown. These undifferentiated tumors express some neuroectodermal, mesenchymal, and epithelial markers. Recently published work suggests that these tumors may have risen either from neural crest or mesenchymal stem cells. These genomic and phenotypic features may be responsible for the aggressive nature of this disease and understanding the tumor biology may help better treatment options for this metastatic cancer.

RESULTS: Our study on expression analysis of primary Ewing tumors using Affymetrix's Human Exon arrays identified a highly expressed novel long intergenic non-coding RNA (lincRNA), FEZF1-AS1 in these tumors. Its DNA sequence has no homology in most vertebrates. RNA-mediated knockdown of the lincRNA in Ewing cell lines decreased expression of some of the neural lineage genes as well as genes associated with cell adhesion and migration. In vitro matrigel assays detected a decrease in cell invasion capability of the lincRNA-knockdown cells. In the in vivo studies, the lincRNA-overexpressed cells had better engraftment and tumor growth in the liver than the normal controls. On attempt to differentiate the lincRNA-knockdown Ewing cell lines, we noted that a decrease in the lincRNA expression led to a decrease in the expression of neuroectodermal markers after a week of differentiation when compared to the control cells. We further detected temporal expression of this lincRNA during neuronal differentiation from embryonic stem cells.

CONCLUSIONS: Our study identified a unique lincRNA in Ewing sarcoma that may be partly responsible for inducing expression of the neural lineage genes in these tumors as its reduced expression impaired differentiation in the Ewing cell lines. Its prometastatic behavior helps the aggressive nature of these tumors. Its expression during neural differentiation along with its involvement in cell migration suggests that FEZF1-AS1 may be responsible for imparting neural stem cell like-characteristics to Ewing sarcoma.

Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, Timothy J. Triche. Ewing sarcoma associated long non-coding RNA determines neural cell fate of the tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2517.
Abstract 2518: Crosstalk between stem and non-stem cells in glioblastoma promotes radioresistance in a CD109-dependent manner
Authors: Minata Mutsuko , Nakano Ichiro , Kim Sunghak , PavliuKov Marat , Wang Jia , Komarova Svetlana , Wang Jun
Published: July 2016

Glioblastoma (GBM) is a lethal brain tumor that contains cancer stem cells that are bestowed with tumor initiating and treatment resistant properties. Patient-derived glioma stem-like cells (GSCs) that resemble the clinically relevant MES subtype harbor more aggressive and therapy resistant properties. Here we report that exposure of GSCs to ionizing radiation (IR) provokes inter-cellular signals from therapy-induced senescent non-stem cancer cells to stimulate compensatory growth in cancer stem cells resulting in persistent transcriptomic and phenotypic shift toward a more MES subtype. This IR-induced gain of MES features in GSCs is accompanied by conversion of CD133+ stem cell populations to CD133- /CD109+ cells. In both de novo and IR-induced MES GSCs, CD109+, but not CD109- populations are highly tumorigenic and multipotent in vivo. Inhibition of CD109 attenuates clonogenicity and radioresistance in MES GSCs GBM. Clinically, CD109 expression is significantly associated with the MES GBMs and poorer prognosis of GBM patients. Taken together, our data imply that radiation of GSCs induces direct transformation of cancer stem cells to the MES subtype accompanied by a loss of the widely adopted stem cell marker CD133 and a gain of a novel, tumor propagating, and clinically relevant MES stem cell marker, CD109.

Citation Format: Mutsuko Minata, Ichiro Nakano, Sunghak Kim, Marat PavliuKov, Jia Wang, Svetlana Komarova, Jun Wang. Crosstalk between stem and non-stem cells in glioblastoma promotes radioresistance in a CD109-dependent manner. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2518.
Abstract 2523: Transcriptional profiling of glioblastoma stem-like cells reveals enrichment of ion channels with functional implications for malignancy
Authors: Pollak Julia , Rai Karan G. , Paddison Patrick J. , Rostomily Robert C. , Ramirez Jan-Marino
Published: July 2016

