bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3451: Non-genetic RTK-mediated cetuximab resistance in colorectal cancer offers multiple targets for therapeutic intervention
Authors: Graves-Deal Ramona , Bogatcheva Galina , Damalanka Vishnu , Klampfer Lidija , Janetka James W. , Coffey Robert J. , Singh Bhuminder
Published: September 2020

Using 3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 derivatives (CC, SC, CC-CR), we previously identified that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to resistance to anti-EGFR monoclonal antibody, cetuximab. CC cells are sensitive to cetuximab, while SC and CC-CR cells are resistant in 3D. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. In fact, we now show that the cetuximab/crizotinib combination leads to synergistic growth inhibition in both SC and CC-CR. In addition to steady-state upregulation of MET and RON phosphorylation in SC cells, we also observe upregulation of ERBB3 phosphorylation after cetuximab addition, indicating a need for monitoring RTK activity during treatment. We have also identified a set of KRAS wild-type human CRC patient-derived tumor xenografts (PDXs) that show increased MET/RON phosphorylation. As noted previously, addition of the MET ligand (HGF) and ERBB3 ligand (NRG1) induced cetuximab resistance in CC cells and HGF-induced cetuximab resistance was overcome by crizotinib addition. We now show that MET/RON-dependent cetuximab resistance is due to autocrine production of their cognate ligands HGF/HGFL, respectively. For these studies, we employed selective inhibitors of the proteases (HGFA, Matriptase, and Hepsin) that mediate processing and maturation of HGF/HGFL; these inhibitors (ZFH7116 and VD2173) were able to overcome cetuximab resistance in SC and CC-CR cells. Thus, RTK ligand processing is an additional therapeutic target to counter cetuximab resistance in CRC.

Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh. Non-genetic RTK-mediated cetuximab resistance in colorectal cancer offers multiple targets for therapeutic intervention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3451.
Abstract 3513: Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population
Authors: Sipeky Csilla , Tammela Teuvo L. , Auvinen Anssi , Schleutker Johanna
Published: September 2020

Background: Prostate cancer (PC) is the second most common cancer in men worldwide with a rising prevalence. However, only limited number of clinically actionable variants are known. The objective of this study is to identify novel PC susceptibility loci with potential clinical relevance utilizing the increased genetic drift and reduced selective pressure of the recently bottlenecked powerful resource of the Finnish population.

Methods: We meta-analysed >185.000 germline single nucleotide polymorphisms (SNPs) in 2738 PC cases and 2401 controls of Finnish origin in the Collaborative Oncological Gene-Environment Study (COGS) using Illumina iSelect custom SNP genotyping platform.

Results: Altogether 160 variants remain significant on GWAS level (p<5 × 10−8) in 18 different gene regions. Out of the 160 identified PC susceptibility hits 78 (49%) are novel variants not reported earlier in association with PC. PC associated signals are in close proximity to one another forming genetic hot-spots on chromosomes 8, 7, 11, 17 and 19. The strength of association varies for 101 PC risk variants (OR 1.24-1.86) and 59 protective SNPs (OR 0.59-0.80). The strongest risk gene is CASC8 (OR=1.86; p=1.214 × 10−11). The most significant signals were found at the 8p21.2 chromosomal region (p<7.6 × 10−16). Functional annotation identified a missense coding SNP at KLK3 gene to be a candidate causal variant. We showed evidence for association both with early-onset PC (OR 1.73; P=0.02), high serum PSA level at diagnosis (OR 1.36; P=0.024) and with aggressive PC (Gleason score ≥8; OR 1.44; P=0.02) at 17q21.

Conclusion: The results facilitate risk stratification for screening, clinical studies, treatment choices and functional research of PC

Citation Format: Csilla Sipeky, Teuvo L. Tammela, Anssi Auvinen, Johanna Schleutker. Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3513.
Abstract 3557: Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma
Authors: Park Wungki , Chen Jiapeng , Chou Joanne F. , Iacobuzio-Donague Christine , Riaz Nadeem , O'Reilly Eileen M.
Published: September 2020

Introduction: Homologous recombination deficiency (HRD) is an emerging biomarker for DNA-damage-response (DDR)-targeted therapies in pancreatic cancer (PDAC). There are different methods available to identify HRD in other cancers, however these have not been evaluated comprehensively in PDAC for their response prediction to first-line platinum-based therapies (1L-platinum).

Methods: Patients with advanced (stage 3-4) PDAC who had germline and somatic MSK-IMPACT were included. We evaluated genetic methods for HRD and their association with clinical outcomes on 1L-platinum or 1L-non-platinum therapies. Homologous recombination (HR)-genes included: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1. We evaluated the status of pathogenic HR-gene mutations (HRm): (1) germline vs. somatic HRm; (2) core HRm (cHRm) (BRCA1, BRCA2, PALB2) vs. non-core (ncHRm); (3) zygosity (monoallelic vs. biallelic HRm). Additionally, HRD genetic signatures using large-scale state transition (LST) and signature 3 (Sig3) were evaluated.

