bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 33: Ex vivo drug sensitivity assay with a panel of cancer patient-derived spheroids of small cell neuroendocrine carcinoma of uterine cervix
Authors: Tanaka Mie , Kubota Satoshi , Ito Yu , Kiyohara Yumiko , Endo Hiroko , Kondo Jumpei , Nakagawa Satoshi , Okazawa Akiko , Matsuzaki Shinya , Kimura Toshihiro , Kobayashi Eiji , Ueda Yutaka , Yoshino Kiyoshi , Kamiura Shoji , Kimura Tadashi , Inoue Masahiro
Published: August 2019

Small cell neuroendocrine carcinoma (SCNEC) of uterine cervix is a rare tumor accounting for approximately 1-2% of uterine cervical tumors. SCNEC of uterine cervix is highly invasive and has an extremely poorer prognosis than other histologic types for which no standard treatment is established. To establish a new management strategy against SCNEC of uterine cervix, we developed a drug sensitivity assay based on a 3D primary culture system. We previously developed the cancer tissue-originated spheroid (CTOS) method, a primary culture method from patients’ tumors. To date, we established a panel of 12 SCNEC CTOS lines with the success rate of 100%. For each line, multiple CTOSs were placed in one well of a 96 well plate and dose response analysis was performed for seven anticancer drugs; paclitaxel, carboplatin, irinotecan, SN-38, cisplatin, etoposide and gemcitabine. After 7 days of culture, the CTOSs viability was evaluated by measuring intracellular ATP levels, corrected by the size of CTOS at day0. All drugs had substantial variations in sensitivity among the lines. Cerv54 was far more sensitive to irinotecan than other lines while was similarly sensitive to SN-38. We revealed that cancer cells of cerv54 had high levels of carboxylesterase(CES)1 expression, which converts irinotecan to SN38. Since cerv54 with CES1 knockdown by pGFP-C-shCES1 lentivirus had lower sensitivity than sh-scramble, CES1 expression is related to the irinotecan sensitivity in cerv54. CES1 expression in cancer cells may be useful for predicting the effect of irinotecan based chemotherapy. In addition, this study indicates that sensitivity test using CTOS might be applicable to precision medicine by selecting sensitive drugs for each patient.

Citation Format: Mie Tanaka, Satoshi Kubota, Yu Ito, Yumiko Kiyohara, Hiroko Endo, Jumpei Kondo, Satoshi Nakagawa, Akiko Okazawa, Shinya Matsuzaki, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Shoji Kamiura, Tadashi Kimura, Masahiro Inoue. Ex vivo drug sensitivity assay with a panel of cancer patient-derived spheroids of small cell neuroendocrine carcinoma of uterine cervix [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 33.
Abstract 3303: Development and initial validation of a prognostic score based on structured data from EHRs
Authors: Backenroth Daniel , Haimson Josh D. , Meropol Neal J. , Baxi Shrujal S.
Published: August 2019

Introduction

Real world data (RWD) is increasingly used to supplement clinical trial data. Prognostic scores (PS) such as ECOG performance status (ECOG) are important for matching patient populations and assessing treatment impact, yet such PS are often missing from patient records or are embedded in physician narratives. An accurate PS that does not rely on physician assessment or data entry would have broad utility. We therefore undertook development of a PS based solely on structured data from RWD across numerous cancer diagnoses (the structured PS). We then sought initial validation of the structured PS in patients treated with checkpoint inhibitors (CIT).

Methods

Using the Flatiron Health electronic health record-derived database, we applied LASSO regression to develop the structured PS to predict for overall survival (OS) after starting any first-line (1L) cancer therapy. Data included laboratory values and vital signs from between 30 days before and 15 days after start of treatment as well as age. The structured PS was developed from ~39K patients with multiple myeloma, chronic lymphocytic leukemia or one of 8 solid tumor malignancies. We evaluated the structured PS using concordance, i.e., how often the score correctly predicts the relative OS of two randomly selected patients, on ~24K patients, comparing to a baseline based on age and ECOG, when available. We then measured the association of OS with the structured PS at start of 1L CIT in patients with five tumor types where 1L CIT is common.

Results

The concordance of the structured PS was 66%-73%, on average 6% higher than that of age and ECOG.

Table 1 shows by cancer type # of patients and median OS from 1L CIT for quartiles of the structured PS (NR=not reached).

Conclusion

A structured PS can be an important pan-tumor variable in investigations of OS using RWD, including for patients treated with first-line CIT.

OS from 1L CIT by quartiles of structured PSDiseasenQ1 median (95% CI) in monthsQ2 median (95% CI) in monthsQ3 median (95% CI) in monthsQ4 median (95% CI in months)Head and neck3704 (3-5)9 (7-12)14 (12-Inf)NR (NR-Inf)Melanoma16355 (4-6)20 (15-26)33 (22-Inf)NR (NR-Inf)Non-small cell lung cancer41714 (3-4)9 (8-10)14 (13-16)24 (21-29)Renal cell carcinoma2775 (3-7)23 (12-Inf)20 (13-Inf)NR (28-Inf)Urothelial cancer6122 (2-3)6 (4-7)9 (7-13)NR (15-Inf)

Note: This abstract was not presented at the meeting.