Glioblastoma Multiforme (GBM) is the most prevalent and aggressive form of cancer in the adult central nervous system. Ion channels are increasingly being linked to cancer progression through the regulation of cell proliferation and migration. However, the role of ion channels in GBM tumor formation and progression is not well understood. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence, suggesting that ion channel expression may be perturbed in this population. Here, we used RNA-sequencing to assess the expression patterns of ion channels and transporters and identify uniquely enriched ion channels in GSCs. Twenty-two patient-derived GSC samples were expression profiled along with human neural stem cell (NSC) and astrocyte control cell populations. Differential expression analysis revealed a set of ion channels highly enriched in GSCs compared with controls. Real-time PCR analysis confirmed the increased expression of ion channels of interest across selected GSC lines compared to NSCs. The expression pattern of ion channel candidates was also more likely to be associated with distinct GBM molecular subtypes. Next, an integrative approach was taken to further identify ion channels unique to GSCs; the abovementioned findings were compared to results from transcriptome analyses of GBM bulk tumor cells (The Cancer Genome Atlas) and region-specific GBM cells (Ivy Glioblastoma Atlas Project). Ion channels that were identified in these analyses were associated with altered clinical outcomes. The functional implications of these expression changes were further assessed with targeted drug screening of GSCs and NSCs. Pharmacological antagonists of GSC-enriched ion channels suppressed stem cell viability. These antagonists similarly hindered BrdU incorporation of dividing GSCs, suggesting that these channels play a role in stem cell proliferative capacity. Finally, calcium imaging was used to test the real-time functional responses of GSCs to channel blockers, and these outcomes will be discussed. Collectively, these findings suggest the presence of ion channels that uniquely identify GSCs from other neural cell types and influence GSC proliferation, a hallmark of GBM tumor recurrence.

Citation Format: Julia Pollak, Karan G. Rai, Patrick J. Paddison, Robert C. Rostomily, Jan-Marino Ramirez. Transcriptional profiling of glioblastoma stem-like cells reveals enrichment of ion channels with functional implications for malignancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2523.
Abstract 2525: Sema3C promotes glioma stem cell survival and radioresistance
Authors: Man Jianghong , Shoemake Jocelyn , Wu Qiulian , Yu Jennifer
Published: July 2016

Introduction: Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the non-stem tumor cell (NSTC) population is not well defined.

Methods/Materials: GSCs were enriched from patient specimens and functionally validated. We used a candidate approach to screen for secreted factors that were preferentially used by GSCs but not NSTCs. Expression was assessed by Western blot, and confirmed by immunohistochemistry and immunofluorescence in vitro and in human and mouse GBM tissues. Ligand-receptor interactions were confirmed by co-immunoprecipitation. Rac activity was assessed by Rac-GTP pulldown. Co-culture epistasis experiments were performed using knockdown and recombinant protein approaches. Glioma stem cell marker analysis (CD133, Sox2, Olig2), cell viability (ATP-dependent assays), apoptosis (TUNEL, PI/AnnexinV, cleaved caspase 3/7), self-renewal (tumorsphere formation and limiting dilution assay) and invasion (transwell migration assay) were performed. GSCs were separated in PlexinD1 hi and lo populations by FACS. Radiation (3 Gy) was delivered by Cs-137 irradiator. GSCs were used to establish orthotopic xenograft models of glioblastoma and tumor growth and animal survival were assessed.

Results: We have found that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/NF-κB signaling in an autocrine and paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Furthermore, GSCs that expressed high levels of Plexin receptors were more resistant to radiation, and Sema3C and Plexin receptors were upregulated after irradiation. Together, these data support that Sema3C signaling contributes to radiation resistance.

Conclusions: Our study supports targeting Sema3C to break this GSC-specific autocrine/paracrine loop to improve glioblastoma treatment, potentially with a high therapeutic index.

Citation Format: Jianghong Man, Jocelyn Shoemake, Qiulian Wu, Jennifer Yu. Sema3C promotes glioma stem cell survival and radioresistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2525.
Abstract 2526: Regulation of angiogenic factors in glioblastoma progression
Authors: Larrain Carolina , Wesley Umadevi V. , Clark Paul , Kuo John S. , Dempsey Robert
Published: July 2016

Background & Purpose: Glioblastoma is the most malignant primary brain tumor in humans and has a very low survival rate. The aggressiveness of this cancer can be attributed to the presence of glioblastoma stem cells (GSC), which are highly invasive and therapy resistant. Increased aggressiveness of GSCs is attributed to the release of angiogenic factors, which promotes the formation of new blood vessels that enhances tumor cell survival and proliferation. The neovascularization also provides a scaffold for tumor cells to migrate, enabling metastasis. Therefore, identifying the altered expression of angiogenic factors is of clinical importance. In this study, we examined the changes in the expression of pro-angiogenic factors in GSCs as compared to the original tumor from which they were derived. We also determined if differentiation of GSC towards a less invasive phenotype decreased the levels of these pro-angiogenic factors. Methods: GBM tumor cells were grown in complete media containing 10% Fetal Calf Serum (FCS) and GSCs were grown in media containing B27, heparin, EGF, and FGF. GSCs were differentiated by growing them in media containing 10% FCS and B27 with vitamin A, for about one week. We examined the expression of a panel of pro-angiogenic factors in GSCs (33-GSC) and in the original tumor cells (33-T) from which GSCs were derived. We then examined if differentiation of 33-GSC decreased the levels of these pro-angiogenic factors. Changes in protein levels were evaluated by immunofluorescence staining. The mRNA levels were quantitated using real time Q-PCR. Results: Immunofluorescence staining showed that the GSCs express higher levels of pro-angiogenic factors examined (11 out of 16). GSCs were successfully differentiated into astrocytes as indicated by morphology and GFAP expression. The differentiation of GSCs into astrocytes was sufficient to cause decreased expression of VEGF and c-MYC. Our data showed 27 fold increase in VEGF mRNA levels, 63 fold increase in MMP2 mRNA levels, 11 fold increase in MMP9 mRNA levels, and 2 fold increase in c-MYC mRNA levels in GSCs compared to the tumor line, indicating the regulation of these pro-angiogenic factors at transcriptional level. Conclusions: Increased expression of pro-angiogenic factors in GSCs may render these cells to be more aggressive and invasive, and suggests that differential expression of angiogenic factors in GSC cells may play an important role in the GBM progression, and therapy resistance.

