Publications by authors named "Kyle Chang"

48 Publications

Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis.

Cancer Prev Res (Phila) 2021 Sep 15;14(9):851-862. Epub 2021 Jul 15.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in and mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using tools, , and models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416926PMC
September 2021

Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.
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http://dx.doi.org/10.1073/pnas.2024853118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307535PMC
July 2021

Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

Gut 2021 May 31. Epub 2021 May 31.

Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.

Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.

Results: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as and was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.

Conclusion: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.
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http://dx.doi.org/10.1136/gutjnl-2020-322835DOI Listing
May 2021

Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing.

Cancer Discov 2021 May 10. Epub 2021 May 10.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8 T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial , which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1285DOI Listing
May 2021

Circulating Plasma Tumor DNA Is Superior to Plasma Tumor RNA Detection in Ewing Sarcoma Patients: ptDNA and ptRNA in Ewing Sarcoma.

J Mol Diagn 2021 07 20;23(7):872-881. Epub 2021 Apr 20.

Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Electronic address:

The detection of tumor-specific nucleic acids from blood increasingly is being used as a method of liquid biopsy and minimal residual disease detection. However, achieving high sensitivity and high specificity remains a challenge. Here, we perform a direct comparison of two droplet digital PCR (ddPCR)-based detection methods, circulating plasma tumor RNA and circulating plasma tumor DNA (ptDNA), in blood samples from newly diagnosed Ewing sarcoma patients. First, we developed three specific ddPCR-based assays to detect EWS-FLI1 or EWS-ERG fusion transcripts, which naturally showed superior sensitivity to DNA detection on in vitro control samples. Next, we identified the patient-specific EWS-FLI1 or EWS-ERG breakpoint from five patient tumor samples and designed ddPCR-based, patient-specific ptDNA assays for each patient. These patient-specific assays show that although plasma tumor RNA can be detected in select newly diagnosed patients, positive results are low and statistically unreliable compared with ptDNA assays, which reproducibly detect robust positive results across most patients. Furthermore, the unique disease biology of Ewing sarcoma enabled us to show that most cell-free RNA is not tumor-derived, although cell-free-DNA burden is affected strongly by tumor-derived DNA burden. Here, we conclude that, even with optimized highly sensitive and specific assays, tumor DNA detection is superior to RNA detection in Ewing sarcoma patients.
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http://dx.doi.org/10.1016/j.jmoldx.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261897PMC
July 2021

Single-Cell Expression Landscape of SARS-CoV-2 Receptor and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of and SARS-CoV-2-priming proteases and in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of , , and . Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that levels were highest in normal alveolar type 2 (AT2) cells and that was expressed in 65% of normal AT2 cells. Conversely, the expression of was highest and most frequently detected (75%) in lung cells with malignant features. -positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated , and the scavengers and . Notably, the viral scavenger was significantly positively correlated with expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.
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http://dx.doi.org/10.3390/cancers13061250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998226PMC
March 2021

Marijuana Use and Sexual Risk Behavior Among Young Black Men Who Have Sex with Men in California.

J Racial Ethn Health Disparities 2020 Nov 16. Epub 2020 Nov 16.

School of Social Work, California State University, Long Beach, Long Beach, CA, USA.

Young black men who have sex with men (YBMSM) are disproportionately affected by HIV and continue to experience higher rates of new HIV infections when compared to other population groups. As part of the Peer Promotion of Wellness and Enhanced Linkage to Resources Project, we examined problem marijuana use and the overall sexual risk profile of 250 YBMSM. Eighty percent reported prior use of marijuana in their lifetime (n = 200). Among those, problem marijuana use was correlated with problem use of alcohol (r = 0.51, p < 0.001) and other drugs (r = 0.29, p < 0.001); lower household income (r = - .22, p < .01); homelessness (r = 0.15, p < 0.05); incarceration (r = 0.16, p < 0.05); exchanging sex for money, drugs, or shelter (r = 0.18, p < 0.05); having sex with someone known or suspected of having HIV and/or an STI (r = 0.20, p < 0.01); having sex with someone known or suspected of being an injector (r = 0.24, p < 0.01); and having unprotected sex while under the influence of alcohol or drugs (r = 0.32, p < 0.001). The complex relationship between marijuana and sexual risk behavior was examined while accounting for the possible moderating effects of alcohol or other drugs. Problem marijuana, alcohol, and other drug use each made unique contributions to predicting risky sex behavior. A significant marijuana and other drug interaction was found to predict sexual risk behaviors. Future efforts should include holistic intervention approaches for YBMSM that consider factors facilitating high-risk sexual behaviors.
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http://dx.doi.org/10.1007/s40615-020-00915-3DOI Listing
November 2020

Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples.

