bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2272: A prospective study of urinary prostaglandin E2 metabolite, Helicobacter pylori antibodies, and gastric cancer risk
Authors: Wang Tianyi , Cai Hui , Zheng Wei , Michel Angelika , Pawlita Michael , Milne Ginger , Xiang Yong-Bing , Gao Yu-Tang , Li Hong-Lan , Rothman Nathaniel , Lan Qing , Shu Xiao-Ou , Epplein Meira
Published: July 2017

Background. Previous studies suggest that a stable end-product of prostaglandin E2, the urinary metabolite PGE-M, is excreted in the urine and can be used as an index of systemic prostaglandin E2 (PGE2) production. In the present study we investigate the PGE-M, Helicobacter pylori (H. pylori), and gastric cancer association.

Methods. The present analysis included 359 prospectively ascertained gastric cancer cases and 700 individually matched controls from two population-based prospective cohort studies, the Shanghai Women’s Health Study and Shanghai Men’s Health Study. Urinary PGE-M was measured by a liquid chromatography/tandem mass spectrometric method. Sero-positivity to 15 H. pylori recombinantly expressed fusion proteins was detected by H. pylori multiplex serology.

Results. Adjusting for H. pylori, increasing PGE-M was associated with higher risk of gastric cancer (Quartile 4 vs. 1, OR=1.76, 95% CI: 1.17-2.66, Ptrend =0.004). This association remained after excluding those diagnosed within two years from sample collection (OR=1.73, 95% CI: 1.12-2.65, Ptrend =0.007). However it was no longer present among individuals with 10 or more years of follow-up (2-4.9 years, OR=3.15, 95% CI: 1.11-8.91; 5-9.9 years, OR=2.23, 95% CI: 1.22-4.06; ≥10 years, OR=0.73, 95% CI: 0.31-1.70). The association of PGE-M with gastric cancer risk was not modified by H. pylori status, but added predictive ability beyond H. pylori; compared to H. pylori-negative individuals with below-median PGE-M levels, H. pylori-positive individuals with above-median PGE-M levels had a 5-fold increase in the odds ratio of gastric cancer (OR=5.08, 95% CI: 2.47-10.43).

Conclusion. In China, higher PGE-M levels may indicate an increased risk of gastric cancer independent of the risk conferred by H. pylori infection status, particularly for cancers diagnosed within 10 years of sample collection.

Citation Format: Tianyi Wang, Hui Cai, Wei Zheng, Angelika Michel, Michael Pawlita, Ginger Milne, Yong-Bing Xiang, Yu-Tang Gao, Hong-Lan Li, Nathaniel Rothman, Qing Lan, Xiao-Ou Shu, Meira Epplein. A prospective study of urinary prostaglandin E2 metabolite, Helicobacter pylori antibodies, and gastric cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2272. doi:10.1158/1538-7445.AM2017-2272
Abstract 2273: Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations
Authors: Huang Joyce , Butler Lesley , Midttun Øivind , Wang Renwei , Jin Aizhen , Gao Yu-Tang , Ueland Per , Koh Woon-Puay , Yuan Jian-Min
Published: July 2017

Background: Choline, methionine, and betaine are methyl group donors associated with DNA methylation. Diets deficient in choline and methionine have been shown to promote pancreatic carcinogenesis in experimental animals. We have previously reported an inverse association between dietary intake of choline and pancreatic cancer risk in a prospective cohort of Singapore Chinese. In the present study biomarkers of dietary choline and other methyl donor nutrients were evaluated in relation to pancreatic cancer risk.

Method: Two case-control studies were nested within the Shanghai Cohort Study (129 cases and 258 matched controls) and the Singapore Chinese Health Study (58 cases and 104 matched controls). Concentrations of choline, methionine, betaine, dimethylglycine (DMG), and trimethylamine-N-oxide (TMAO) were

measured by LC-MS/MS in pre-diagnostic serum samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression method with adjustment for potential confounders.

Results: Choline, methionine, and betaine were moderately associated with each other (spearman correlation coefficient: 0.28 ~0.43). In the pooled analysis, serum choline, betaine, and methionine were inversely associated with risk of pancreatic cancer, while TMAO, an oxidative metabolite of choline produced by gut microbiota, was positively associated with risk of pancreatic cancer. Compared with the lowest quartile, ORs (95%CIs) of pancreatic cancer for the highest quartiles of choline, methionine, betaine, and TMAO were 0.37 (0.17-0.80), 0.39 (0.22-0.69), 0.49 (0.28-0.85), and 1.60 (0.94-2.74), respectively (all Ps for trend < 0.05). DMG was not associated with pancreatic cancer risk.

Conclusion: The novel inverse associations of serum choline, methionine, and betaine with risk of pancreatic cancer support the notion that methyl groups related to DNA methylation may modulate the risk of pancreatic cancer development. The positive association between TMAO and pancreatic cancer risk suggested gut microbiota may play an important role in pancreatic carcinogenesis.

