bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B012: Defining the role of the BAF complex in primary liver cancers
Authors: Dzama Margarita M. , Scoville Deena M. , Bucklan Emma D. , Raab Jesse R. 
Published: December 2022

Abstract
Incidence and mortality from primary liver cancer are increasing and few effective therapies exist for this deadly disease. Mutations in genes important for chromatin mediated gene regulation commonly occur in both hepatocellular carcinoma and cholangiocarcinoma, the two most common primary liver cancers. Chromatin regulators have been shown to be key modulators of both sensitivity and resistance to therapy response, and therapeutic targeting of chromatin regulators is under development for a wide range of cancers. To uncover chromatin genes that modulate therapy response, we performed epigenome-focused CRISPR screening in the presence of multiple kinases inhibitors (sorafenib, donafenib, cabozantinib). We found that disruption of a specific form of the SWI/SNF chromatin remodeling complex, called BAF, led to therapy resistance. The BAF complex is frequently mutated in both hepatocellular carcinoma and cholangiocarcinoma. Recent studies show that loss of ARID1A and ARID1B, members of the BAF complex, gives rise to liver tumors with morphologies of both hepatocellular carcinoma and cholangiocarcinoma. Critically, because multikinase inhibitors are the most common treatments for advanced hepatocellular carcinoma, our findings suggest patients with BAF mutations would not respond well to these drugs. Using gene expression analysis, genome-wide chromatin localization, and chromatin accessibility assays we are uncovering how altered chromatin state underlies multikinase inhibitor response in BAF mutant tumors. Using high-throughput epigenome focused CRISPR screens we will identify novel modulators of therapy response in liver cancer.
Citation Format: Margarita M. Dzama, Deena M. Scoville, Emma D. Bucklan, Jesse R. Raab. Defining the role of the BAF complex in primary liver cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B012.
Abstract B022: CHD1 promotes sensitivity to aurora kinase inhibitors by modulating the interaction of AURKA with TPX2
Authors: Li Haoyan , Wang Yin , Lin Kevin , Venkadakrishnan Varadha Balaji , Bakht Martin , Tremble Kaitlyn , Lu Yue , Beltran Himisha , Zhao Di 
Published: December 2022

Abstract
Clinical studies have shown that subsets of cancer patients achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain-helicase-DNA-binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the co-activator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.
Citation Format: Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Kaitlyn Tremble, Yue Lu, Himisha Beltran, Di Zhao. CHD1 promotes sensitivity to aurora kinase inhibitors by modulating the interaction of AURKA with TPX2. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B022.
Abstract IA011: Transcriptional dependencies of tuft cell lung tumors
Authors: Vakoc Christopher R. 
Published: December 2022

Abstract
Using genetic screens performed in cancer cell lines, we previously identified a tuft cell variant of small cell lung cancer. This novel tumor entity is characterized by high expression of, and addiction to, POU2F3, which encodes a POU homeodomain transcription factor. Subsequent work by several laboratories has revealed tuft cell tumors exist in several different anatomical sites (e.g., thymus, prostate, GI tract), indicating a broader relevance of this cell lineage in human cancer. In my presentation, I will present our efforts to reveal transcriptional mechanisms in tuft cell lung tumors, focusing on the identification of OCA-T1 and OCA-T2 as coactivators of POU2F3.
Citation Format: Christopher R. Vakoc. Transcriptional dependencies of tuft cell lung tumors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA011.
Abstract IA018: Reading and writing extrachromosomal DNA
Authors: Chang Howard Y. 
Published: December 2022

Abstract
Cancer patients face an extraordinary challenge when oncogenes unleash themselves from chromosomes. Extrachromosomal DNA (ecDNA) are large, megabase-sized circular episomes containing oncogenes and regulatory DNA elements. EcDNAs have a remarkable transcriptional advantage and rapidly change copy number–a moving target driving accelerated evolution in cancer. We present a method for targeted purification of megabase-sized ecDNA by combining in-vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA (CRISPR-CATCH). Targeted purification of ecDNA versus chromosomal DNA enabled phasing of genetic variants and provided definitive proof of oncogenic mutations exclusively on ecDNAs, discovery of ecDNA-specific demethylation with single molecule resolution, and accurate reconstruction of megabase- sized ecDNA structures with base-pair resolution. We model and test the impact of non-chromosomal oncogene inheritance—random identity by descent—on ecDNA on variation and selection. Integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA generation, and live-cell imaging, we identify a set of basic “rules” for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatment. These new tool kits for reading and writing ecDNAs promise to unravel the genetic and epigenetic landscapes of ecDNA biogenesis, dynamics, and function.
Citation Format: Howard Y. Chang. Reading and writing extrachromosomal DNA. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA018.
Abstract IA021: Targeting epigenetic regulators of oncogenic transcription factors
Authors: Chinnaiyan Arul M. 
Published: December 2022