Results: Two-hundred and sixty-two patients with advanced PDAC who received care at Memorial Sloan Kettering were included. There was no difference in overall survival (OS) for patients with either germline or somatic HRm, hence they were analyzed together as HRD. Median [95% CI] follow-up among surviving patients (n=75) was 21.9 [1.4-57.0] months, median OS was 15.5 [14.6-19] months, and median progression-free survival (PFS) was 7 [6.1-8.1] months. The effect of HRD on PFS was dependent on whether the patient received 1L-platinum or not. After controlling for stage at diagnosis, patients with HRD had a reduced risk of progression or death compared to patients without HRD when treated with 1L-platnium (HR: 0.44 [95%CI: 0.29-0.67], p<0.01). Biallelic HRm and cHRm were associated with higher LST and tumor mutation burden. Sig3-positive patients were also associated with improved PFS compared to Sig3-negative patients when treated with 1L-platinum.

Conclusion: Patients who have PDAC with HRD defined by HRm had better OS irrespective of 1L-platinum, although they had better PFS when treated with 1L-platinum compared to 1L-non-platinum. Among methods to identify HRD, pathogenic HR-gene mutations remain the standard when using a targeted-sequencing approach. Further investigation is warranted.

Citation Format: Wungki Park, Jiapeng Chen, Joanne F. Chou, Christine Iacobuzio-Donague, Nadeem Riaz, Eileen M. O'Reilly. Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3557.
Abstract 3571: Oxidative stress and the ovarian surface epithelium: TGF-β1 stimulation of IOSE cell lines reveals novel upregulation of NADPH oxidase 4, a membrane bound hydrogen peroxide producing enzyme
Authors: Meitzler Jennifer L. , Diebold Becky A. , Antony Smitha , Wu Yongzhong , Juhasz Agnes , Dahan Iris , Jiang Guojian , Lu Jiamo , Wang Stephen , Konaté Mariam M. , Roy Krishnendu , Doroshow James H.
Published: September 2020

Normal ovarian surface epithelium (OSE) has been widely studied as the origin of ovarian cancer. Repetitive ovulation has been implicated in cancer initiation based on damage and inflammation incurred to the OSE upon continuous cycles of tear and repair. Transforming growth factor-beta (TGF-β) plays a role in this normal ovulatory cycle, having been shown to inhibit human OSE proliferation and induce apoptosis, which may prevent the over-proliferation of cells. NADPH oxidase 4 (NOX4), a membrane-associated hydrogen peroxide-producing enzyme, has previously been shown to be sensitive to TGF-β1, with increased expression stimulated in smooth muscle cells and fibroblasts. Here we describe for the first time TGF-β1 induced upregulation of NOX4 in immortalized OSE (IOSE) cells (IOSE121, IOSE144, IOSE364, IOSE386 and IOSE397). This time-dependent increased expression (>5 fold at 2 ng/ml TGF-β1, 24 h) was simulated by direct overexpression of NOX4 in IOSE397 cells and has demonstrated that increased NOX4, in the absence of further growth factor related effects, affords induction of p18 and p21. In addition, using immunohistochemical evaluation of human ovarian cancers in tissue microarrays (n=17 patients), we observed significantly increased expression of NOX4, suggesting that NOX4 upregulation may contribute to the malignant transformation of ovarian cells.

Citation Format: Jennifer L. Meitzler, Becky A. Diebold, Smitha Antony, Yongzhong Wu, Agnes Juhasz, Iris Dahan, Guojian Jiang, Jiamo Lu, Stephen Wang, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Oxidative stress and the ovarian surface epithelium: TGF-β1 stimulation of IOSE cell lines reveals novel upregulation of NADPH oxidase 4, a membrane bound hydrogen peroxide producing enzyme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3571.
Abstract 3627: Comparison of genetic profiles of small and large duct type intrahepatic cholangiocarcinoma with distal extrahepatic cholangiocarcinoma
Authors: Kim Hayeon , Lee Soo Yeon , Kim Aeree , Kim Baek-hui , Kim Chung-yeul
Published: September 2020