Citation Format: Daniel Backenroth, Josh D. Haimson, Neal J. Meropol, Shrujal S. Baxi. Development and initial validation of a prognostic score based on structured data from EHRs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3303.
Abstract 3324: Non-invasive detection of aberrant DNA methylation in colorectal cancer by multiplex methylation specific PCR
Authors: Ye Lili , Zheng Chunting , Jie Yuan , Li Bin , Li Yuan , Hu Kunling , Zeng Liuhong , Wang Yuying , Mao Mao , Ding Peirong , Shi Taiping , Ye Mingzhi
Published: August 2019

Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide, with an increasing prevalence. The 5-year relative survival rate for advanced stages is very low, with only 14% for stage IV. However, that of the early stage of CRC is about 90%. Therefore, it is important to screen CRC in the early stage. Epigenetic alterations linked to the carcinogenesis of CRC have been shown to occur earlier and more frequently than genetic alterations in CRC. Here, our study aims to develop a CRC screening methodology by applying the multiplex methylation specific PCR (MMSP) assay to detect CRC-specific methylation biomarkers, which has been pre-selected from public databases and subsequently validated in CRC samples of the Chinese population. Experimentally, cell free DNA (cfDNA) is extracted from ~4ml peripheral blood plasma. Following bisulfite conversion of the cfDNA, MMSP were applied to amplify and detect CRC-specific methylated CpG sites within the cfDNA. From the results of 28 CRCs and 52 control specimens, a sensitivity of 85.7% and the a specificity of 92.3% was achieved. Current standard and most widely used method of detecting CRC is colonoscopy screening. However, colonoscopy requires bowel preparation, and the sedation for patients is a complex and time-consuming procedure with high cost. Additionally, this invasive method also increases the possibility of infection and complications and patient compliance still largely remains a problem. Our non-invasive MMSP assay therefore provides an alternative non-invasive screening option that is cost-effective, meeting the urgent demand of early CRC detection. In addition, because colonoscopy screening currently has low adherence in Chinese population, our method holds great potential for increasing CRC screening rate in China.

Citation Format: Lili Ye, Chunting Zheng, Yuan Jie, Bin Li, Yuan Li, Kunling Hu, Liuhong Zeng, Yuying Wang, Mao Mao, Peirong Ding, Taiping Shi, Mingzhi Ye. Non-invasive detection of aberrant DNA methylation in colorectal cancer by multiplex methylation specific PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3324.
Abstract 3339: Ethnic disparity in ovarian malignancy tumor markers: MIA and ROMA
Authors: Dunton Charles , Fritsche Herbert , Bullock Rowan
Published: August 2019

Objective: Review and analyze serum values of Risk of Ovarian Malignancy Algorithm (ROMA) and Multivariate Index Assay (MIA) in subgroups of women who underwent surgery for adnexal masses to determine sensitivity in different ethnic populations.

Methods: Serum samples from 179 women diagnosed with ovarian malignancy were analyzed for ROMA and MIA results. Biomarker data was obtained from previous prospective studies that validated the MIA test. Of these, 167 women were Caucasian (C) and 12 African-American (AA) in the MIA testing. Sample for ROMA included 161 C and 11 AA. Sensitivity (true positive rate) for preoperative test results were calculated using DTCompair package of the R programming language. In premenopausal women, a risk of ovarian malignancy algorithm (ROMA) value equal to or greater than 1.14 indicates a high risk of finding epithelial ovarian cancer. In premenopausal women, MIA values of greater than 5.0 are associated with greater risk of malignancy.

In postmenopausal women, a ROMA value equal to or greater than 2.99 indicates a high risk of finding epithelial ovarian cancer.

In postmenopausal women, MIA values of greater than 4.4 are associated with greater risk of malignancy.

Results: Primary ovarian malignancy was diagnosed in 179 cases (167 C/12 AA).

Sensitivity testing results are seen for each subgroup and for MIA levels and CA125 results:

Primary Ovarian Malignancy: Caucasian MIA 97.0%, ROMA 89.4%, AA MIA 75.0% ROMA 45.5%.

Sensitivity of ROMA in AA premenopausal women was 50% and in postmenopausal women 33.3 %.

Conclusion: Our results demonstrate that ROMA in both C andAA women with adnexal masses have lower sensitivity for detection of malignancy than does MIA. It is more pronounced in AA women. Implementation of MIA in evaluation of adnexal masses will increase sensitivity of detection of malignancy compared to CA125 testing, with most marked results in AA women.