Abstract
The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodeling and is altered in over 20% of cancers. We recently developed and evaluated a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supraphysiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumor growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
Citation Format: Arul M. Chinnaiyan. Targeting epigenetic regulators of oncogenic transcription factors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA021.
Abstract A006: Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study
Authors: Andersen Shaneda Warren , Walts Zoe , Brent Ronni , Parlato Lisa 
Published: December 2022

Abstract
Background: Obesity may increase colorectal cancer (CRC) risk, primarily through mechanisms of increased inflammation. BMI is the most commonly used measure of adiposity; however, it may less accurately measure adiposity in Black populations, highlighting the need for biomarkers of inflammation to evaluate risk. Herein, we investigate the associations between BMI, albumin as a biomarker of inflammation, and CRC risk. Methods: Participant data arise from 71,141 participants of the Southern Community Cohort Study, of which 724 were diagnosed with incident CRC; 69% of the cohort are Black, and 56% have household income &lt;$15,000. A subset of 277 cases and 642 controls had serum albumin concentration measured from blood samples taken at enrollment. Controls were selected through incidence density sampling of the cohort and individually matched to cases by age, sex, and race. Cox proportional hazards were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and CRC risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95%CIs for associations between albumin concentrations and CRC risk. WHO categories of BMI and albumin concentration tertiles determined through the control’s distribution were used. Results: Participants with underweight (&lt;18.5) compared to normal (18.5-24.9) BMI had increased CRC risk (HR:1.69, 95%CI:0.95-2.98). Null associations were observed between overweight and obese BMI and CRC risk compared to normal BMI participants. Associations between BMI and CRC risk did not vary by sex or race (p-interactions&gt;0.05). Albumin concentration was lower in Black participants and inversely associated with CRC risk (per-standard-deviation increase: OR:0.86, 95%CI:0.74,0.99). Associations were most apparent in participants who self-identified as Black race (OR 0.81, 95%CI:0.68,0.97), or female (OR:0.80, 95%CI:0.65,0.98). There was no evidence that albumin mediated the association between BMI and CRC risk, however BMI modified the association between albumin and CRC (BMI &lt;30: OR: 0.90 95%CI:0.73,1.11; BMI ≥30: OR:0.75, 95%CI:0.60,0.95; p-interaction=0.07). Conclusions: Our results support the role of an inflammatory mechanism to increase CRC risk. The null associations between overweight and obese BMI with CRC risk displays the limited predictive utility of BMI in Black populations. Lower albumin concentrations and increased inflammation in Black populations, particularly in the presence of increased adiposity, may represent a contributing factor to racial disparity in CRC incidence.
Citation Format: Shaneda Warren Andersen, Zoe Walts, Ronni Brent, Lisa Parlato. Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A006.
Abstract A023: Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer
Authors: Davis Jennifer S. , Chavez Janelle C. , Kok Melissa , Miguel Yazmin San , Lee Hwa Young , Henderson Henry , Overman Michael J. , Morris Van Karlyle , Kee Bryan , Fogelman David , Advani Shailesh M. , Johnson Benny , Parseghian Christine , Shen John Paul , Dasari Arvind , Shaw Kenna R. , Vilar Eduardo , Raghav Kanwal P. , Shureiqi Imad , Wolff Robert A. , Meric-Bernstam Funda , Maru Dipen , Menter David G. , Kopetz Scott , Chang Shine 
Published: December 2022