Citation Format: Joyce Huang, Lesley Butler, Øivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan. Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2017-2273
Abstract 2286: Atopic allergic conditions and risk of pancreatic cancer: the Multiethnic Cohort
Authors: Huang Brian Z. , Marchand Loic Le , Haiman Christopher A. , Monroe Kristine , Wilkens Lynne , Zhang Zuo-Feng , Setiawan Veronica Wendy
Published: July 2017

Background: Previous studies, mostly case-control studies, have suggested that atopic allergic conditions (AACs) are associated with a decreased risk of pancreatic cancer. Scarce data, however, are available from prospective, US multiethnic populations. In this largest prospective study to date, we investigated the association between AACs (asthma, hay fever, or allergy) and risk of developing pancreatic cancer in the US Multiethnic Cohort Study (MEC).

Methods: AACs were assessed via a baseline questionnaire when participants joined the MEC in 1993-1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer incidence by AACs status were calculated using Cox regression, adjusting for age, sex, race/ethnicity, education, smoking status, family history of pancreatic cancer, body mass index, diabetes, and alcohol intake.

Results: During an average of 16.2-year follow-up, 1,455 incident cases of pancreatic cancer were identified among 187,226 white, African-American, Native Hawaiian, Japanese-American, and Latino men and women. AACs were not associated with pancreatic cancer incidence (HR=1.00; 95% CI: 0.88, 1.12). The null association was observed in men and women and across racial/ethnic groups, smoking status, BMI groups, diabetes status, and family history of pancreatic cancer.

Conclusions: Based on these results, AACs is unlikely to be associated with risk of pancreatic cancer.

Citation Format: Brian Z. Huang, Loic Le Marchand, Christopher A. Haiman, Kristine Monroe, Lynne Wilkens, Zuo-Feng Zhang, Veronica Wendy Setiawan. Atopic allergic conditions and risk of pancreatic cancer: the Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2286. doi:10.1158/1538-7445.AM2017-2286
Abstract 229: Establishing reference intervals of human urine proteome for monitoring physiological and pathological changes
Authors: Leng Wenchuan , Ni Xiaotian , Sun Changqing , Malovannaya Anna , Wang Yi , Qin Jun
Published: July 2017

Urine as a true non-invasive sampling source holds great potential for biomarker discovery. But the lack of method for profiling urine proteome in high throughput and systematic evaluation of variations in urine proteomes based on large number of population have been being the major obstacles for successfully finding new biomarkers from urine. Due to low throughput, only limited number of urine samples can be measured in discovery phase of biomarker studies, which make it hard to determine whether proteins differentially expressed between groups represent actual differences between control and disease states or just physiological variations among individuals. So, candidate biomarkers often fail in validation phase. Here, we report a streamlined workflow with capacity of measuring 8 urine proteomes per day per MS at the coverage of more than 1500 proteins. With this workflow, we systematically evaluated variations in 497 human urine proteomes from 167 apparently healthy donors, allowing us to evaluate day to day and inter-personal variation in human urine proteome. Then personal and pan-human reference intervals (RIs) of urine proteome were established based on this large-scale dataset. We demonstrated that RIs can be used to monitor physiological changes by detecting transient outlier proteins, such as trans-continental travel and common flu. And it was also found that if the underlying cause is physiological variation, outlier proteins will fall back to the normal range in the follow up measurement, as exemplified in the intercontinental travel case. Persistent outlier proteins may be indicative of non-physiological conditions. These results indicate that periodical measurements of a person’s urine proteome could establish a personal health archive that would be valuable for detecting future health issues. Furthermore, we proposed a complete novel strategy dependent on RIs-based algorithm for biomarker discovery and validation to screen for diseases, which were exemplified by analyzing 154 urine proteomes from patients with 7 types of cancers. The algorithm can distinguish normal people from cancer patients with specificity of 0.95 and sensitivity of 0.85. This study paves a way to use urine proteome for health monitoring and disease screening.

Citation Format: Wenchuan Leng, Xiaotian Ni, Changqing Sun, Anna Malovannaya, Yi Wang, Jun Qin. Establishing reference intervals of human urine proteome for monitoring physiological and pathological changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 229. doi:10.1158/1538-7445.AM2017-229
Abstract 2294: Atypical nevi and risk of incident skin cancer in US men: a prospective study
Authors: LI WEN-QING , Cho Eunyoung , Goldstein Alisa , Huang Yen-Tsung , Weinstock Martin , Qureshi Abrar
Published: July 2017

Background and Aims: Atypical nevi (AN) are a strong risk factor as well as a precursor of melanoma. However, most previous studies on the associations between atypical nevi (AN) and the risk of melanoma have been conducted in retrospective case-control settings and the few available prospective studies have been based on small sample sizes. Further, few studies have examined the associations between AN and risk of keratinocyte carcinomas (formerly called non-melanoma skin cancer). We prospectively examined the risk of incident melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) associated with AN.