Cholangiocarcinoma comprises epithelial malignancy that occurs in various sites in the biliary tree. Cholangiocarcinoma is categorized into intrahepatic, perihilar, and distal bile duct carcinomas according to its anatomical position. According to the fifth edition of World Health Organization Classification of Tumors, intrahepatic cholangiocarcinoma (ICC) is further classified into small- and large duct types on histopathological basis. We analyzed molecular profiles of different types of cholangiocarcinoma by next-generation sequencing (NGS). We utilized the Oncomine Comprehensive Assay (OCA) panel v2 on the IonTorrent™ NGS platform to explore genetic differences among the two histologic types of ICC and distal extrahepatic cholangiocarcinoma (DEC). Formalin-fixed paraffin-embedded tumor tissues were obtained from 25 patients who underwent surgical resection of cholangiocarcinoma in Korea University Guro Hospital between 2010 and 2018. We analyzed 7 and 8 small- and large duct type ICCs and 10 DECs. NGS assay of the included cases showed distinct genetic alterations between ICC and DEC, which were enriched in different biological pathways. Unsupervised hierarchical clustering analysis showed two distinct groups. The first group consisted of 12 cases (9 DECs and 3 large duct type ICCs). The second group included 13 cases (7 large duct type and 6 small duct type ICCs). Molecular alteration patterns of a subset of large duct type ICCs were more closely related to DECs than small duct type ICCs. All included small duct type ICCs were considered genetically distinct from DECs. Our study suggested an association between anatomical and histopathological classifications of intra- and extrahepatic cholangiocarcinomas.

Citation Format: Hayeon Kim, Soo Yeon Lee, Aeree Kim, Baek-hui Kim, Chung-yeul Kim. Comparison of genetic profiles of small and large duct type intrahepatic cholangiocarcinoma with distal extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3627.
Abstract 3789: Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin
Authors: Boyd Nathaniel H. , Vigneswaran Krish , Lallani Shoeb , Oh Se-Yeong , Boucher Andrew , Olson Jeffrey , Read Renee
Published: September 2020

Glioblastoma (GBM) is a particularly lethal brain neoplasm accounting for half of malignant primary brain tumors diagnosed in adults and maintains a devastating diagnosis, with a median survival of 14 months despite standard clinical interventions of surgical, chemotherapeutic, and radiation treatments. GBM tumorigenicity is often driven by aberrations in receptor tyrosine kinases (RTKs) such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using a Drosophila glioma model and human patient-derived glioma cells, we identified YAP/TAZ, effectors of the Hippo pathway that promote expression of stemness factors and oncogenes via activation of the TEAD transcription factors, as drivers of glioma tumorigenicity. This led to the discovery that YAP/TAZ are highly expressed in human patient-derived glioma stem cells and that knockdown of these inhibits cell growth. We hypothesized that Verteporfin, a benzoporphyrin derivative approved by the FDA for the treatment of macular degeneration, may have therapeutic benefit for glioblastoma due to its published ability to inhibit interaction between YAP and TEAD transcription factors. Using in vitro culture-based assays and in vivo in GBM xenograft models, we observed Verteporfin specifically induces apoptosis in GBM cells, slows tumor growth, and durably suppressesexpression of known and novel TEAD transcriptional targets in tumor tissue. We validated several direct targets using chromatin immunoprecipitation, and are seeking to further identify the full transcriptional program controlled by YAP/TAZ-TEAD in GBM. Our efforts have led to a phase 0 clinical trial where we were able to observe Verteporfin uptake in GBM tumors in human patients. These data indicate that Verteporfin is a promising therapeutic target for GBM.

Citation Format: Nathaniel H. Boyd, Krish Vigneswaran, Shoeb Lallani, Se-Yeong Oh, Andrew Boucher, Jeffrey Olson, Renee Read. Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3789.
Abstract 3958: Establishment of an in vitro model to study cancer associated fibroblasts and their direct effect on desmoplasia
Authors: Nissen Neel Ingemann , Karsdal Morten , Willumsen Nicholas
Published: September 2020

Background: The extracellular matrix (ECM) and desmoplasia is emerging as key components in defining prognosis and response to treatment. Cancer associated fibroblasts (CAFs) are vital contributors to the desmoplastic reaction and novel ambitious therapies targeting tumor specific ECM and CAFs are being developed. However, it is still debated whether in fact desmoplasia acts as a barrier to- or promoter of - tumor growth. Therefore, there is a need to establish novel models of desmoplasia to improve the understanding of CAFs and associated cancer specific ECM alterations in order to be successful in drug development and prediction of treatment success. By applying the “Scar-in-a-jar” (SiaJ) model, we established an in vitro model including healthy fibroblasts and CAFs derived from the pancreas to study ECM changes and desmoplasia.

Methods: Primary healthy fibroblasts and CAFs were cultured for up to 12 days in the presence or absence of TGF-β. Type I (PRO-C1), type III (PRO-C3) and type VI (PRO-C6) collagen formation were quantified in cell supernatant using enzyme-linked immunosorbent assays. Metabolic activity was evaluated by AlamarBlue.

Results: In healthy fibroblasts no collagen formation could be detected without TGF-β. However, the presence of TGF-β induced PRO-C1, PRO-C3 and PRO-C6 formation with levels increasing up to 20-fold (p<0.0001). Furthermore, PRO-C1, PRO-C3 and PRO-C6 levels where significantly increased in CAFs compared to healthy fibroblasts independent of TGF-β stimulation. There was no difference in metabolic activity across cell line.