Key Words: Ethnicity, CA125, and Multivariate Index Assay

Sensitivity of MIA vs. ROMA Ovarian MalignancyRaceTestStatusMenopauseNumberSensitivityCaucasianMIAAll16797.0CaucasianMIAPre4395.3CaucasianMIAPost12497.6CaucasianROMAAll16189.4CaucasianROMAPre4092.5CaucasianROMAPost12188.4African AmericaMIAAll1275African AmericaMIAPre977.8African AmericaMIAPost366.7African AmericaROMAAll1145.5African AmericaROMAPre850.0African AmericaROMAPost333.3

Citation Format: Charles Dunton, Herbert Fritsche, Rowan Bullock. Ethnic disparity in ovarian malignancy tumor markers: MIA and ROMA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3339.
Abstract 3345: Making the link between breastfeeding and breast cancer risk reduction among Hispanic women of childbearing age
Authors: Sondgeroth Karoline , Ruiz-Holguin Rosalba , Padilla Joe , Ramos Rebeca , Palacios Rebecca
Published: August 2019

Background/Purpose. Breast Cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer related deaths for women in Texas (TX). In the border county of El Paso, TX, the breast cancer incidence and mortality rates are higher for Hispanic women relative to all races combined. Evidence indicates that breastfeeding can be protective against BC by (1) limiting breast cells’ ability to act abnormally, (2) lowering estrogen levels, and (3) promoting healthier lifestyle choices. Research also indicates that the longer a woman breastfeeds, the lower her risk of developing BC. Unfortunately, among all infants born in TX in 2015, only 48% were exclusively breastfed for up to 3 months and only 24.1% were exclusively breastfed for up to 6 months. The goal of the Breastfeeding Breast Cancer Connection Program (BFBCCP) is to increase intent to breastfeed among Hispanic women of childbearing age (18-44 years) by providing a brief education intervention focused on the importance of breastfeeding and BC prevention.

Methods. Study participants included 50 Hispanic women of childbearing age living at the El Paso Housing Authority in El Paso, TX. The study consisted of an intervention group (n=25) and a control group (n=25). The control group received only educational brochures about breastfeeding, whereas, the intervention group received an educational presentation about the importance of breastfeeding and BC prevention. Measures assessed in this study included: 1) knowledge of breastfeeding and BC 2) attitudes towards breastfeeding in the workplace, and 3) behavioral intentions to breastfeed. All measures were assessed via a pre and post self-report survey in the participants preferred language.

Results/Findings. Overall, Hispanic women participating in the BFBCCP learned more about the importance of breastfeeding, particularly as it relates to BC prevention, reported greater levels of intent to breastfeed, and reported more positive attitudes towards breastfeeding in the workplace compared to the control group. Given their high BC incidence and mortality rates, Hispanic women in the TX border region would benefit from interventions like BFCCP that promote exclusive breastfeeding for a duration of six mos. to one year as a means of reducing their BC risk. The next step is to assess the efficacy of the BFCCP in increasing breastfeeding completion and duration among pregnant Hispanic women.

Citation Format: Karoline Sondgeroth, Rosalba Ruiz-Holguin, Joe Padilla, Rebeca Ramos, Rebecca Palacios. Making the link between breastfeeding and breast cancer risk reduction among Hispanic women of childbearing age [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3345.
Abstract 3361: A prescription for new trial designs for drug development focused on the neoadjuvant setting: Save lives, resources, and time
Authors: Karlsson Andreas , Shieh Yiwey , Dempsey Andre , Yau Christina , Dmichele Angela , Yes Doug , Veer Laura van't , Hylton Nola , Eklund Martin , Esserman Laura
Published: August 2019

Background: Traditionally, new drug combinations are first tested for safety and efficacy in the stage 4 setting. The I-SPY 2 TRIAL has focused on bringing promising new combinations into the phase 2/3 high-risk setting once safety is established. I-SPY 2 is an adaptive neoadjuvant platform trial for women with stage 2/3 breast cancer at high risk for early recurrence. In this setting, complete pathologic response (pCR) is the primary endpoint. We and others have demonstrated that pCR is highly predictive of distant recurrence free survival at 3 years. In I-SPY 2 the hazard rate is 0.2 (Confidence Interval 0.11-0.37), regardless of subtypes or agent. Agents that extend progression free survival in the metastatic setting, can be lifesaving when given at an earlier stage setting.

Methods: The health economic benefits of achieving pCR were investigated using a Markov model describing the risk of recurrence, progression and death. The risk of recurrence was informed by I-SPY 2 and the risk of cancer progression and the associated treatment costs were based on literature values. We assumed constant recurrence rate without accounting for subtype specific rates in this first version of the model.

Results: For each additional patient with pathologic complete response a net monetary benefit of $170,000 (Credible Interval 95% 100,000—250,000) and a gain of 4 life-years (CrI 95% 2—6) was predicted. The ICER for pCR is -$45,000. This represents the aggregate benefit across all I-SPY cancers. Modeling accounting for cancer subtype is in process and will be presented also.