Citation Format: Carolina Larrain, Umadevi V. Wesley, Paul Clark, John S. Kuo, Robert Dempsey. Regulation of angiogenic factors in glioblastoma progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2526.
Abstract 2529: Expression of ABCF1 with stem cell markers CD133/GEP/beta-catenin in fetal liver and liver cancer cells
Authors: Fung Sze Wai , Cheung Phyllis Fung Yi , Yip Chi Wai , Tsao George Sai Wah , Cheung Siu Tim
Published: July 2016

Understanding stem cell biology in relation to cancer is of growing importance with the cancer stem cells (CSCs) notion and recurring deregulated stem cell pathways reported in cancers. ATP-binding cassette (ABC) transporter ABCB1 (also named P-glycoprotein and MDR1) has shown to be CSC marker, mediate multidrug-resistance in model systems though with controversial clinical relevance. We have systemically examined the expression profiles of ABC genes in hepatocellular carcinoma (HCC) clinical samples. ABCF1 was significantly over-expressed in HCCs compared to the adjacent non-tumor liver tissues (P<0.001) and associated with recurrence-free survival after curative partial hepatectomy (log rank, P = 0.010). Recurrences have conventionally been attributed to aggressive cancer features and, recently, CSC features, as CSCs in small load could grow to tumor bulk. We therefore further explored the significance of ABCF1 in both fetal liver and liver cancer cells in respect to stem cell signaling. Expression of ABCF1 in fetal, neonatal and adult mouse livers were examined by immunohistochemistry, western blot and flow cytometry. Consistently, elevated ABCF1 expression was demonstrated in early embryonic stages [embryonic day 13 (E13): 42.4%; E15: 24.6%] but rarely in neonates and adult livers [1.5% and 1.2%, respectively]. Also, ABCF1 co-stained with stem cell-related marker β-catenin and hepatic CSC markers CD133 and GEP in fetal hepatocytes and in HCC cells (Table 1). ABCF1 suppression by siRNA enhanced chemo-sensitivity of the HCC cells Hep3B compared to control cells on cisplatin (cell apoptosis 7.5% vs 1.7%, P<0.001) and 5-Fluorouracil (11.7% vs 4.7%, P<0.001). Subcellular fractionation analysis on HCC cells showed that ABCF1 protein was present in both the cytoplasmic and membrane fractions. The current study highlighted the functional significance of ABCF1 in liver development and liver cancer as stem cell-related molecule regulating chemo-resistance. Table 1.Co-expression of ABCF1 and hepatic stem cell markers in mouse fetal livers and HCC cellsFetal liver cells (E15)Liver cancer cells (Hep3B)ABCF1+24.6%34.5%CD133+16.3%88.8%ABCF1+ CD133+20.9%34.3%GEP+45.7%65.7%ABCF1+ GEP+24.0%29.7%β-catenin+40.6%20.9%ABCF1+ β-catenin+13.5%17.5%

Citation Format: Sze Wai Fung, Phyllis Fung Yi Cheung, Chi Wai Yip, George Sai Wah Tsao, Siu Tim Cheung. Expression of ABCF1 with stem cell markers CD133/GEP/beta-catenin in fetal liver and liver cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2529.
Abstract 2530: Live cell detection of intracellular biomarkers maintains cancer stem cells for further experimentation
Authors: Weldon Don , Williams Yuko , Patel Amish , McClellan Steven
Published: July 2016

Cancer stem cells are widely studied as a potential therapeutic target in cancer research. Their expression of cell surface biomarkers such as EpCAM, CD44, and CD133 have been well characterized as a method for identification and enrichment from heterogeneous populations. Additional biomarkers with more functional relevance to self-renewal such as the transcription factors Sox-2 and Nanog, are intracellular and traditionally require fixation and permeabilization of the sample. Here we describe a method for identification and enrichment of live cancer stem cells based on intracellular biomarker expression.