Conclusions: TGF-β stimulation led to increased ECM protein expression in healthy fibroblasts but not in CAFs. However, CAFs expressed higher levels of collagens than healthy fibroblasts independent of TGF-β. These results suggest a distinct role of CAFs in their contribution to desmoplasia compared to healthy fibroblasts. The “Scar-in-a-Jar” model can provide a novel in vitro tool to study CAF activity and their direct effect on desmoplasia.

Citation Format: Neel Ingemann Nissen, Morten Karsdal, Nicholas Willumsen. Establishment of an in vitro model to study cancer associated fibroblasts and their direct effect on desmoplasia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3958.
Abstract 4: Choking cancer: Developing a pathway of Withaferin A for the prevention of angiogenesis
Authors: Samant Rishab Rajeev , Samant Rajeev S.
Published: September 2020

Cancer is arguably the most perplexing medical issue of today and manifests in many forms. Most cancers grow as solid tumors, and if they receive enough nutrients, they can metastasize. These tumors receive their nutrients from new blood vessels that grow in the direction of the tumor when the tumor sends bio-chemical signals such as VEGF (vascular endothelial growth factor). Stopping angiogenesis – new blood vessel formation – can cause the tumors to choke and die, which prevents metastasis. One-way of stopping angiogenesis is by using nutraceuticals: foods with a medical benefit. One well-recognized nutraceutical that stops angiogenesis is turmeric. However, not all nutraceuticals possess this property. This project determines if there exist any other easily accessible nutraceuticals possessing effective antiangiogenic properties. I used three different nutraceuticals: basil, ashwagandha, and valerian. Basil was my positive control because there are several published accounts of basil possessing antiangiogenic qualities. My negative control was saline. My hypothesis is that ashwagandha would have a strong antiangiogenic property. Although no study showed that ashwagandha possesses this property, several review articles stated that ashwagandha stopped cancer growth. I used CAMs (chick chorioallantoic membrane) as a to model study angiogenesis. I kept the CAMs, ex-ovo, in individual ceramic bowls lined with plastic wrap and incubated them for a certain number of days. I then took photos of my results and used Powerpoint to analyze them. My conclusion supported my hypothesis because ashwagandha blocked angiogenesis by 67%. This was almost identical to holy basil's rate of stopping angiogenesis.

To obtain clues as to how ashwagandha stopped angiogenesis, I used a previously published study by Szarc et.al. (PLoS One. 2014;9(2):e87850) and analyzed the results using Gene Expression Omnibus (Geo Database: GEO2R-GSE53O49) to obtain the top 250 changes in gene expression upon treatment of breast cancer cells (MCF7 and MDA-MB-231) with ashwaghanda. Examination of the list for angiogenesis related gene expression changes, revealed 19 significantly changing genes following ashwagandha treatment. I used the Search Tool for the Retrieval of Interacting Genes/Proteins: STRING- analysis, to reveal the interaction network between these 19 genes. I found that these genes were influencing DNA replication and cell cycle machinery. Thus, my findings suggest that ashwaghanda can inhibit the cell cycle of cancer cells to stop tumor growth. It possibly affects proliferation of endothelial cells to block angiogenesis.

Citation Format: Rishab Rajeev Samant, Rajeev S. Samant. Choking cancer: Developing a pathway of Withaferin A for the prevention of angiogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4.
Abstract 4617: Association between DNA oxidative damage and radiotherapy-induced skin toxicities in breast cancer patients
Authors: Mihyu Moody M. , Reis Isildinha M. , Takita Cristiane , Wright Jean L. , Lee Eunkyung , Nelson Omar L. , Yang George R. , Bakalar Johnna L. , Hu Jennifer J.
Published: September 2020

Background: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death in the female population in the United States. Although radiotherapy (RT) has been shown to improve prognosis in breast cancer patients, RT may also lead to side effects that impact overall quality of life in some patients. The objective of this study was to investigate whether an oxidative damage biomarker, 8-hydroxy-2-deoxyguanosine (8-OHdG), is associated with RT-induced early adverse skin reactions (EASRs) in breast cancer patients.

Methods: 8-OHdG data before (pre-RT) and after RT (post-RT) were obtained from 475 breast cancer patients. RT-induced EASRs were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (v3.0) scale. Univariate logistic regression analyses were conducted to evaluate associations between above-median 8-OHdG (> 85 ng/ml) and RT-induced grade 2+ EASRs. A propensity score (PS) was derived from a logistic regression model for predicting RT-induced EASRs on the basis of patient, tumor, and treatment characteristics. Then, the association between 8-OHdG and RT-induced EASRs was assessed in four risk groups defined by quartiles of PS.