Conclusion: A short term endpoint, response to chemotherapy in the neoadjuvant setting, which is highly correlated with long term outcome, provides the opportunity to focus drug development on improving that endpoint. Enabling more patients to achieve a pCR would provide enormous benefit in terms of lives and resources saved. The economic modeling, along with the findings from I-SPY 2 suggests that we should shift drug development to the high risk early setting and evolve drug designs to improve every patient’s outcome. In I-SPY 2, we are shifting our platform trial design to increase every patient’s chance to achieve pCR. Platform adaptive trials in the early stage neoadjuvant setting are ideal for advancing the field and maximizing benefit for patients.

Citation Format: Andreas Karlsson, Yiwey Shieh, Andre Dempsey, Christina Yau, Angela Dmichele, Doug Yes, Laura van't Veer, Nola Hylton, Martin Eklund, Laura Esserman. A prescription for new trial designs for drug development focused on the neoadjuvant setting: Save lives, resources, and time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3361.
Abstract 337: Degradation of AXL overcome acquired cross-resistance to gefitinib and osimertinib in non-small cell lung cancer cells
Authors: Kim Donghwa , Bach Duc-Hiep , Fan Yan-hua , Luu Thi-Thu-Trang , Hong Ji-Young , Park Hyen-Joo , Lee Sang Kook
Published: August 2019

Epidermal growth factor receptor (EGFR) mutation is one of the major driver oncogenes in non-small cell lung cancer (NSCLC) and most frequently found in Asian patients. Although the first generation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have led to improved prognoses for NSCLC patients, acquired resistance has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. Recently, AXL has been reported to play a role in drug resistance mechanisms for many anti-cancer drugs, including erlotinib and cetuximab, as well as in ionizing radiation therapy for multiple cancers. In the present study, we demonstrate the involvement of AXL in the acquired resistance to gefitinib and osimertinib of EGFR-mutant NSCLC cells, then show the combination effect of an AXL degrader and EGFR-TKIs to overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells. We found that AXL was overexpressed and its degradation was delayed in EGFR-TKI-resistant NSCLC cells. Yuanhuadine (YD), a natural antitumor agent, effectively suppressed the expression of AXL by accelerating protein degradation. YD combined with gefitinib or osimertinib synergistically inhibited the growth of resistant cells in vitro and suppressed tumor growth in a nude mouse xenograft model. Moreover, administration of YD with gefitinib effectively delayed gefitinib-driven acquired resistance in a long-term xenograft model. Our results suggest that the combination of YD with either gefitinib or osimertinib is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC by targeting AXL degradation.

Citation Format: Donghwa Kim, Duc-Hiep Bach, Yan-hua Fan, Thi-Thu-Trang Luu, Ji-Young Hong, Hyen-Joo Park, Sang Kook Lee. Degradation of AXL overcome acquired cross-resistance to gefitinib and osimertinib in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 337.
Abstract 3370: Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers
Authors: Osmanbeyoglu Hatice Ulku , Shimizu Fumiko , Rynne-Vidal Angela , Yeung Tsz-Lun , Jelinic Petar , Mok Samuel C. , Chiosis Gabriela , Levine Douglas A. , Leslie Christina
Published: August 2019

Epigenomic data on transcription factor occupancy and chromatin accessibility can elucidate the developmental origin of cancer cells and reveal the enhancer landscape of key oncogenic transcriptional regulators. We develop a computational strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to combine cell line chromatin accessibility data with large tumor expression data sets and model the effect of enhancers on transcriptional programs in multiple cancers. We generated a new ATAC-seq data set profiling chromatin accessibility in gynecologic and basal breast cancer cell lines and applied PSIONIC to 723 patient and 96 cell line RNA-seq profiles from ovarian, uterine, and basal breast cancers. Our computational framework enables us to share information across tumors to learn patient-specific TF activities, revealing regulatory differences between and within tumor types. Many of theidentified TFs were significantly associated with survival outcome in basal breast, uterine serous and endometrioid carcinomas. To validate one PSIONIC-derived prognostic TF, we performed immunohistochemical analyses in 31 uterine serous tumors for ETV6 and confirmed that the corresponding protein expression pattern was also significantly associated with prognosis. Moreover, PSIONIC-predicted activity for MTF1 in cell line models correlated with sensitivity to MTF1 inhibition, showing the potential of our approach for personalized therapy.