Methods: In the Health Professionals Follow-up Study, information on AN was collected by self-report. Only those confirmed cases of AN by a supplementary questionnaire, the Atypical Nevus Screening Questionnaire (ANQ), were included in the analyses. Diagnosis of skin cancers was reported biennially and information on melanoma and SCC was pathologically confirmed. A total of 50193 men were included in our study, with 1239 confirmed cases of AN with information on diagnosis year. Cases of AN that were not confirmed or did not respond to the ANQ were excluded from the analyses. Time-dependent Cox-regression analyses were conducted for the associations between AN and risk of incident melanoma, SCC, and BCC respectively.

Results: We identified 545 melanoma cases, 1721 SCC cases, and 13498 BCC cases during the follow-up (1986-2012). A history of AN was significantly associated with increased risk of incident melanoma (hazard ratio [HR]=3.50, 95% confidence interval [CI]: 2.13-5.76) overall and at different body sites (head and neck, trunk, or limbs). The risk of melanoma was particularly augmented with the increasing number of AN that were surgically removed (HR=1.26, 95% CI: 1.16-1.37 per AN) and for cases of AN with tissue re-excision from the nevus removal sites (HR=4.59, 95% CI: 1.70-12.41). A history of AN was also significantly associated with increased risk of BCC (HR=1.84, 95% CI: 1.60-2.10) and was only associated with risk of SCC at the trunk sites (HR=3.09, 95% CI: 1.24-7.72).

Conclusions: A history of AN significantly increased the risk of subsequent melanoma in a prospective study of men. A history of AN may also be associated with increased risk of BCC overall and trunk SCC, which requires further studies to replicate.

Citation Format: WEN-QING LI, Eunyoung Cho, Alisa Goldstein, Yen-Tsung Huang, Martin Weinstock, Abrar Qureshi. Atypical nevi and risk of incident skin cancer in US men: a prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2294. doi:10.1158/1538-7445.AM2017-2294
Abstract 2301: Genital use of talc and risk of ovarian cancer: A meta-analysis
Authors: Boffetta Paolo , Berge Wera
Published: July 2017

Some epidemiological studies suggest an association between genital use of talc powders and increased risk of ovarian cancer, but the evidence is not consistent. We performed a meta-analysis of epidemiologic studies to formally evaluate this suspected association. A systematic search was conducted in Medline, Embase and Scopus, leading to the identification of 24 case-control studies and 3 cohort studies, including 302,705 women with ovarian cancer. In the meta-analysis, we used a random-effect model to calculate summary estimates of the association between genital use of talc and occurrence of ovarian cancer. We assessed potential sources of between-study heterogeneity and presence of publication bias. The summary relative risk (RR) for ever use of genital talc and ovarian cancer was 1.22 (95% confidence interval [CI] 1.13-1.30). The RR for case-control studies was 1.26 (95% CI 1.17-1.35) and for cohort studies was 1.02 (95% CI 0.85-1.20, p heterogeneity=0.007). Serous carcinoma was the only histologic type for which an association was detected (RR 1.24; 95% CI 1.15-1.34). There was no trend in RR with either duration or frequency of genital talc use. This meta-analysis resulted in a weak but statistically significant association between genital use of talc and ovarian cancer, which appears to be limited to serous carcinoma. The heterogeneity of results by study design and the lack of a trend for duration and frequency of use, however, detract from a causal interpretation of this association.

Note: This abstract was not presented at the meeting.

Citation Format: Paolo Boffetta, Wera Berge. Genital use of talc and risk of ovarian cancer: A meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2301. doi:10.1158/1538-7445.AM2017-2301
Abstract 2302: Differences in risk factor-colorectal adenoma associations according to non-steroidal anti-inflammatory drug use
Authors: Mujtaba Sobia , Bostick Roberd M.
Published: July 2017

Multiple observational studies and large, randomized controlled trials indicate that non-steroidal anti-inflammatory drugs (NSAIDs) strongly reduce risk for colorectal neoplasms. The strengths of these findings suggest that NSAIDs may so mask various risk factor-colorectal neoplasm associations, that they may be undetectable among NSAID users. Temporal changes and between-population differences in regular NSAID use prevalence may account for some of the inconsistencies in reported findings for risk factor-colorectal neoplasm associations. We investigated whether associations of known colorectal cancer risk factors with colorectal adenoma differed by non-aspirin NSAID use using pooled data from 3 colonoscopy-based case-control studies of incident, sporadic colorectal adenoma conducted in Minnesota, North Carolina, and South Carolina between 1991 and 2002. Participants (n=789 cases, 2,035 polyp-free controls) provided risk factor data prior to colonoscopy. The multivariable-adjusted odds ratios (OR) (95% confidence intervals [CI]) for those in the highest relative to the lowest quartiles of exposure, by regular non-aspirin NSAID non-use/use, respectively, were 1.57 (CI 0.96, 2.55) vs. 1.22 (CI 0.40, 3.70) for total fat, 1.37 (CI 0.86, 2.18) vs. 0.78 (CI 0.26, 2.35) for saturated fat, 0.92 (CI 0.67, 1.26) vs. 1.31 (CI 0.62, 2.76) for total calcium, 0.88 (CI 0.64, 1.22) vs. 1.38 (CI 0.65, 2.93) for total fruits and vegetables, 1.05 (CI 0.73, 1.50) vs. 0.73 (CI 0.33, 1.62) for red and processed meats, and 0.84 (CI 0.65, 1.10) vs. 0.97 (CI 0.54,1.75) for physical activity. For current smokers relative to never smokers, the ORs (CIs) among regular non-NSAID users/non-users were 2.88 (CI 2.20, 3.77) vs. 1.64 (CI 0.85, 3.17), respectively, and for those who were obese relative to those who were normal weight, they were 1.65 (CI 1.27, 2.16) vs. 1.20 (CI 0.70, 2.04). The associations of age, height, and intakes of alcohol, dietary fiber, and total folate with adenoma did not substantially differ according to NSAID use.