Results: Overall, 59% of patients developed RT-induced grade 2+ EASRs and 28% developed moist desquamation. There were no significant associations between RT-induced EASRs and high 8-OHdG levels at both pre-RT and post-RT. However, there was a significant association between patients in the 2nd quartile PS that had high post-RT 8-OHdG levels and grade 2+ EASRs (OR=2.51, 95%CI=1.17, 5.40, p=0.0183).

Conclusions: The results from this study suggest that 8-OHdG is a potential biomarker for RT-induced EASRs in a breast cancer population with low to medium (2nd quartile) propensity for RT-induced EASRs.

Citation Format: Moody M. Mihyu, Isildinha M. Reis, Cristiane Takita, Jean L. Wright, Eunkyung Lee, Omar L. Nelson, George R. Yang, Johnna L. Bakalar, Jennifer J. Hu. Association between DNA oxidative damage and radiotherapy-induced skin toxicities in breast cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4617.
Abstract 4651: Interaction between outdoor ultraviolet radiation and indoor tanning bed use on skin cancer risk
Authors: Rhee Jongeun , Li Tricia , Li Wen-Qing , Qureshi Abrar A. , Cho Eunyoung
Published: September 2020

Background: Solar ultraviolet (UV) radiation and the use of UV-emitting tanning devices are risk factors for melanoma and non-melanoma skin cancer (NMSC). Despite abundant evidence, frequent outdoor sunbathers are more likely to use indoor tanning beds. In our study, we aim to investigate the interaction between indoor tanning bed use and exposure to solar UV radiation associated with the risk of skin cancer.

Methods: The study population was participants of the Nurses' Health Study II, which started in 1989 including 116,430 registered female nurses aged 25-42. Participants biennially self-reported diagnosis of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Cases for melanoma and SCC were confirmed by medical records. Information on indoor tanning bed use during high school/college or age 25-35 was collected. Cumulative average UV exposure at residence during follow-up was calculated for each participant. We built Cox proportional hazards models adjusting for potential confounders. Interactions between cumulative UV exposure and indoor tanning use were tested in multivariable-adjusted models for three types of skin cancer.

Results: We found significant interactions between cumulative average UV during follow-up and indoor tanning bed use during high school/college years (P for interaction=0.01) on the risk of BCC, but not during the age 25-35 (P for interaction=0.15). Subjects who were exposed to high UV and used tanning bed during high school/college (RR: 1.54, 95% CI 1.38, 1.72) or during age 25-35 (RR: 1.56, 95% CI: 1.43, 1.69) had nearly 50% increased risk of BCC compared to subjects who were exposed to low UV and did not use tanning bed. Increased risk but non-significant interactions were found for SCC (indoor tanning during high school/college years: P for interaction=0.29, during age 25-35: P for interaction=0.09). Subjects who were exposed to high UV and used tanning bed during age 25-35 had approximately double the risk of SCC (RR:

2.04, 95% CI: 1.51, 2.76), compared to the reference group. No significant interactions were found for the risk of melanoma.

Conclusions: We found significant interaction between outdoor UV and indoor tanning bed use during high school/college years on the risk of BCC but not SCC or melanoma.

Citation Format: Jongeun Rhee, Tricia Li, Wen-Qing Li, Abrar A. Qureshi, Eunyoung Cho. Interaction between outdoor ultraviolet radiation and indoor tanning bed use on skin cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4651.
Abstract 4654: Supplemental one-carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative
Authors: Brasky Theodore M. , Ray Roberta M. , Navarro Sandi L. , Schenk Jeannette M. , Newton Alison M. , Neuhouser Marian L.
Published: September 2020

We and others have reported associations between B vitamins principally involved in one-carbon metabolism and increased lung cancer risk; however results for women have been inconsistent. Here we report on the association of supplemental vitamins B6, folic acid, and B12 intake and lung cancer risk using data from the Women's Health Initiative (WHI) study of postmenopausal women. Between 1993 and 1998, 161,808 women were recruited to participate in the WHI at 40 US clinical centers. After exclusions, 159,232 women were available for analysis and followed prospectively for 18.3 years. Among them, 3,836 incident lung cancer cases were diagnosed. At baseline, supplemental B vitamins from multivitamins, vitamin mixtures, and individual supplements were assessed. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between supplemental B vitamin intake and lung cancer risk. Relative to non-users, women who took ≥50 mg/d of vitamin B6 had 18% (HR 0.82, 95% CI: 0.70-0.97) reduced lung cancer risk. Associations did not differ significantly by smoking status or lung cancer histology. Intakes of folic acid and vitamin B12 were not associated with risk. There is a need for replication of our findings from large, prospective studies with high-quality measurement of supplement intakes. As such, no recommendation can be made at present on the use of B6 supplements for lung cancer prevention in women.