Live human head and neck squamous cell carcinoma (HNSCC) cell lines, UM-SCC-47 and UM-SCC-104 were used as a model for Cancer stem cells in a mixed population. They were assayed for their expression of EpCAM, CD44, and CD133 by flow cytometry. Additionally, Aldehyde dehydrogenase (ALDH) activity was also detected in a population of the HNSCC cell lines further corroborating the presence of a cancer stem cell population. Live cell probes specific to Nanog and Sox-2 were used to enrich for cells expressing the targets of interest through Fluorescent Activated Cell Sorting (FACS).

This live cell biomarker approach was also recently demonstrated on solid tumors which were digested and cultured as single cells where they were then incubated with the live cell probes. FACS sorting was utilized to enrich for a cancer stem cell population. More importantly after detection these cells remain live and intact allowing them to be returned to culture and further studied.

Citation Format: Don Weldon, Yuko Williams, Amish Patel, Steven McClellan. Live cell detection of intracellular biomarkers maintains cancer stem cells for further experimentation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2530.
Abstract 2543: A family affair: Prostate cancer risk and family history of breast or prostate cancer
Authors: Barber Lauren E. , Gerke Travis A. , Markt Sarah C. , Parmigiani Giovanni , Mucci Lorelei A.
Published: July 2016

Background - There is suggestive evidence of familial clustering of breast and prostate cancer in first-degree relatives; women with a family history of prostate cancer are at increased risk of breast cancer. Few studies have investigated joint family history of breast and prostate cancer and prostate cancer risk, and no study to date has examined lethal prostate cancer.

Methods - We studied 42,672 from the Health Professionals Follow-up Study between 1996 to 2012. During follow-up, 4,258 prostate cancer cases were diagnosed, of whom 380 were lethal disease. Men self-reported family history of breast and prostate cancer, including in siblings or parents. Using cause-specific hazards regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) of the association between family history and prostate cancer risk and progression.

Results - About 8% of men had a family history of prostate cancer, 8.7% had a family history of breast cancer, and 1.4% of men had a family history of both breast and prostate cancer. A family history of prostate cancer was significantly associated with an increased risk of prostate cancer (HR: 1.69; 95% CI: 1.54-1.85). Increased risk was higher for men with a father diagnosed with prostate cancer (HR: 1.64 95% CI: 1.49-1.80) than for men with a diagnosis in a brother(s) (HR: 1.51 95% CI: 1.27-1.80). A positive family history of breast cancer was associated with a small, but significant 22% increased risk (HR: 1.22; 95% CI: 1.11-1.35). Familial breast cancer in a sister (HR: 1.22 95% CI: 1.06-1.41) increased risk more than familial breast cancer in a mother (HR: 1.12; 95% CI: 0.99-1.25). Men with a family history of both prostate and breast cancer had a 52% (HR: 1.52; 95%CI: 1.23-1.88) increased risk of prostate cancer compared to men with no family history of either cancer. Risk of lethal prostate cancer was also significantly increased for men with a positive family history of prostate cancer (HR: 1.64; 95% CI: 1.20-2.24), as well as for men with a family history of breast cancer (HR: 1.47; 95% CI: 1.07-2.01).

Conclusions - These results support the findings of familial aggregation of breast and prostate cancer, and for the first time suggest an association between familial breast cancer and lethal prostate cancer. Data from this prospective study have translational relevance for family counseling of cancer patients.

Citation Format: Lauren E. Barber, Travis A. Gerke, Sarah C. Markt, Giovanni Parmigiani, Lorelei A. Mucci. A family affair: Prostate cancer risk and family history of breast or prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2543.
Abstract 2546: With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs
Authors: Olsson Hakan L.
Published: July 2016

Hereditary cancer that has monogenic inheritance affects every tenth patient, on average, who is diagnosed with cancer, and it has been suggested based on twin studies, that approximately 30% of all cancer patients have a genetic predisposition to developing cancer. The author posited that familial syndromes become more organ specific with increasing age at tumour presentation to the point that very late in life, only a few organs are affected by tumours disease. The reason for this could be that the tumour originates from a more differentiated, organ-specific progenitor/stem cell later in life, while the progenitor/stem cell might be involved in organogenesis in different organs earlier in life. Examples are given for skin cancer and breast cancer.

Summary: Patients with familial cancer who present with cancer at an older age at tumour presentation have a more organ restricted disease. This could be because the tumor has a more differentiated progenitor/stem cell origin. Examples are given for families with breast cancer, melanoma, and non- melanoma skin cancer.

References: Olsson H. A hypothesis about tumour development and the clinical features of hereditary cancer. European Journal of Cancer 2001 2023-2029.