These findings suggest that regular non-aspirin NSAID use may mask, beyond simple confounding, associations of various risk factors with colorectal adenoma, suggesting that differential proportions of regular NSAID users between study populations may explain some inconsistencies in reported risk factor-colorectal neoplasm associations, and support routinely assessing such associations stratified by regular non-aspirin NSAID use.

Citation Format: Sobia Mujtaba, Roberd M. Bostick. Differences in risk factor-colorectal adenoma associations according to non-steroidal anti-inflammatory drug use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2302. doi:10.1158/1538-7445.AM2017-2302
Abstract 2318: Cyclopamine sensitizes endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation in trail-resistant gastric cancer cells
Authors: Na Yoo Jin , Lee Dae-Hee , Kim Jung Lim , Kim Bo Ram , Park Seong Hye , Jo Min Jee , Jeong Yoon A , Oh Sang Cheul
Published: July 2017

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been known as one of the most effective cancer treatment owing to its selective killing effect of cancer but not normal cells. However it has been reported that several gastric cancer cells showed resistance to TRAIL because of scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we elucidated cyclopamine sensitizes to TRAIL-induced apoptosis by elevating the expression level of DR5 in gastric cancer cells. Interestingly, survivin hampers existence of DR5 protein under normal condition. Cyclopamine decreases expression level of survivin. It is a reason for cyclopamine to act as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress by Reactive Oxygen species (ROS), and CHOP, which as a last protein of ER stress pathway regulates stability of survivin protein by proteasome degradation. Taken together, our results indicate that cyclopamine can be used for the purpose of combination therapy in TRAIL-resistant gastric cancer cells.

Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Sang Cheul Oh. Cyclopamine sensitizes endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation in trail-resistant gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2318. doi:10.1158/1538-7445.AM2017-2318
Abstract 2319: Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer
Authors: Li Weiwei , Ma Yiming , He Longmei , Wang Hongying
Published: July 2017

Colorectal carcinoma (CRC) patients show resistance to EGFR-TKI (epidermal growth factor receptor -tyrosine kinase inhibitor) treatment. Protease-activated receptor 2 (PAR2) has been shown to transactivate EGFR. We aim to investigate whether PAR2 sensitizes EGFR-TKI-induced apoptosis in CRC. Firstly, inhibition of PAR2 with shRNA or ENMD-1068 (a selective antagonist of PAR2) significantly sensitized EGFR-TKI (gefitinib or AG1478)-induced apoptosis, which was measured with Annexin V/ PI staining and activation of caspase-3 in different CRC cell lines. In xenograft tumor model, gefitinib treatment dramatically reduced the tumor volume in HT-29-shPAR2 compared with HT-29-vector. Mechanism study showed that PAR2 knockdown significantly reduced bcl-xL expression at both mRNA and protein level. Consistently, activation of PAR2 upregulated bcl-xL. Furthermore, inhibition of protein phosphatase (PP) with okadaic acid significantly downregulated bcl-xL. Moreover, knockdown of PP1 with siRNA blocked PAR2-induced accumulation of bcl-xL. In summary, our findings suggest that inhibition of PAR2 sensitizes EGFR-TKI-induced apoptosis via downregulation of bcl-xL in colorectal cancer. Considering the extensive expression of PAR2 and PAR2-activating proteases in colon, it strongly indicates that inhibition of PAR2 may be a potential avenue to overcome EGFR-TKI resistance in patients with CRC.

Citation Format: Weiwei Li, Yiming Ma, Longmei He, Hongying Wang. Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2319. doi:10.1158/1538-7445.AM2017-2319
Abstract 2343: The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer
Authors: Kashiwagi Shinichiro , Asano Yuka , Goto Wataru , Takada Koji , Takashima Tsutomu , Morisaki Tamami , Noda Satoru , Onoda Naoyoshi , Hirakawa Kosei , Ohira Masaichi
Published: July 2017

Background: The effectiveness of palbociclib (CDK4/6 inhibitor) for estrogen receptor positive breast cancer has been demonstrated by large-scale clinical studies, with the drug garnering attention as a key drug for breast cancer subtypes with endocrine sensitivity in the future. According to PALOMA-3 trial, palbociclib has been demonstrated to contribute to the extension of progression-free survival in patients with advanced hormone receptor-positive and HER2-negative metastatic breast cancer after endocrine therapy. On the other hand, in the case of triple-negative breast cancer (TNBC), luminal AR (LAR) related to androgen signaling is believed to have endocrine activity. Previous clinical data revealed that palbociclib shows high sensitivity in luminal breast cancer cell lines with endocrine activity, with effectiveness also expected in LAR. In this study, we created TNBC cell lines that forcibly express AR and examined the effectiveness of palbociclib for TNBC.