Clin Cancer Res 2021 02 13;27(4):1082-1093. Epub 2020 Nov 13.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.

Experimental Design: Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.

Results: Potentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.

Conclusions: Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887035PMC
February 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Augmented Lipocalin-2 Is Associated with Chronic Obstructive Pulmonary Disease and Counteracts Lung Adenocarcinoma Development.

Am J Respir Crit Care Med 2021 01;203(1):90-101

Department of Epidemiology.

Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene () and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood. Delineate the role of induction in LUAD pathogenesis. Normal airway brushings, uninvolved lung tissues, and tumors from mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between and / littermates. was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to mice, / littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines. Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development by maintaining antitumor immunity.
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http://dx.doi.org/10.1164/rccm.202004-1079OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781147PMC
January 2021

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Gut 2021 Mar 8;70(3):555-566. Epub 2020 Jul 8.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Objective: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.

Design: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).

Results: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.

Conclusions: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.

Trial Registration Number: gov Identifier: NCT02052908.
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http://dx.doi.org/10.1136/gutjnl-2020-320946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790993PMC
March 2021

Proactive visual and statistical analysis of genomic data in Epiviz.

Bioinformatics 2020 04;36(7):2195-2201

Institute for Advanced Computer Studies, University of Maryland, College Park, MD 20742, USA.

Motivation: Integrative analysis of genomic data that includes statistical methods in combination with visual exploration has gained widespread adoption. Many existing methods involve a combination of tools and resources: user interfaces that provide visualization of large genomic datasets, and computational environments that focus on data analyses over various subsets of a given dataset. Over the last few years, we have developed Epiviz as an integrative and interactive genomic data analysis tool that incorporates visualization tightly with state-of-the-art statistical analysis framework.

Results: In this article, we present Epiviz Feed, a proactive and automatic visual analytics system integrated with Epiviz that alleviates the burden of manually executing data analysis required to test biologically meaningful hypotheses. Results of interest that are proactively identified by server-side computations are listed as notifications in a feed. The feed turns genomic data analysis into a collaborative work between the analyst and the computational environment, which shortens the analysis time and allows the analyst to explore results efficiently.

We discuss three ways where the proposed system advances the field of genomic data analysis: (i) takes the first step of proactive data analysis by utilizing available CPU power from the server to automate the analysis process; (ii) summarizes hypothesis test results in a way that analysts can easily understand and investigate; (iii) enables filtering and grouping of analysis results for quick search. This effort provides initial work on systems that substantially expand how computational and visualization frameworks can be tightly integrated to facilitate interactive genomic data analysis.

Availability And Implementation: The source code for Epiviz Feed application is available at http://github.com/epiviz/epiviz_feed_polymer. The Epiviz Computational Server is available at http://github.com/epiviz/epiviz-feed-computation. Please refer to Epiviz documentation site for details: http://epiviz.github.io/.
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http://dx.doi.org/10.1093/bioinformatics/btz883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868663PMC
April 2020

Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate.

Clin Cancer Res 2020 01 5;26(1):11-17. Epub 2019 Aug 5.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Mismatch repair (MMR)-deficient colorectal cancers (dMMR colorectal cancer) are characterized by the expression of highly immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as upregulation of inflammatory cytokines. These features are key to understanding why immunotherapy (specifically PD-1 and/or CTLA-4 checkpoint blockade) has proved to be highly effective for the treatment of patients with advanced dMMR colorectal cancer. Importantly, preclinical studies also suggest that this correlation between potent tumor neoantigens and the immune microenvironment is present in early (premalignant) stages of dMMR colorectal tumorigenesis as well, even in the absence of a high somatic mutation burden. Here, we discuss recent efforts to characterize how neoantigens and the tumor immune microenvironment coevolve throughout the dMMR adenoma-to-carcinoma pathway. We further highlight how this preclinical evidence forms the rational basis for developing novel immunotherapy-based colorectal cancer prevention strategies for patients with Lynch syndrome.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942620PMC
January 2020

Functional characterization of variants identified in familial adenomatous polyposis adenomas.

Oncotarget 2019 Jun 11;10(39):3939-3951. Epub 2019 Jun 11.