Olsson H. With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs. Journal of Cancer and Therapy (in press). Examples of the median age at diagnosis for melanoma (*) and breast cancer (**) in familial settingsFamilies with melanoma. CDKN2A positive melanoma cases. (melanoma, pancreas, smoking associated cancer)39*Families with melanoma. CDKN2A negative melanoma cases. (melanoma and skin cancer)48*Four or more tumors in the cancer registry, at least one of which is a melanoma. Multiple melanoma cases with other tumors and CDKN2A mutations.60*Four or more tumors in the cancer registry, at least one of which isa melanoma. Melanoma, other tumours and adenocarcinomas.67*Four or more tumors in the cancer registry, at least one of which is a melanoma. Melanoma and skin cancer.78*Li Fraumeni's syndrome<40**BRCA144**BRCA245**BRCAX (majority breast only families)48**Vertical inheritance52**Horizontal inheritance (possible recessive inheritance, breast cancer only families).63**

Citation Format: Hakan L. Olsson. With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2546.
Abstract 2549: Familial risk of upper gastrointestinal cancers by tumor location
Authors: Kharazmi Elham , Babaei Masoud , Fallah Mahdi , Chen Thianhui , Sundquist Kristina , Hemminki Kari
Published: July 2016

Background: Upper gastrointestinal (UGI) cancers are within the most common malignancies worldwide. Familial clustering of UGI cancers and the significance of family history have been addressed in the past. We aimed to further elucidate the familial risk based on specified tumor locations.

Methods: Using the Swedish Family-Cancer Database, we determined the familial risk of UGI cancer patients diagnosed between 1958 and 2012. Standardized incidence ratio (SIR) was used for calculating concordant and discordant familial cancers risks, stratified by tumor locations. All results were adjusted for sex, age group, period, and socioeconomic status.

Results: Risk of esophageal cancer in first-degree relatives (FDRs) of esophageal cancer patients was 2•4-fold higher than that in those without such a family history. Familial risk for concordant cancer in upper and middle third of esophagus was 3•2- and 5•6-fold, respectively. Family history of esophageal cancer in lower part was associated with increased risk of gastric cardia cancer in FDRs and vice versa. Family history of both adenocarcinoma and SCC of esophageal cancer increased the familial risk of concordant (similar) and discordant subtypes. Occurrence of gastric cancer in the body and the antrum of stomach in a FDR were associated with an increased risk of gastric cancer 6- to 7-fold in the same location in family members, respectively.

Conclusion: Family history of UGI cancers in some specific locations like upper and middle third of esophagus, body and antrum of stomach can be considered as an important predictive evidence for the same cancers in relatives.

Citation Format: Elham Kharazmi, Masoud Babaei, Mahdi Fallah, Thianhui Chen, Kristina Sundquist, Kari Hemminki. Familial risk of upper gastrointestinal cancers by tumor location. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2549.
Abstract 2565: Prostate cancer GWAS from more than 89,000 men identifies more than 30 novel prostate cancer susceptibility loci
Authors: Schumacher Fredrick R. , Al Olama Ali A. , Berndt Sonja I. , Wiklund Fredrik , Conti David V. , Ahmed Mahbubl , Benlloch Sarah , Easton Douglas F. , Kraft Peter , Chanock Stephen J. , Henderson Brian E. , Kote-Jarai Zsofia , Haiman Christopher A. , Eeles Rosalind A.
Published: July 2016

Genome-wide association studies (GWAS) and fine-mapping efforts have identified over 100 loci associated with prostate cancer susceptibility. Combined multiplicatively, these loci capture 33% of the familial risk for prostate cancer among European-ancestral populations. In order to identify novel prostate cancer susceptibility loci we conducted a GWAS involving over 53,000 prostate cancer cases and 36,000 controls using the OncoArray that includes a 260K GWAS backbone and a custom portion of 310K SNPs developed from previous GWAS and fine-mapping studies of multiple cancer types (http://epi.grants.cancer.gov/oncoarray/). Following standard quality control procedures, the prostate cancer OncoArray genotyped data were imputed using the October 2014 release of the 1000 genomes project data as a reference and analyzed by participating study for overall and advanced prostate cancer using logistic regression. The study-specific results were combined using inverse variance fixed effect meta-analysis. Regions surrounding previously associated variants (+/- 500kb of the reported index variant) were excluded to identify novel associations. In the OncoArray meta-analysis, we identified more than 30 novel loci significantly associated (P<5.0×10-8) with overall, advanced (Gleason ≥8, death from PrCa, PSA>100, or disease stage “Distant”), or early-onset (≤55 years of age) prostate cancer. Previous GWAS of prostate cancer are being imputed to the latest release of the 1000 genomes project to enhance our statistical power for novel discovery. In total our overall meta-analysis will incorporate over 176,000 individuals of European ancestry - more than 95,000 prostate cancer cases and 79,000 controls. The current results, as well as the larger ongoing meta-analysis, provide further insight into the underlying mechanisms of prostate cancer carcinogenesis and will improve the utility of genetic risk scores for targeted screening and prostate cancer prevention.