Materials and Methods: MCF-7 and T-47D were used as luminal breast cancer cell lines, while MDA-MB-231 and BT-549 were used as TNBC cell lines. In addition, we created TNBC cell lines that forcibly express AR, called AR-MDA-MB-231, by the transfection of pEGFP-C1-AR Plasmid Vector using Lipofectamine® 3000 Reagent. We confirmed the expression of AR by qRT-PCR as well as Western blotting and examined the impact of palbociclib on proliferation as well as apoptosis of breast cancer cell lines.

Results: AR was found to have been expressed only in luminal breast cancer cell lines but not TNBC cell lines. It was confirmed that AR was expressed in AR-MDA-MB-231 which are stable cell lines with the properties of LAR. In a CCK assay, palbociclib showed high sensitivity in AR-MDA-MB-231 as in luminal breast cancer cell lines. Furthermore, in an apoptosis assay using FACS and cell cycle assay, apoptosis was induced in AR-MDA-MB-231 and cell cycle arrest at the G1S check point was confirmed.

Conclusion: palbociclib (CDK4/6 inhibitor) showed effectiveness for TNBC cell lines that compulsively express AR, suggesting it may be one treatment option for TNBC in the future.

Citation Format: Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Tsutomu Takashima, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira. The novel potential of palbociclib (CDK4/6 inhibitor) in the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2343. doi:10.1158/1538-7445.AM2017-2343
Abstract 2374: Mixed-Lineage Kinase 3 signals through the FRA1-MMP1 axis to drive triple-negative breast cancer invasion and transendothelial migration
Authors: Rattanasinchai Chotirat , Llewellyn Brandon , Conrad Susan E. , Gallo Kathleen A.
Published: July 2017

Mixed-lineage kinase 3 (MLK3), a mitogen-activated kinase kinase kinase (MAP3K), contributes to metastasis of triple-negative breast cancer (TNBC), in part through its regulation of paxillin phosphorylation and focal adhesion turnover. However the signaling mechanisms through which MLK3 promotes invasion and metastasis are not fully understood. We found that in non-metastatic, estrogen receptor positive (ER+) breast cancer cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), as well as matrix metalloproteinases (MMPs), MMP-1 and MMP-9. MLK3-induced MMP-1 induction is abrogated by FRA-1 silencing, demonstrating that MLK3 signals through FRA-1 to control MMP-1. In complementary experiments performed in metastatic TNBC models, high levels of FRA-1 are significantly reduced upon gene silencing of MLK3 or by MLK3 disruption using the CRISPR/Cas9n approach. Furthermore, both MMP-1 and MMP-9 are decreased upon ablation of MLK3 or MLK inhibitor treatment. Reduced endothelial permeability and transendothelial migration is observed in experiments with MLK3-depleted TNBC cells compared with parental counterparts. In addition, MLK inhibitor treatment or MLK3 depletion renders TNBC cells defective in Matrigel invasion. Furthermore, circulating tumor cells (CTCs) derived from a TNBC-bearing mouse which show an intermediate epithelial-mesenchymal phenotype display increased levels of MLK3, FRA-1, and MMP-1 compared with parental cells, supporting a role for the MLK3-FRA-1-MMP-1 signaling axis in tumor cell invasion and vascular intravasation. Consistent with the role of MMP-1 in multiple steps of metastasis, high levels of MMP-1 in breast cancer patient tumor samples are associated with increased distant metastases and poorer overall survival, particularly in TNBC. Our results demonstrating the requirement for MLK3 in controlling the FRA-1/MMP-1 axis suggest that MLK3 is a potentially effective therapeutic target for TNBC.

Citation Format: Chotirat Rattanasinchai, Brandon Llewellyn, Susan E. Conrad, Kathleen A. Gallo. Mixed-Lineage Kinase 3 signals through the FRA1-MMP1 axis to drive triple-negative breast cancer invasion and transendothelial migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2374. doi:10.1158/1538-7445.AM2017-2374
Abstract 240: Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study
Authors: Perez-Mayoral Julyann , Julian Sachelly , Soto-Salgado Marievelisse , Gonzalez Michael J. , Cruz-Correa Marcia
Published: July 2017