Citation Format: Hatice Ulku Osmanbeyoglu, Fumiko Shimizu, Angela Rynne-Vidal, Tsz-Lun Yeung, Petar Jelinic, Samuel C. Mok, Gabriela Chiosis, Douglas A. Levine, Christina Leslie. Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3370.
Abstract 3379: Assessment of tumor mutation burden using a novel panel design strategy utilizing highly mutated genomic regions
Authors: Pati Amrita , Klass Daniel , Huang Zhongyun , Loyzer Melissa , Lovejoy Alex
Published: August 2019

Background

Tumor Mutation Burden (TMB) has grown in importance as a predictive biomarker for predicting response to check-point immunotherapy in several cancer disease areas such as non-small cell lung cancer (NSCLC) and melanoma. Although TMB derived from analysis of WES data is the current gold standard measure of the number of neoantigens in the system, WES is often cost-prohibitive as a routine practice for clinical interpretation. Targeted panels offer a more flexible and cost-effective option, but TMB estimates based on these subsets of the exome can be more variable and often disagree with each other. Current best practices for TMB panels advocate for panels with sizes of 1 Mb with high correlation between panel-derived TMB and WES TMB demonstrating effectiveness of a panel at assessing TMB accurately.

Methods

We present a systematic approach to designing panels for detecting TMB effectively while minimizing cost of sequencing, based on our Surveillance panel design algorithm. Our approach relies on the prioritization of highly recurrent non-driver mutations present in large cohorts (such as TCGA) for disease areas of interest. Such an approach greatly boosts the number of observations of short variants using a targeted panel while still meeting expectations outlined within current best practices such as a high correlation with WES-derived TMB, and high PPA and NPA with WES-derived TMB. Our NGS based workflow combines whole genome library preparation, hybrid capture target enrichment, high-throughput sequencing and a proprietary analysis algorithm that utilizes short exonic variants that are likely to be somatic.

Results

Using a combination of in silico data and clinical cohorts, we demonstrate the effectiveness of the above approach in designing panels for the assessment of TMB. Results show high correlations between panel-derived TMB and WES-derived TMB at panel sizes as low as 450Kb while highlighting the steady decrease in variability of the TMB score as panel size increases. We apply this panel and WES analysis to clinical NSCLC and CRC samples to demonstrate that recommendations from current best practices are met in terms of PPA and NPA with WES-derived TMB and high correlation with WES-derived TMB.

Citation Format: Amrita Pati, Daniel Klass, Zhongyun Huang, Melissa Loyzer, Alex Lovejoy. Assessment of tumor mutation burden using a novel panel design strategy utilizing highly mutated genomic regions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3379.
Abstract 3380: Methylome analysis of non-alcoholic fatty liver disease-associated hepatocellular carcinoma reveals etiology-specic pathway perturbations
Authors: Wu Qiong
Published: August 2019

Chronic hepatitis B infection (HBV) and non-alcoholic fatty liver disease (NAFLD) have been shown to induce aberrant DNA methylation that may contribute to the development of hepatocellular carcinoma (HCC), which is one of the most common liver cancers. Most previous studies on DNA methylation in HCC have focused on altered methylation at gene promoters and CpG islands/shores. However, it has been increasingly recognized that DNA methylation in other genomic regions, including distal enhancers and gene bodies, could also play important roles in gene regulation in cancers. In our whole-genome bisulfite sequencing (WGBS) analysis of 10 human HBV-associated tumors and 10 human NAFLD-associated tumors, methylation states at all CpG sites in the genome of HCC tumors are comprehensively studied. To see how the methylomes of these two groups of HCC samples are related to other liver-related normal and pathogenic samples, we collected published WGBS data for HCC tumor, tumor adjacent and normal liver samples. Global hypermethylation of NAFLD-HCC has been identified compared with HBV-HCC and differentially methylated regions in enhancer and gene body regions also have been detected. Different methylation patterns for HCC pathogenesis with different etiologies have been detected and may offer potentially more specific therapeutic targets. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309.

Citation Format: Qiong Wu. Methylome analysis of non-alcoholic fatty liver disease-associated hepatocellular carcinoma reveals etiology-specic pathway perturbations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3380.
Abstract 3387: Comprehensive detection and analysis of mutant-SF3B1 splice pattern
Authors: Alsafadi Samar , Bellanger Dorine , Cornella Michele , Lehnert Erik , Roman-Roman Sergio , Stern Marc-Henri , Popova Tatiana
Published: August 2019

Aberrant alternative splicing is emerging as a frequent and important process in cancer. Splice aberrations are mainly associated with missense mutations within genes encoding splice factors involved in 3′-splice site recognition. SF3B1, U2AF1, SRSF2 and ZRSR2 are the most frequently mutated genes encoding splicing factors in tumors. Interestingly, these mutations are mutually exclusive and each leads to a distinct aberrant splice pattern.

Based on RNA-seq analyses of 74 primary tumors of uveal melanoma, we previously defined the aberrant splice pattern of SF3B1 hotspot mutations. In order to further characterize the catalogue of pathogenic mutations in SF3B1 that induce the aberrant splice pattern, we used a Sequence Bloom Tree (SBT) constructed from RNA-seq data for a total of 11,350 different tumors from the TCGA (Collaborative project with Seven Bridges Cancer Genome Cloud) to rapidly screen for samples consistent with the aberrant splice pattern.