Citation Format: Fredrick R. Schumacher, Ali A. Al Olama, Sonja I. Berndt, Fredrik Wiklund, David V. Conti, Mahbubl Ahmed, Sarah Benlloch, Douglas F. Easton, Peter Kraft, Stephen J. Chanock, Brian E. Henderson, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles. Prostate cancer GWAS from more than 89,000 men identifies more than 30 novel prostate cancer susceptibility loci. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2565.
Abstract 2566: Comprehensive analysis to identify functional basis of prostate cancer risk SNPs
Authors: Middha Mridu , Xu Xing , Vaananen Riina-Minna , Hayes James , Taimen Pekka , Gao Xiaoni , Lilja Hans G. , Pettersson Kim , Klein Robert J.
Published: July 2016

Introduction:

Genome-wide association studies (GWAS) have identified numerous common single nucleotide polymorphisms (SNPs) associated with the risk of developing prostate cancer. Many of these prostate cancer GWAS hits occur in intergenic regions, distant from any annotated gene. Little is yet known about how these SNPs function to alter an individual's risk of prostate cancer. Here we test the hypothesis that many of these SNPs, or SNPs with which they are correlated, alter regulatory regions and thus gene expression in the prostate.

Materials and Methods:

To test if prostate cancer risk SNPs are correlated with gene expression changes, we conducted expression quantitative trait locus (eQTL) association analysis. Using genome-wide high-density genotypes and gene expression data from 56 tumor and 58 adjacent normal prostate tissues we asked if any of the prostate cancer risk SNPs correlate with expression changes in nearby genes using linear regression, adjusting gene expression levels for principal components of ancestry and different batches. We also asked if individuals who have a higher genetic risk of prostate cancer based on the genotype of all of their risk SNPs show different gene expression patterns in the prostate than those at lower risk of prostate cancer.

Results:

We have identified several novel cis-eQTLs in prostate tissue for prostate cancer risk SNPs including rs1933488 with RGS17. We have also replicated several previously known cis-eQTLs, including those for IRX4, PPP1R14A, and FOXP4. Individuals at higher genetic risk of developing prostate cancer have altered expression of 37 genes (p<0.001) in their tumor tissue compared to individuals at lower genetic risk.

Conclusions:

These data demonstrate that several prostate cancer risk SNPs are associated with expression changes in nearby genes in both pathologically malignant and pathologically benign prostate tissue from patients who underwent radical prostatectomy. Additional genes, including HMOX1, CSGALNACT1, and WDR36 show altered expression in patients with different levels of genetic risk of prostate cancer.

Citation Format: Mridu Middha, Xing Xu, Riina-Minna Vaananen, James Hayes, Pekka Taimen, Xiaoni Gao, Hans G. Lilja, Kim Pettersson, Robert J. Klein. Comprehensive analysis to identify functional basis of prostate cancer risk SNPs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2566.
Abstract 2576: Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma in situ
Authors: Liu Ying , Yun Shumei , Lian Min , Colditz Graham
Published: July 2016

Objectives: To examine the relationship between radiation therapy delay and risk of subsequent breast events in the ipsilateral breast and to identify factors that are associated with delay in women with ductal carcinoma in situ (DCIS).

Methods: From the Missouri Cancer Registry, we identified the women who were diagnosed with first primary DCIS between 1996 and 2011 and treated with breast conserving surgery (BCS). Radiation therapy delay was defined as the first radiation therapy that was delivered greater than eight weeks after BCS. Propensity scores were calculated for radiation therapy delay and no radiation therapy during the first course of treatment. A propensity score-adjusted Cox proportional hazards regression analysis was conducted to estimate the hazard ratio (HR) of ipsilateral breast tumors. Logistic regression analysis was conducted to identify factors associated with delay.

Results: Among 5,916 patients, 1,053 (17.8%) received radiation therapy greater than eight weeks after BCS and 1,702 (28.8%) did not receive radiation therapy during the first course of treatment. During the 72- month follow-up, 182 (3.1%) developed ipsilateral breast tumors. After adjustment for propensity scores, the HR of ipsilateral breast tumors was 1.26 (95% CI, 1.00-1.59; p = 0.049) for radiation therapy delay and 1.35 (95% CI, 1.03-1.76; p = 0.03) for no radiation therapy compared with timely radiation therapy. Radiation therapy delay was associated with black race, being non-married and on Medicaid, later years of diagnosis, larger tumor size micropapillary architecture, and positive surgical margin.

Conclusions: Receipt of radiation therapy greater than eight weeks after BCS was associated with a significantly increased risk of ipsilateral breast tumors in women with DCIS. Timeliness of radiation therapy should be improved, particularly for black and Medicaid patients.