Abstract
Background: The relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in late-stage patients. Increased body mass may negate aspirin use for cancer prevention, but the influence of body mass index (BMI) on post-diagnosis aspirin use is unclear. This study aims to evaluate impacts of pre-diagnosis BMI and post-diagnosis aspirin use on overall survival in late-stage CRC patients on the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) clinical protocol. Methods: Patients with metastatic or treatment refractory disease were consented on the ATTACC protocol at MD Anderson Cancer Center and invited to complete a survey on risk factors relevant to CRC etiology. Using survey data, BMI was calculated from the decade prior to initial CRC diagnosis for 656 patients. Survival was measured from stage IV diagnosis until death or last follow-up. Cox Proportional Hazards models were constructed to estimate associations of pre-diagnosis obesity and post-diagnosis aspirin use with overall survival. Results: Controlling for age, sex, race, stage at initial diagnosis, and weight change between pre-diagnosis and survey date, patients with pre-diagnosis obesity had significantly higher likelihood of death (HR 1.45, 95% CI: 1.11, 1.91) compared to those with normal pre-diagnosis BMI. Further, only patients with normal weight pre-diagnosis experienced a survival benefit with post-diagnosis aspirin use (HR 0.59, 95% CI: 0.39, 0.90). Conclusions: Our findings suggest potentially differential tumor development resulting from the long-term physiologic host environment, here obesity. Confirmation and further evaluation are needed to determine whether pre-diagnosis BMI may predict benefit from post-diagnosis aspirin use.
Citation Format: Jennifer S. Davis, Janelle C. Chavez, Melissa Kok, Yazmin San Miguel, Hwa Young Lee, Henry Henderson, Michael J. Overman, Van Karlyle Morris, Bryan Kee, David Fogelman, Shailesh M. Advani, Benny Johnson, Christine Parseghian, John Paul Shen, Arvind Dasari, Kenna R. Shaw, Eduardo Vilar, Kanwal P. Raghav, Imad Shureiqi, Robert A. Wolff, Funda Meric-Bernstam, Dipen Maru, David G. Menter, Scott Kopetz, Shine Chang. Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A023.
Abstract A028: Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images
Authors: Lin Jia-Ren , Chen Yu-An , Campton Daniel , Cooper Jeremy , Coy Shannon , Yapp Clarence , McCarty Erin , Ligon Keith L. , Reese Steven , George Tad , Santagata Sandro , Sorger Peter 
Published: December 2022

Abstract
Histopathology using Hematoxylin and Eosin (H&E) stained tissue sections plays a central role in the diagnosis and staging of diseases. The transition to digital H&E pathology affords an opportunity for integration with recently developed, highly multiplexed tissue imaging methods. Here we describe an approach (and instrument) for collecting and analyzing H&E and high-plex immunofluorescence (IF) images from the same cells at subcellular-resolution in a whole-slide format suitable for translational and clinical research and eventual deployment in a diagnostic setting. IF and H&E images provide highly complementary information for analysis by human experts and machine learning algorithms. Using images of 40 human colorectal cancer resections, we demonstrate the automated generation and ranking of computational models, based either on immune infiltration or tumor-intrinsic features, that are highly predictive of progression-free survival. When these models are combined, a hazard ratio of ~0.045 can be achieved, suggesting the potential of integrated H&E and high-plex imaging in the generation of high performance prognostic biomarkers.
Citation Format: Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, Keith L. Ligon, Steven Reese, Tad George, Sandro Santagata, Peter Sorger. Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A028.
Abstract B019: APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer
Authors: Lengner Christopher 
Published: December 2022

Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector b-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive b-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.
Citation Format: Christopher Lengner. APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B019.
Abstract IA012: Risk factors for early-onset colorectal cancer
Authors: Hayes Richard B. 
Published: December 2022

Abstract
Colorectal cancer (CRC) incidence has been declining in the U.S. overall; however, the incidence of CRC in individuals less than 50 years of age (early-onset disease) has been increasing over the last several decades in the U.S. and elsewhere. Furthermore, cancers diagnosed in people less than 50 years of age tend to be characterized by advanced stage and greater propensity for recurrence, increasing the urgency of this emerging public health problem. Responding to the rapid rise in early-onset CRC, some CRC screening guidelines have changed to lower the screening age from 50 to 45, for average risk individuals. Our purpose was to identify genetic, environmental and lifestyle risk factors for early-onset CRC which could be used in predictive modelling to identify the younger individuals who would most benefit from screening. This research, which included more than 3,500 early-onset CRC and 3,500 comparison controls, serves to comprehensively assess genetic, environmental and lifestyle risks in early-onset CRC, as well as to develop a risk prediction tool specifically for this age group. We found that a polygenic risk score is associated with early-onset CRC, particularly for those without a family history of CRC. Several known CRC environmental and lifestyle risk factors are also linked with early-onset disease. In summary, the absolute risk for CRC in young people is low; however, genetic, environmental and lifestyle information provides initial stratification into low and high-risk groups. These findings may contribute to the identification of individuals susceptible to early-onset CRC for tailored early detection or other preventive interventions.
Citation Format: Richard B. Hayes. Risk factors for early-onset colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA012.
A Deep Dive into the Circulating ctDNA Cosmos to Vanquish Neuroblastoma
Authors: Deubzer Hedwig E. , Astrahantseff Kathy , Lodrini Marco 
Published: December 2022

Summary:Single biopsies fail to reflect intratumor heterogeneity and tumor evolution. In this issue of Cancer Discovery, Bosse and colleagues show an important role for circulating cell-free tumor DNA sequencing to detect the genomic evolution of neuroblastoma under ALK inhibitor therapy and identify novel (sub)clonal pathogenic variants involved in disease progression under conventional therapy.See related article by Bosse et al., p. 2800 (5).