Based on this analysis, 75 tumors from different tissues of origin presented with the mutant-SF3B1 pattern, including 70 tumors harboring SF3B1 mutations: 48 cases of the hotspot mutations (21 tumors with SF3B1R625, 6 with SF3B1K666 and 21 with SF3B1K700) and 22 cases harbored non-hotspot SF3B1 mutations. No mutation or deletion in SF3B1 was detected in 5 tumors. Taking into account that the threshold of scores defining the significant presence of the aberrant splice pattern varies between tumor types, we proceeded to an in cellulo validation of a set of newly described mutations of SF3B1 and confirmed the induction of the aberrant splice pattern.

Overall, our study highlights the potential of splice patterns as a biomarker in absence of detectable splice related mutations and sheds light on an efficient, large-scale computational approach to screen clinical cases for splice patterns.

Citation Format: Samar Alsafadi, Dorine Bellanger, Michele Cornella, Erik Lehnert, Sergio Roman-Roman, Marc-Henri Stern, Tatiana Popova. Comprehensive detection and analysis of mutant-SF3B1 splice pattern [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3387.
Abstract 3388: Tumor suppressor genes may promote tumorigenesis through allele specific expression
Authors: Clayton Evan
Published: August 2019

Cancer has long thought to be a disease which develops from de novo cancer driver mutations in oncogenes and tumor suppressor genes (TSGs). The purpose of our study is to examine how TSGs contribute to tumorigenesis. Accordingly, we studied loss-of-function (LoF) mutations in TSGs within 2504 individuals from 1000 Genomes Project (1KGP) and 233 patients across four different cancer types from The Cancer Genome Atlas (TCGA). We found a large fraction of 1KGP individuals were carriers of heterozygous LoF mutations in TSGs. However, compound heterozygosity of LoF mutations in at least one TSG was only found in 20% of our TCGA patients. Further, analysis of allele specific expression (ASE) in these tumors identified several TSGs where the mutant allele is overexpressed relative to the reference allele. This evidence of ASE suggests TSGs have the potential to drive tumorigenesis in the heterozygous condition, if the reference allele is sufficiently repressed.

Citation Format: Evan Clayton. Tumor suppressor genes may promote tumorigenesis through allele specific expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3388.
Abstract 3397: The mechanism of PI3K activation at the atomic level
Authors: Zhang Mingzhen , Jang Hyunbum , Nussinov Ruth
Published: August 2019

PI3Ks are a family of lipid kinases in the PI3K/Akt/mTOR pathway that regulates cellular processes. PI3Kα harbors the frequent somatic oncogenic driver mutations conferring gain of function. It is an obligate heterodimer with the regulatory p85α subunit and catalytic p110α subunit. Here, we determine the PI3Kα activation mechanism by nSH2 release at the atomic resolution. The PIP2 substrate binding site is far from ATP and the membrane binding surface is buried in the inactive PI3Kα, raising the question of how catalysis is executed. Our results show that release of nSH2 domain from PI3Kα triggers significant conformational change in p110α, exposing kinase domain for membrane interaction. The C-lobe of kinase domain shows the structural rearrangement to reduce the distance between the ATP and the substrate binding site, offering an explanation to how phosphoryl transfer is executed. This explains how oncogenic mutations promote PI3Kα activation by facilitating nSH2 release and offers an innovative, PI3K isoform-specific drug discovery principle that prevents substrate phosphorylation by targeting isoform-specific residues in the substrate binding site.

Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of PI3K activation at the atomic level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3397.
Abstract 3414: Identifying dysregulated lncRNAs and miRNAs in low grade glioma: Uncovering signaling pathways and novel therapeutic targets
Authors: Carney Stephen , Nuñez Felipe , Lowenstein Pedro R. , Castro Maria G.
Published: August 2019

A molecular subtype of low grade gliomas (LGG) is characterized by mutations in Alpha-Thalassemia Mental Retardation X-linked (ATRX), TP53 and isocitrate dehydrogenase 1 (IDH1R132H, mIDH1). Our lab has generated a genetically engineered mouse model that harbors the characteristic genetic lesions found in this molecular subtype of LGG. We determined that mouse neurospheres (NS) bearing these mutations showed downregulation of signaling pathways involved in oligodendrocyte differentiation. The production of 2-hydroxyglutarate (2HG) by mIDH1 induces histone and DNA hypermethylation, which has been shown to impair neural precursor cells’ differentiation. We aim to investigate how the presence of mIDH1 impacts the epigenetic regulation of long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs in human mutant IDH1 glioma cell cultures obtained from patients at the time of surgery. We hypothesize that the dysregulation/remodeling of lncRNAs, miRNAs and mRNAs contributes to the invasiveness, differentiation status and stemness of glioma cells. Only a handful of lncRNAs have been studied in relation to their role in neural cells’ lineage commitment and glioma stem cells’ biology. We identified 127 differentially expressed (DE) lncRNA (FDR<0.01) in a human primary glioma cell culture SJGBM2, which has a ATRX mutation and was stably-transfected to express mIDH1. Of the 14 DE miRNAs identified, hsa-miR-210-3p and hsa-miR-4461, which have been linked to tumor invasiveness. The results from this work will reveal novel mechanistic pathways by which lncRNA/miRNAs and differentially expressed mRNAs impact downstream signaling pathways in LGG and uncover new therapeutic targets for this molecular glioma subtype.