Colorectal cancer (CRC) is the leading cause of cancer death in Puerto Rico and second cause of death in the US. It is well accepted that modifiable lifestyle habits such as diet, contribute to CRC development. Diet could reduce up to 70% of CRC cases. Dietary patterns vary according to race/ethnicity. Puerto Rican Hispanics (PRH) have been shown to have a distinct diet compared to US non-Hispanic Whites (NHW). According to the BRFSS, only 17.7% of PRH and 23.4% of NHW consume fruit and vegetables five times per day. The objective of this study was to describe the association of specific food groups consumption with the risk of colorectal neoplasia (CRN: polyps and/or CRC) in PRH. The validated Colon Cancer Family Registry food frequency questionnaire was administered to healthy individuals (controls) and individuals with CRN (cases) recruited through the Puerto Rico Colorectal Cancer Registry (PURIFICAR). Models adjusted by age, gender, educational attainment and family history of CRC were fitted to estimate the odds ratios (OR) with 95% confidence intervals (CI) through a polytomous logistic regression models comparing cases and controls. A total of 577 subjects were included in the study (controls=254; polyps=50; and CRC=273). The frequency of consumption of fruits, low fat dairy products, eggs, pasta/rice, non-fried chicken, and seafood were significantly different between controls and CRN cases (p<0.05). Adjusted models showed that a higher consumption of fruits (OR≥once per day=0.29) and full-fat dairy products (OR≥once per day=0.22) were associated with decreased risk of polyps (p<0.05). A frequency of consumption of 2-4 times per week, when compared to ≤ 1 per week, of full-fat dairy products (OR2-4 times per week=0.51), seafood (OR2-4 times per week=0.49), and red meats (OR2-4 times per week=0.56) was associated with a decreased risk of CRC (p<0.05). Our results showed that a higher consumption of fruits and full-fat dairy products significantly reduce the risk of polyps in PRH. In addition, consumption of seafood, full-fat dairy, and red meats up to 4 times per week may reduce the risk of CRC in PRH. Educational interventions for cancer prevention in PRH should incorporate nutritional information tailor to our community.

Citation Format: Julyann Perez-Mayoral, Sachelly Julian, Marievelisse Soto-Salgado, Michael J. Gonzalez, Marcia Cruz-Correa. Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2017-240
Abstract 2408: Epigenomic characterization of MSC from myeloid malignancies
Authors: Rodríguez-Paredes Manuel , Geyh Stefanie , Gazorpak Mahshid , Gutekunst Julian , Bormann Felix , Haas Rainer , Schröder Thomas , Lyko Frank
Published: July 2017

Ineffective hematopoiesis is a hallmark of myeloid malignancies such as Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML). Our previous research has shown that mesenchymal stromal cells (MSC), one of the main cellular regulatory components of the bone marrow niche and essential for the differentiation of new blood cells from Hematopoietic Stem Cells (HSC), are molecularly and functionally impaired in MDS and AML patients. More specifically, these cells display reduced proliferative and differentiation capacities, an increased cellular senescence, or the altered expression of key hematopoietic factors, defects that can provide an explanation for the cytopenia associated with these diseases. But most interestingly, we have also discovered that MDS- and AML-derived MSC present aberrant methylomes. Our data, based on 450k DNA methylation microarrays, show that these abnormalities are shared by the MSC from both malignancies and affect key transcription factors like TBX15, PITX2 or HOXB6, formerly linked to differentiation and development. This results can account for some of the defects observed in the disease-related MSC and represent an important paradigm for cancer-induced epigenetic changes in normal cells. Aiming to further explore the importance of this epigenetic deregulation, we performed RNAseq experiments using MSC from healthy donors as well as from MDS and AML patients. This approach not only suggests a profound impact of the epigenetic aberrancies on gene expression, but also allowed us to identify TGFβ as the soluble factor that, released by the malignant cells in the bone marrow, appears to trigger the above-mentioned defects in the MDS- and AML-derived MSC. Indeed, our results show that, when treated with TGFβ, healthy MSC undergo the deregulation of TBX15, PITX2 or HOXB6 and develop some of the observed aberrant phenotypes. Conversely, the treatment of MDS- and AML-derived MSC with a TGFβ antagonist like SD208 can abrogate these effects. Finally, our preliminary DNA methylation data reveal a very similar deregulation in the methylome of MSC from Multiple Myeloma (MM) patients, strongly suggesting that the same scenario could also be common to other hematological malignancies from the lymphoid branch.

Citation Format: Manuel Rodríguez-Paredes, Stefanie Geyh, Mahshid Gazorpak, Julian Gutekunst, Felix Bormann, Rainer Haas, Thomas Schröder, Frank Lyko. Epigenomic characterization of MSC from myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2408. doi:10.1158/1538-7445.AM2017-2408
Abstract 2410: Toward mutation analysis of regulatory elements: Epigenetic profiling of primary breast tumors
Authors: Ghamrasni Samah El , Guilhamon Paul , Quevedo Rene , Yang Cindy , Lupien Mathieu , Pugh Trevor
Published: July 2017