Citation Format: Ying Liu, Shumei Yun, Min Lian, Graham Colditz. Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma in situ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2576.
Abstract 2586: Evaluation of risk-based colposcopy in the ALTS trial
Authors: Liu Angela H. , Schiffman Mark , Gage Julia C. , Castle Philip E. , Wentzensen Nicolas
Published: July 2016

Objective: Women referred to colposcopy have a wide spectrum of underlying risk of precancer that could influence colposcopic practice and management. We sought to evaluate important risk-strata based on HPV status, cytology, and colposcopic impression in women undergoing colposcopy.

Methods: Among participants in the ASCUS-LSIL Triage Study, we stratified women from the immediate colposcopy and HPV triage study arms based on enrollment HPV typing, study cytology, and colposcopic impression. In each group, absolute risk of CIN3+ at enrollment colposcopy and cumulative risk over 2-year follow-up were estimated. Immediate CIN3+ risk of LSIL and HSIL cytology were used as thresholds for colposcopy referral and immediate treatment, respectively.

Results: We observed substantial differences in risk of precancer across strata. Women with HSIL cytology, who were HPV16-positive, and high-grade colpscopic impression had a 71% baseline and 78% 2-year risk of CIN3+, respectively. HPV16-positive women with HSIL cytology and low-grade impression, and women with high-grade impression and either HSIL cytology or HPV16 infection, also showed significant CIN3+ risk exceeding the risk of HSIL. In contrast, women with normal colposcopy, <HSIL cytology, and absence of HPV16 infection had the lowest baseline CIN3+ risk (3.2%), below the colposcopy referral threshold in ALTS.

Conclusion: Risk assessment at colposcopy can inform colposcopy-biopsy practice and guide management. In the low-risk group, biopsy yields little additional disease and a normal colposcopy may confer higher reassurance that CIN3+ is not present; while in the highest risk groups, immediate treatment without biopsy confirmation could be considered according to current guidelines. Analyses evaluating the benefit of multiple biopsies in these risk strata are underway and will be presented at the meeting.

Citation Format: Angela H. Liu, Mark Schiffman, Julia C. Gage, Philip E. Castle, Nicolas Wentzensen. Evaluation of risk-based colposcopy in the ALTS trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2586.
Abstract 2588: Prediction of the 5-year risk of hepatocellular carcinoma during long-term antiviral therapy in the general Korean population
Authors: Shim Jae-Jun , Oh In Hwan , Kim Jung Wook , Lee Chang Kyun , Jang Jae Young , Lee Ju-Seog , Kim Byung-Ho
Published: July 2016

Oral antiviral therapy using nucleos(t)ide analogues can decrease risk for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, wide use of antiviral therapy is limited by stringent treatment indications in many countries. We compared preventive effect of antiviral therapy on HCC development between current and new extended indication for the treatment. We established Korean cohort with chronic hepatitis B virus (HBV) infection using the fifth National Health and Nutrition Examination Survey (KNHANES). The cohort represented 993,872 subjects with chronic HBV infection more than 40 years in Korea. We estimated five-year risk of HCC before and after antiviral therapy using a HCC prediction score (REACH-B). The National Health Insurance (NHI) in Korea, the European Association for the Study of the Liver (EASL) guideline, and a new extended indication were compared. During a 5-year period, predicted HCC cases were 2,725 per 100,000 individuals (0.55% / year). When the cohort was treated under the Korean NHI indication, EASL, and new extended indication, HCC risk decreased to 2,531 (-7.1%), 2,089 (-23.3%), and 1,122 (-58.8%) cases per 100,000 individuals, respectively (P < 0.0001). As participation rate in antiviral therapy among eligible patients increased every 10%, HCC risk decreased to -0.74%, -2.39%, and -5.87%, respectively. New extended indication could decrease HCC risk eight times more than the current Korean NHI indication. Prediction of HCC development among chronic HBV infection is feasible in the virtual population level. Considering the large preventive effect of antiviral therapy, the treatment indications should be revised to increase eligible patients. Indications for antiviral treatment used in this study and predicted reduction of HCC riskKorean NHIEASLNew extended indicationLiver enzymeAST or ALT ≥ 80 IU/LALT ≥ ULN x 1AnyHBV DNA level≥ 20,000 IU/mL≥ 2,000 IU/mL≥ 2,000 IU/mLHCC risk reduction, mean (SD) (%)-7.14 (0.14)-23.33 (0.26)-58.82 (0.07)

Citation Format: Jae-Jun Shim, In Hwan Oh, Jung Wook Kim, Chang Kyun Lee, Jae Young Jang, Ju-Seog Lee, Byung-Ho Kim. Prediction of the 5-year risk of hepatocellular carcinoma during long-term antiviral therapy in the general Korean population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2588.
Abstract 2592: The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series
Authors: Winder Abigail , Sobecki-Rausch Janelle , Maniar Kruti , Novak Karen , Kim Julie , Lurain John
Published: July 2016

Objective: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia (GTN) that develops from chorionic-type intermediate trophoblasts, simulates carcinoma, often presents many years following a pregnancy event, is associated with low or normal human chorionic gonadotropin (hCG) levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in the management of both localized and metastatic ETT.