SC is supported by the T32 Cancer Biology Training Grant, the work is supported by grants from NIH/NINDS to MGC and PRL.

Citation Format: Stephen Carney, Felipe Nuñez, Pedro R. Lowenstein, Maria G. Castro. Identifying dysregulated lncRNAs and miRNAs in low grade glioma: Uncovering signaling pathways and novel therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3414.
Abstract 3417: Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway
Authors: Lindgren David , Sjolund Jonas , Nilsson Helen , Ljungberg Borje , Johansson Martin , Axelson Hakan
Published: August 2019

Tumors arising from the nephron of the kidney are collectively called renal cell carcinomas (RCCs). Recent high-throughput genomics endeavors, such as the TCGA initiative, have provided a roadmap for a deepened molecular understanding of these tumor types. With the aim to characterize RCCs that do not conform to the most common subtypes of RCC we scrutinized RNA-Seq transcriptomes of kidney tumor samples supplied by the TCGA project. Dimensionality reduction analyses revealed one defined a transcriptional subset of RCCs, which upon re-review of tissue histology could be classified as clear cell papillary RCC (ccpRCC). In line with previous analyses, samples were defined by overexpression of KRT7, CA9, CCND1 and GATA3 and harbored few genomic alterations as well as a limited number of gene mutations; only mTOR was found recurrently mutated. We observed upregulation of the Hypoxia inducible factor (HIF) pathway, possibly caused by VHLinactivation by gene promoter methylation in the majority of ccpRCCs. This may explain the morphological resemblance of ccpRCCs to VHL driven conventional clear cell RCCs. Further, the methylomes of ccpRCCs were distinct from other tumors and transcription factors specific for epithelial cells of the distal nephron were overexpressed, thus suggesting distinct tumor ontogeny of ccpRCCs compared to other renal tumors.

Citation Format: David Lindgren, Jonas Sjolund, Helen Nilsson, Borje Ljungberg, Martin Johansson, Hakan Axelson. Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3417.
Abstract 3421: Comparison of mutations in different subtypes of sarcomas and its clinical implications
Authors: Song Xinghua , Lian Zuping , Xiao YanBin , Bu Kunpeng , Qiu Ye , Ji Tao , Liu Dan , Liu Angen , Wang Kai
Published: August 2019

Background:

Sarcoma is a malignant cancer that arises from transformed cells of mesenchymal origin. Sarcoma has the characteristics of low incidence and wide distribution of onset age. Sarcoma patients have poor prognosis and very limited selection of approved targeted drugs. Till now, the genomic features of sarcoma patients in China have not been well understood. Here we present the comprehensive genomic features of 202 sarcoma patients and compared mutations in different subtypes of sarcomas.

Methods:

Deep sequencing targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 202 sarcoma patients. Based on the histology patients included 33 osteosarcoma (OS), 24 rhabdomyosarcoma (RMS), 20 liposarcoma (LPS), 19 fibrosarcoma (FBS), 16 leiomyosarcoma (LMS), 14 Ewing’s sarcoma (ES), 11 hemangiosarcoma (HMS), 10 synovial sarcoma (SS), 9 chondrosarcoma (CDS), and 46 others in this study. Genomic alterations (GAs) including single nucleotide variants (SNVs), insertions and deletions, copy number variations (CNV) and fusions were assessed.

Results:

Based on the deep sequencing results, there are 1219 somatic mutations detected in all 202 sarcomas, average 6.0 mutations per sample. The most common GAs of LPS, ES and SS’s are consistent with those mentioned in NCCN guidelines (MDM2 55%, EWSR1 78.6% and SS18 80%, respectively). OS, RMS and LMS shared the same most common GAs of TP53 (25%-50%). The second ranked common GAs were NCOR1 (24%), FRS2 (20.8%), ATRX (25%) genes, and the third ranked GAs were RB1 (24%), CDK4 (16.7%) and MAP2K4 (25%) genes. 161/202 patients (79.7%) harbored at least one actionable mutations which might benefit from FDA approved drugs or drugs were under investigation in clinical trials. All FBS, 93.8% LMS and 90.9% HMS have actionable mutations, however, only 10% SS and 35.7% ES have actionable mutations. 8 samples have CNV (including MDM2/4, EGFR and CCND1) which was related to hyper-progression of immunotherapy. All these 8 samples were bone tumor including 4 OS, 1 CDS, 2 ES and 1 fibrosarcoma of bone.