Non-coding mutations found in regulatory elements can function as driver mutations in breast cancer by changing the binding affinity of transcription factors for DNA, thereby resulting in direct change of expression of genes that promote cancer development. Identifying such additional driver mutations can reveal the molecular mechanisms favorable to breast cancer development and progression, as well as reveal new biomarkers to better tailor personalized/precision cancer medicine. In this study we have collected 20 primary luminal breast tumors and optimized experimental workflow to dissociate solid tumors and map open chromatin using ATAC-seq. In our initial experiments using ATAC-seq profiling of bulk tumor tissues, we were able to call an average of 15x103 peaks. Subsequently, flow cytometry analysis showed the presence of 15-25% of immune cells in our primary tumors. Therefore, we have optimized a workflow to eliminate immune cells and focus mainly on epithelial tumor cells. Primary breast tumors were digested using collagenase and further dissociated with dispase. Cells were sorted into two populations (mammary epithelial and immune cells) using anti-CD45, anti-CD49f and anti-EpCAM antibodies. Sorted mammary epithelial cells were then used for ATAC- and RNA-seq library preparation as well as for generation of patient derived organoids. Our new workflow resulted in an increased number of called peaks (40x103 vs 15x103), as well as a significant increase in the percentage of unique peaks compared to bulk sequencing (45% vs 15%). By refining our workflow to enrich for tumour content, we will continue our ongoing effort to profile these open chromatin regions and contextualize the mutations within in a large cohort of luminal breast cancers using targeted sequencing. These data will be compared with large-scale whole genome data generated by our group and made publicly available by others.

Citation Format: Samah El Ghamrasni, Paul Guilhamon, Rene Quevedo, Cindy Yang, Mathieu Lupien, Trevor Pugh. Toward mutation analysis of regulatory elements: Epigenetic profiling of primary breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2410. doi:10.1158/1538-7445.AM2017-2410
Abstract 2411: The role of A-to-I RNA editing in human cancer
Authors: Liang Han
Published: July 2017

Recent studies show that A-to-I RNA editing introduces a large number of specific nucleotide changes in cancer transcriptomes. Using the genomic/transcriptomic data from The Cancer Genome Atlas, we systematically characterized the landscape of RNA editing in a variety of cancer types and revealed many sites with clinically relevant patterns. We further integrated proteomic data from the Clinical Proteomic Tumor Analysis Consortium and found that mutations and RNA editing introduced similar numbers of amino acids changes per tumor sample in breast and ovarian cancers. The amino acid changes engendered by these RNA editing events may significantly alter protein stability. Some of the identified RNA editing events show critical consequent changes driving tumor growth and altering therapeutic activity. We also identified the RNA editing hotspots in miRNAs across cancer types, and some of RNA editing events modify the miRNA target genes. They could function as potential therapeutic targets and therapeutics. Our study suggests a large contribution of A-to-I RNA editing to protein diversity and gene regulation, and highlights its translational potential as both biomarkers and therapeutic targets.

Citation Format: Han Liang. The role of A-to-I RNA editing in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2411. doi:10.1158/1538-7445.AM2017-2411
Abstract 2413: SIRT1 regulates Mxd1 throughout melanoma progression
Authors: Meliso Fabiana M. , Micali Danilo , Silva Camila T. , Sabedot Thais S. , Coetzee Simon G. , Koch Adrian , Fahlbusch Fabian B. , Noushmehr Houtan , Schneider-Stock Regine , Jasiulionis Miriam G.
Published: July 2017

In a murine melanoma model of malignant transformation promoted by sustained stress, increased levels of reactive oxygen species were found to result in DNA damage and were related to massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found down-regulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to up-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, the upregulation of which is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.

Citation Format: Fabiana M. Meliso, Danilo Micali, Camila T. Silva, Thais S. Sabedot, Simon G. Coetzee, Adrian Koch, Fabian B. Fahlbusch, Houtan Noushmehr, Regine Schneider-Stock, Miriam G. Jasiulionis. SIRT1 regulates Mxd1 throughout melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2017-2413
Abstract 2467: Mutation analysis using next-generation sequencing in histologically heterogeneous of primary lung cancers
Authors: Koba Hayato , Kimura Hideharu , Kasahara Kazuo
Published: July 2017

Rare cases of primary lung cancer are known to have different histological types. Recently, small cell carcinoma was reported to be developed in adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations after EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. The purposes of this study are to evaluate mutational status in two different histological types separately, and to further understand the molecular pathogenesis. Twelve tumor samples from 6 patients were collected in our institution. 4 patients had primary adenocarcinoma and small cell carcinoma transformed after EGFR-TKI. One patient had primary adenocarcinoma and squamous cell carcinoma transformed after EGFR-TKI. The other one patient had carcinosarcoma in a surgically resected tumor. Two samples per patient were collected from histologically different areas within a resected tumor or the 2 distinct metastatic sites. DNA was extracted from formalin-fixed, paraffin-embedded tumor tissues. Next-generation sequencings in the 12 samples were performed on 160 cancer-related genes using GeneRead™ DNAseq Targeted Panels V2 Human comprehensive Cancer Panel (QIAGEN). In a carcinosarcoma case with deletional mutation in EGFR gene, a total 504 in adenocarcinoma and 595 in sarcoma variants in 160 genes were detected with high confidence. The gene of identical alterations, as truncal alterations, were EGFR, CBLB, TP53 and MEN1 and the number of that as an unique alteration corresponding to each histology is 25 for adenocarcinoma and 85 for sarcoma. We show relations between the histological types and the genomic alterations, identical alterations and unique alterations, in each patient. Furthermore, we raise essential factors for the histological transformation.