Citation Format: Theodore M. Brasky, Roberta M. Ray, Sandi L. Navarro, Jeannette M. Schenk, Alison M. Newton, Marian L. Neuhouser. Supplemental one-carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4654.
Abstract 4660: Chronic obstructive pulmonary disease as an independent risk factor for cancer
Authors: Finkelstein Joseph , Huo Xingyue
Published: September 2020

Background: Low-grade systemic inflammation is considered a hallmark of chronic obstructive pulmonary disease (COPD) that potentially links COPD to increased cancer risk. However relationship between COPD and cancer remains controversial. The main purpose of this study was to assess the relationship between COPD and all-cause cancer among adult smokers in a nested case-control study.

Methods: The study used the 2018 Behavioral Risk Factor Surveillance System (BRFSS) dataset. Only individuals of 40 years and older who smoked at least 100 cigarettes in their lifetime were included into analysis. A nested case-control design has been employed with COPD as an exposure and cancer as an outcome. Cases with COPD were matched at 1:1 ratio with controls without COPD by age group, race, and sex using simple random sampling. Chi-square test was applied to determine whether the prevalence of cancer in the resulting groups was statistically significantly different. Conditional logistic regression was used to estimate the association between cancer and COPD after adjusting for covariates (education, income, BMI, marital, drinking and exercise status).

Results: Overall, 146,141 participants aged 40 or more who smoked at least 100 cigarettes in their entire lives were included into the study. 25,528 subjects with COPD were matched with non-COPD subjects by individual case-control matching at a 1:1 ratio. People who had COPD were more likely to report being diagnosed with cancer (OR=1.40, [95%CI, 1.32-1.48]) than non-COPD participants after adjusting for confounders. The result was similar in the original population (OR=1.39, [95%CI, 1.28-1.51]).

Conclusion: Our findings demonstrate that the diagnosis of COPD was significantly associated with cancer among smokers who aged more than 40 years old.

Citation Format: Joseph Finkelstein, Xingyue Huo. Chronic obstructive pulmonary disease as an independent risk factor for cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4660.
Abstract 4667: Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two large U.S. cohorts
Authors: Hurwitz Lauren M. , Michels Kara A. , Cook Michael B. , Pfeiffer Ruth M. , Trabert Britton
Published: September 2020

Purpose: Daily low-dose aspirin is recommended for certain individuals for prevention of cardiovascular disease and colorectal cancer. However, there are known risks associated with aspirin use. Identifying subgroups of individuals most likely to benefit from aspirin for cancer prevention would help to tailor risk-benefit calculations to maximize benefits and minimize risks. We investigated whether associations between daily aspirin use and risk of several cancers vary by other cancer risk factors, including age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer.

Methods: We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995-2011), a population-based cohort study, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2009), a multicenter randomized controlled trial. Daily aspirin use was self-reported at baseline and defined as use ≥5 days/week. Our main outcome measures were incident colorectal, ovarian, breast, endometrial, and aggressive prostate cancers. We used multivariable Cox proportional hazards regression to examine associations between daily aspirin use and risk of each cancer, overall and across strata of risk factors.

Results: Compared with non-use and non-daily use, daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.80-0.89). Risk reductions were generally consistent across strata of other risk factors but attenuated with increasing BMI (p-interaction=0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI: 0.80-1.08) but a reduced risk among obese women (HR: 0.73, 95% CI: 0.52-0.98, p-interaction=0.12). We observed suggestive modest risk reductions for breast (HR: 0.96, 95% CI: 0.91-1.00) and aggressive prostate (HR: 0.95, 95% CI: 0.90-1.00) cancer and a null association for endometrial cancer (HR: 0.96, 95% CI: 0.86-1.07), with no strong effect modification observed.

Conclusions: Daily aspirin use was associated with reduced colorectal cancer risk across strata of cancer risk factors. The magnitude of the benefit varied by BMI for colorectal cancer and was restricted to obese women for ovarian cancer. The potential modifying effect of BMI warrants further investigation and may need to be considered in risk-benefit calculations for aspirin use.

Citation Format: Lauren M. Hurwitz, Kara A. Michels, Michael B. Cook, Ruth M. Pfeiffer, Britton Trabert. Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two large U.S. cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4667.
Abstract 4678: The role of EGR1 and AP1 in acute myeloid leukemia cell reprogramming toward cell cycle arrest and apoptosis
Authors: Roberts Michael , Kageler Lauren , Bendinelli Kayla , Bonner Shannon , Borah Ashir , Forrester Jeffrey
Published: September 2020