Conclusions:

Through the comprehensive genomic profiling, different types of sarcomas showed different characteristics of genomic alterations, and potential therapeutic targets may be identified for the patients. Further, NGS provides information on whether or not patients may have the potential hyper-progression of immunotherapy.

Citation Format: Xinghua Song, Zuping Lian, YanBin Xiao, Kunpeng Bu, Ye Qiu, Tao Ji, Dan Liu, Angen Liu, Kai Wang. Comparison of mutations in different subtypes of sarcomas and its clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3421.
Abstract 3427: Exome sequencing of primary papillary thyroid cancer and their distant metastases reveals the role of DNA methylation and transcriptional repression genes
Authors: Masoodi Tariq , Siraj Abdul K. , Siraj Sarah , Azam Saud , Qadri Zeeshan , Albalawy Wafaa N. , Parvathareddy Sandeep Kumar , Al-Sobhi Saif S. , Al-Dayel Fouad , Alkuraya Fowzan S. , Al-Kuraya Khawla S.
Published: August 2019

Distant metastasis is a rare occurrence in thyroid cancer, associated with dismal prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain under-explored in metastatic Papillary Thyroid Cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole exome sequencing on 14 matched distant metastases, primary PTC tumors and normal tissues. Point mutations, copy number alterations, cancer cell fractions and mutation signatures were defined using state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Genomic differences were observed between primary and distant metastatic deposits with a median of 62% (range 21% - 92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including BRAF, NRAS and HRAS were shared and preferentially clonal in both sites. On the other hand, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including SIN3A, RBBP1 and CHD4 were found to be restricted in the metastatic lesions. Moreover, mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.

Citation Format: Tariq Masoodi, Abdul K. Siraj, Sarah Siraj, Saud Azam, Zeeshan Qadri, Wafaa N. Albalawy, Sandeep Kumar Parvathareddy, Saif S. Al-Sobhi, Fouad Al-Dayel, Fowzan S. Alkuraya, Khawla S. Al-Kuraya. Exome sequencing of primary papillary thyroid cancer and their distant metastases reveals the role of DNA methylation and transcriptional repression genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3427.
Abstract 3428: The landscape of germline mutations in Chinese patients with solid tumor
Authors: Li Juming , Wei Yongzhong , Chen Xiaoqian , Liu Angen , Shi Junping , Hu Jinwei , Yao Ming
Published: August 2019

Background: Germline mutations harbored by cancer patients can be passed from parents on to offspring, which increases the tumor risk in offspring as well. Therefore, investigating the germline mutations in cancer patients has important clinical implications for treatment selection and familial cancer risk assessment.

Methods: FFPE tumor and matched blood samples were collected from 3645 Chinese patients with solid tumors for next generation sequencing analysis. The NGS panel targeted 450 cancer genes, 47 of these genes were tumor inheritance susceptibility genes that were mentioned by NCCN guidelines. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions were assessed.

Results:Germline mutations were identified in 241 of 3645 Chinese patients with solid tumor (6.6%). The patients with germline mutations included 137 males and 104 females with a median age of 54. Tumor types with higher frequency of germline mutations were: ovarian cancer (22.0%), breast cancer (13.4%), pancreatic cancer (9.9%), cholangiocarcinoma (8.6%), small intestinal cancer (8.6%), colorectal cancer (8.6%), soft tissue sarcoma (6.3%), uterine Cancer (5.9%), gastric cancer (5.8%) and bone cancer (5.1%). The distribution of germline mutations were 14.1% in BRCA1, 13.7% in BRCA2, 10.8% in SPINK1, 9.1% in ATM, 5.8% in RAD50, 4.6% in PALB2, 3.7% in BARD1 and FANCA, 3.3% in MSH6 and 2.9% in MLH1, respectively. The types of germline mutations were SNVs and short Indels, but no long Indels, CNV, gene rearrangements or fusions were observed. The percentage of patients with a family history was 27.4%, without family history was 52.7%, unknown was 19.9%.

Conclusions:Our data revealed that germline mutations occurred in 6.6% of Chinese solid tumor patients. Gynecological tumor, gastrointestinal tumor, bone and soft tissue tumor are the most common types of tumors that harbored germline mutations. The most common mutant genes were HRD (64.5%) and MMR (10.5%) related genes. More than 50% patients with germline mutations had no family history, which suggests the importance of germline mutations detection for all solid tumor patients to verify if there is a risk of genetic transmission to offspring. NGS based panel sequencing showed the advantage of identifying solid tumor patients with germline mutations, and provided the information of familial cancer risk assessment and guided the precise cancer treatment options.

Citation Format: Juming Li, Yongzhong Wei, Xiaoqian Chen, Angen Liu, Junping Shi, Jinwei Hu, Ming Yao. The landscape of germline mutations in Chinese patients with solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3428.