Citation Format: Hayato Koba, Hideharu Kimura, Kazuo Kasahara. Mutation analysis using next-generation sequencing in histologically heterogeneous of primary lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2467. doi:10.1158/1538-7445.AM2017-2467
Abstract 2551: Long noncoding RNA HOXA11 antisense promotes tumor progression via the Notch pathway in serous ovarian cancer
Authors: Kim Hee Jung , Yim Ga Won , Eoh Kyung Jin , Kim Lee Kyung , Lee Jung-Yun , Nam Eun Ji , Kim Sang Wun , Kim Young Tae
Published: July 2017

The biological function of long noncoding RNAs (lncRNAs) is only partially understood. We investigated the expression of the novel HOXA11 antisense (HOXA11as) lncRNA and its oncogenic role in serous ovarian cancer (SOC). HOXA11as expression was examined in 129 serous ovarian cancer tissue samples by real time RT-PCR. Clinicopathologic factors and patient survival were compared between high (N = 27) and low HOXA11as expression group (N = 102). To investigate the role of HOXA11as in cell proliferation, invasion, and migration, HOXA11as expression in ovarian cancer cells was knocked down using RNA interference. HOXA11as expression in cancer tissue was 77-fold higher than that of noncancerous tissue (P < 0.05). Higher HOXA11as expression significantly correlated with histologic grade (P = 0.017) and preoperative CA125 (P = 0.048). HOXA11as overexpression in SOC cells led to increased cell proliferation, invasion, and migration. In addition, HOXA11as was associated with the expression of genes that involve in cell proliferation, invasion, and migration. Moreover, Knockdown of HOXA11as decreased the expression of vascular endothelial growth factor, matrix metalloproteinase-9 and epithelial-mesenchymal transition (EMT), which are important for cell motility and metastasis. Mechanistic investigation revealed that Notch1, Hes1 and p300 proteins could be inhibited by HOXA11as depletion. In multivariate analysis, HOXA11as was a prognostic factor of progressive disease and mortality (HR = 1.730, 2.170 and P = 0.043, 0.033, respectively). Progression-free and overall survival were significantly shorter in patients with high HOXA11as expression. These findings highlight the clinical significance of HOXA11as in predicting the prognosis of SOC patients and suggest its potential in promoting tumor aggressiveness by regulation of the Notch signaling pathway and EMT-related mechanisms.

Note: This abstract was not presented at the meeting.

Citation Format: Hee Jung Kim, Ga Won Yim, Kyung Jin Eoh, Lee Kyung Kim, Jung-Yun Lee, Eun Ji Nam, Sang Wun Kim, Young Tae Kim. Long noncoding RNA HOXA11 antisense promotes tumor progression via the Notch pathway in serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2017-2551
Abstract 2552: MDM2 induces cell fusion in breast cancer and osteosarcoma
Authors: Olivos David J. , Chtcherbinine Mikhail , Wolf Eric R. , McAtarsney Ciarán , Mayo Lindsey D.
Published: July 2017

Cell fusion is a physiological process utilized by a variety of biological systems during fertilization, embryogenesis, and cellular differentiation and morphogenesis. During the malignant transformation of breast and bone tissues, normal and malignant cells become fused to form hybrid structures. These enhanced phenotypes acquire genetic characteristics which support initiation, progression, and oncogenesis. In breast cancer and osteosarcoma cell lines, cell fusion generates chromosomal instability, aneuploidy, and DNA damage while maintaining the characteristics of enhanced migration, invasion, and chemoresistance. We have found that mouse double minute 2 (Mdm2) significantly induces cell fusion and the generation of large multinucleated cells in MDA468, MDA231, MDA157, T47D breast cancer and MG63 osteosarcoma cell lines under normoxia when compared to silenced Mdm2 controls (P<0.0005). Interestingly, silencing mutant p53 in the MDA468 cell line resulted in significantly higher fusion events (P<0.0004) suggesting mutant p53 may play a regulatory role in reducing Mdm2-associated cell fusion. Silenced Mdm2 MDA231 cells showed a three-fold increase under hypoxia whereas MG63 cells showed similar levels of cell fusion events as in normoxic conditions suggesting cell specific dependency to environmental stimulus. The variation in proportions of cell fusion among each cell type suggests this phenomenon is dependent on Mdm2 expression and cell type. CD133+ MDA468 cells have increased fractions of polyploidal cell events suggesting stemness may influence the polyploidal giant cancer cell (PGCC) dynamics. The mechanism by which cell fusion occurs in breast and osteosarcoma is poorly understood. Collectively these data suggest the interplay of Mdm2, p53, and stemness in supporting the formation of fused polypoidal cells and may serve as relevant targets for cancer therapy.

Citation Format: David J. Olivos, Mikhail Chtcherbinine, Eric R. Wolf, Ciarán McAtarsney, Lindsey D. Mayo. MDM2 induces cell fusion in breast cancer and osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2017-2552