EGR and AP1 transcription factors are rapidly upregulated in acute myeloid leukemia cells responding to treatment with phorbol esters. Phorbol ester induced transcriptome changes are accompanied by phenotypic changes including cell cycle arrest, myeloid differentiation, and ultimately apoptosis. Here we present results documenting the transcriptome alterations of the phorbol ester response in HL-60 cells by DNA microarray and RNA-seq analyses, and explore the specific roles of EGR and AP1 in determining the evolving transcriptional program. Overexpression of egr1 or c-fos recapitulates many of the phorbol ester-induced transcriptome alterations and affects cell proliferation, differentiation and survival. Identification of changes in EGR1 and FOS/AP1 target gene expression supports the hypothesis that EGR and AP1 are involved in a genetic reprogramming of AML cells leading to loss of the leukemic phenotype and recovery of apoptotic competency. We also provide a comprehensive bioinformatic analysis of AML patient sample data provided by The Cancer Genome Atlas and the published study from Tyner et al., Nature 562:526-531 (2018) accessible through the Beat AML data viewer (Vizome) regarding expression of egr1. Egr1 high expression correlates with improved overall survival and a particular mutational signature distinct from patients with low egr1 expression. We define a mutational and transcriptional signature for AML patients based on egr1 expression levels that correlates with clinical outcomes.

Citation Format: Michael Roberts, Lauren Kageler, Kayla Bendinelli, Shannon Bonner, Ashir Borah, Jeffrey Forrester. The role of EGR1 and AP1 in acute myeloid leukemia cell reprogramming toward cell cycle arrest and apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4678.
Abstract 4688: Interaction of LEDGF/p75 with oncogenic transcription factors in docetaxel resistant prostate cancer cells
Authors: Hernandez Greisha L. Ortiz , Sanchez-Hernández Evelyn S. , Casiano Carlos A.
Published: September 2020

Prostate Cancer (PCa) progression leads to an advanced stage called metastatic castration PCa (mCRPC), for which currently there is no cure in spite of advances in treatment with new generation anti-androgen drugs and chemotherapy with taxanes such as docetaxel (DTX). Our group demonstrated previously that the stress oncoprotein Lens Epithelium Derived Growth Factor of 75 kD (LEDGF/p75) is upregulated in clinical prostate tumors and contributes to DTX-resistance in mCRPC cells. However, little is known about the molecular mechanisms by which LEDGF/p75 promotes taxane resistance. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In non-PCa cells, the LEDGF/p75 IBD interacts with transcription complexes, such as Menin-MLL and the c-MYC binding protein JPO2, to promote cell survival. However, the relevance of these and others protein-protein interactions (PPIs) in the context of PCa chemoresistance has never been explored. This study was designed to test the hypothesis that interactions between LEDGF/p75, the c-MYC binding protein JPO2, Menin and MLL in DTX-resistant mCRPC cells contribute to chemoresistance. We demonstrated by immunoblotting a significant co-upregulation of JPO2, c-MYC, Menin, MLL, and LEDGF/p75 in the DTX-resistant PC3-DR and DU145-DR cell lines, compared to the parental, drug sensitive cells. We also observed nuclear co-localization of these proteins by immunofluorescence microscopy and confocal microscopy. Using an immunoprecipitation approach, we confirmed that endogenous JPO2, c-MYC, Menin, and MLL co-immunoprecipitate with LEDGF/p75 in the DTX-resistant PCa cell lines. We are extending these studies to other known interacting partners of LEDGF/p75 to determine if they are also upregulated in DTX-resistant PCa cells and interact with this protein in the chemoresistance context. In addition, we have initiated studies to evaluate the effects of pharmacologic and genetic inhibition of LEDGF/p75 and its interacting partners on sensitization of DR cells to DTX. We predict that targeting LEDGF/p75 PPIs will disrupt transcriptional activity contributing to DTX resistance. Our goals are to establish the contribution of these PPIs to LEDGF/p75-mediated transactivation of DTX resistance-associated genes, and target these interactions to overcome PCa chemoresistance.

Citation Format: Greisha L. Ortiz Hernandez, Evelyn S. Sanchez-Hernández, Carlos A. Casiano. Interaction of LEDGF/p75 with oncogenic transcription factors in docetaxel resistant prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4688.
Abstract 4757: TNFAIP8 facilitates metabolic reprogramming in prostate cancer cells
Authors: Niture Suryakant , Lin Minghui , Odera Joab O. , Moore John , Kumar Deepak
Published: September 2020

Tumor necrosis factor-α-induced protein 8 (TNFAIP8), a member of TIPE/TNFAIP8 family, has been associated with multiple oncogenic roles in human cancers. Here we investigated the role of TNFAIP8 in metabolic reprogramming in prostate cancer (PCa) cells. Ectopic expression of TNFAIP8 increased cell survival/proliferation by enhancing metabolic activity in PCa cells. TNFAIP8 activated the PI3K-AKT pathway and up-regulated the expression of cell proliferation markers, cell cycle-related proteins, and PCa stem cell markers. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with glycolysis inhibitor 2-deoxyglucose (2-DG) reduced TNFAIP8 mediated glucose consumption /ATP production and spheroid formation in PCa cells. Moreover, TNFAIP8 maintained mitochondrial membrane potential and increased glycolysis/oxidative phosphorylation. These changes were also consistent with an observed altered metabolomic profile in PCa cells transfected with TNFAIP8. Collectedly, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells.