Methods: A retrospective review of women with ETT treated at a gestational trophoblastic disease center from 2010-2015 identified five women. Medical records were abstracted for demographic data, clinical presentation, hCG levels, prior pregnancy information, disease sites, and treatment with chemotherapy and surgery.

Results: The five women with ETT ranged in age from 28 to 48 years. Clinical presentation was abnormal uterine bleeding prompting dilation and curettage, which established the diagnosis of ETT in three women. One woman presented with repeated spontaneous pneumothorax requiring thoracoscopic resection, which identified a 6 cm ETT in the lung. Another woman was initially treated with methotrexate for a presumed ectopic pregnancy without a response. Two women had no identifiable antecedent pregnancy, two women had spontaneous abortions 19 and 72 months prior to the diagnosis of ETT, and one woman had a normal term delivery 48 months earlier. Four of five women had metastatic disease to the lungs. Three of these women underwent pulmonary wedge resection as well as hysterectomy followed by paclitaxel-cisplatin/paclitaxel-etoposide (TP/TE) chemotherapy, while the other woman was treated with etoposide, methotrexate, actinomycin D/etoposide, cisplatin (EMA/EP) chemotherapy and hysterectomy. The one woman with nonmetastatic disease was treated with hysterectomy only. All five women are currently without evidence of disease.

Conclusions: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum-containing regimen, such as TP/TE or EMA/EP, should be used in women with metastatic disease. All five women with ETT in this series were cured using this approach, including the four with metastatic disease.

Citation Format: Abigail Winder, Janelle Sobecki-Rausch, Kruti Maniar, Karen Novak, Julie Kim, John Lurain. The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2592.
Abstract 2597: Breast and ovarian cancer risks associated with cancer predisposition gene mutations identified by multigene panel testing
Authors: Couch Fergus J. , Goldgar David E. , Hart Steven N. , Hallberg Emily , Moore Raymond , Meeks Huong , Huether Robert , LaDuca Holly , Chao Elizabeth , Dolinsky Jill
Published: July 2016

Multigene panel testing (MGPT) for hereditary cancer is increasing in popularity in the USA. Many panels include genes identified as hereditary breast and/or ovarian cancer (HBOC) genes despite limited data regarding the precise cancer risks associated with mutations in these genes. Here we report on results from BreastNext and OvaNext panel testing of 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, TP53) in a cohort of 15,083 individuals. The majority of individuals were from high-risk breast and/or ovarian (Br/Ov) cancer families, with 92.4% of all probands meeting National Comprehensive Cancer Network HBOC testing criteria. Pathogenic mutations were identified in 9.4% of the overall cohort.

To estimate gene-specific breast and ovarian cancer risks, case-control analyses were performed comparing the frequencies of pathogenic mutations from Caucasian breast or ovarian cancer cases from BreastNext and OvaNext with frequencies from Caucasian, non-Finnish, non-TCGA controls from the Exome Aggregation Consortium (ExAC) database. Mutations in the well studied ATM and CHEK2 genes were associated with moderate risks (OR>2) of breast cancer and mutations in PALB2 were associated with high-risks (OR>5) of breast cancer, consistent with previous reports. In addition, the study suggested that pathogenic mutations in MSH6, RAD51D, CDH1, and NF1 are associated with moderate to high risks of breast cancer. In contrast, RAD51C, RAD51D, and BRIP1 mutations were associated with high risks of ovarian cancer, PALB2 mutations were associated with moderate risks, but ATM and CHEK2 mutations were not associated with increased ovarian cancer risk. In addition, modeling of missense mutations in the predisposition genes using in silico prediction algorithms suggested that missense mutations in CDH1, CHEK2, MSH2, and MSH6 are associated with moderate risks of breast cancer and missense mutations in RAD51C increase risks of ovarian cancer. This large breast and ovarian cancer case-control analysis provides useful data for many predisposition genes previously lacking risk estimates, and should prove useful for clinical risk management of patients after clinical panel testing.

Citation Format: Fergus J. Couch, David E. Goldgar, Steven N. Hart, Emily Hallberg, Raymond Moore, Huong Meeks, Robert Huether, Holly LaDuca, Elizabeth Chao, Jill Dolinsky. Breast and ovarian cancer risks associated with cancer predisposition gene mutations identified by multigene panel testing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2597.