Citation Format: Suryakant Niture, Minghui Lin, Joab O. Odera, John Moore, Deepak Kumar. TNFAIP8 facilitates metabolic reprogramming in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4757.
Abstract 4814: Circular RNA expression in oral squamous cell carcinoma
Authors: Yang Hongyu , Wang Yufan
Published: September 2020

Objective: Circular RNA (circRNA) is a type of non-coding RNA molecule that affects the cellular regulatory network by sequestering microRNA (miRNA) like a sponge. This study was performed to identify differentially-expressed circRNA in oral squamous cell carcinomas (OSCCs). Methods: By using high-throughput transcriptome sequencing technology, we conducted a comprehensive study of circRNAs in human OSCC. The expression levels of circRNAs were determined by qRT-PCR and analyzed the correlations with clinicopathological characteristics in 42 patients. The circRNAs-miRNAs-mRNAs network was performed by bioinformatic integrated analysis.

Results: By high-throughput sequencing, microarray circRNA expression profiles were acquired from patients with OSCCs (n = 8) and controls (n = 8), which totaled 1921 existing circRNA molecules and 10021 novel circRNA molecules. Most of the circular RNA is from exons and distributed in the No. 1 and 2 chromosomes. Eight up-regulated and down-regulated circRNA molecules were identified as differentially-expressed in OSCCs. Among this, the expression of circ_000334, circ_006740, and circ_006371 are significantly down-regulated in 42 pairs of samples.

Conclusion: This study provides new insihgts into oncogenesis and development of OSCC, suggests novel therapeutic strategy for OSCC.

Citation Format: Hongyu Yang, Yufan Wang. Circular RNA expression in oral squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4814.
Abstract 4818: miR-34-AGO-TNRC6A complex transcriptionally up-regulates BLU tumor suppressor via binding of a novel promoter-associated lncRNA in lung cancer
Authors: Ohno Shinichiro , Oikawa Keiki , Harada Yuichirou , Kuroda Masahiko
Published: September 2020

We focused on genes whose expression is induced by miR-34a, a potent tumor suppressor microRNA (miRNA) in lung cancer and many other types of cancer, and sought to elucidate the mechanisms underlying the tumor suppressor function of miR-34a. We found that the miR-34a inhibited the proliferation of lung cancer cells by inducing expression of the BLU(also known as ZMYND10) tumor suppressor. The next-generation sequencing analysis of RNA extracted from lung cancer tissues identified a novel divergent lncRNA expressed from promoter of BLUthat include two predicted miR-34 binding sites. Interestingly, miR-34a failed to induce the BLUtranscription in the mutants lacking these miR-34 binding sites in the lncRNA. In addition, the miR-34-AGO-TNRC6A complex induced transcription of BLUby binding to the lncRNA. This non-canonical miRNA pathway, which induces gene expression via cooperation between an miRNA and promoter-associated lncRNA, is a previously unknown tumor suppression mechanism of miR-34a.

Citation Format: Shinichiro Ohno, Keiki Oikawa, Yuichirou Harada, Masahiko Kuroda. miR-34-AGO-TNRC6A complex transcriptionally up-regulates BLU tumor suppressor via binding of a novel promoter-associated lncRNA in lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4818.
Abstract 4831: Stability of draw-time microRNA concentration in blood collection tubes
Authors: Seong Eunju , George Nicholas M.
Published: September 2020

Plasma microRNA, which is relatively abundant compared to other extracellular RNA species, has drawn attention for its potential implication as biomarkers of various disease conditions. However, the great donor-to-donor variability of specific microRNA levels has been a challenging factor in their further development as a diagnostic biomarker assay. Also widely recognized, the levels of specific microRNAs are sensitive to sample collection, storage and extraction methods. Upon blood draw, the plasma microRNAome undergoes changes in concentration as well as in composition, mostly due to the in vitro blood cell breakdown. In this study, using different blood collection tubes including EDTA and Streck RNA Complete BCT, we compared microRNA extraction from the full plasma vs from isolated plasma exosomes. For each sample, we measured microRNA concentrations by global fluorometric assays and by quantitative PCR for specific microRNAs. The Streck tube minimizes the in vitro changes of microRNAome, thus facilitating detection of rare microRNAs originating from a distant diseased tissue.

Citation Format: Eunju Seong, Nicholas M. George. Stability of draw-time microRNA concentration in blood collection tubes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4831.