Functional and Chemical Genomics, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Germline mutations in the tumor suppressor () define Familial Adenomatous Polyposis (FAP), the genetic predisposition to developing adenomatous polyps. Recent sequencing of FAP adenomas have challenged established dogma that mutations alone represent the adenoma mutational landscape because recurrent somatic mutations in non-WNT pathway genes were also discovered. In particular, one of these novel genes, , presented E20K and E70K mutations that are predicted to be deleterious . We utilized zebrafish embryos to determine if these mutations affect function and perform novel biology in an APC-dependent pathway . Human () and mRNA injection rescued zebrafish knockdown lordosis phenotype while did not. In the FAP zebrafish model, we show that , but not retinoic acid, regulates expression. Injection of and , but not , to homozygous zebrafish initiated gut differentiation while knockdown in wildtype embryos led to decreased intestinal development and differentiation. Finally, targeted sequencing of 37 additional FAP adenomas revealed mutations in 20% of these samples. Overall, our work supports a mechanism where regulates and that overall perturbation could work in concert with germline mutations in advancing adenomas to a more transformed state prior to progression to adenocarcinoma.
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http://dx.doi.org/10.18632/oncotarget.27003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570471PMC
June 2019

Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.

Dis Colon Rectum 2019 04;62(4):429-437

Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.

Objective: The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.

Design: This was a retrospective study.

Settings: The study was conducted at a tertiary-referral institution.

Patients: Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.

Interventions: Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.

Main Outcome Measures: We measured detection of pathogenic germline variants.

Results: A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).

Limitations: This study was limited by its small sample size and advanced-stage patients.

Conclusions: Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.
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http://dx.doi.org/10.1097/DCR.0000000000001322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415928PMC
April 2019

Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition.

Cancer Res 2019 03 14;79(5):918-927. Epub 2019 Jan 14.

Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas.

There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphane+JQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. SIGNIFICANCE: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397680PMC
March 2019

Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome.

JAMA Oncol 2018 08;4(8):1085-1092

Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston.

Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS.

Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS.

Design, Setting, And Participants: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017.

Main Outcomes And Measures: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA.

Results: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling).

Conclusions And Relevance: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.
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http://dx.doi.org/10.1001/jamaoncol.2018.1482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087485PMC
August 2018

Immune Cell Production of Interleukin 17 Induces Stem Cell Features of Pancreatic Intraepithelial Neoplasia Cells.

Gastroenterology 2018 07 29;155(1):210-223.e3. Epub 2018 Mar 29.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background & Aims: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to pancreatic interepithelial neoplasia (PanIN) initiation and progression. We investigated the effects that IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena.

Methods: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KC;G) and Kras(G12D);Trp53(R172H);Pdx1-Cre (KPC) mice (which upon tamoxifen induction spontaneously develop PanINs) and control littermates. Some mice were injected with neutralizing antibodies against IL17A or control antibody. Pancreata were collected, PanIN epithelial cells were isolated by flow cytometry based on lineage tracing, and gene expression profiles were compared. We collected cells from pancreatic tumors of KPC mice, incubated them with IL17 or control media, measured expression of genes regulated by IL17 signaling, injected the cancer cells into immune competent mice, and measured tumor growth. IL17A was overexpressed in pancreata of KC mice from an adenoviral vector. Pancreata were collected from all mice and analyzed by histology and immunohistochemistry. Levels of DCLK1 and other proteins were knocked down in KPC pancreatic cancer cells using small interfering or short hairpin RNAs; cells were analyzed by immunoblotting. We obtained 65 pancreatic tumor specimens from patients, analyzed protein levels by immunohistochemistry, and compared results with patient survival times. We also analyzed gene expression levels and patient outcome using The Cancer Genome Atlas database.

Results: PanIN cells from KC;G mice had a gene expression pattern associated with embryonic stem cells. Mice given injections of IL17-neutralizing antibodies, or with immune cells that did not secrete IL17, lost this expression pattern and had significantly decreased expression of DCLK1 and POU2F3, which regulate tuft cell development. KC mice that overexpressed IL17 formed more PanINs, with more DCLK1-positive cells, than control mice. Pancreatic tumor cells from KPC mice and human Capan-2 cells exposed to IL17A had increased activation of NF-κB and mitogen-activated protein kinase signaling and increased expression of DCLK1 and ALDH1A1 (a marker of embryonic stem cells) compared with cells in control media. These cells also formed tumors faster that cells not exposed to IL17 when they were injected into immunocompetent mice. KPC cells with knockdown of DCLK1 expressed lower levels of ALDH1A1 after incubation with IL17 than cells without knockdown. Expression of the IL17 receptor C was higher in DCLK1-positive PanIN cells from mice compared with DCLK1-negative PanIN cells. In human pancreatic tumor tissues, high levels of DCLK1 associated with a shorter median survival time of patients (17.7 months, compared with 26.6 months of patients whose tumors had low levels of DCLK1). Tumor levels of POU2F3 and LAMC2 were also associated with patient survival time.

Conclusions: In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.
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http://dx.doi.org/10.1053/j.gastro.2018.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035075PMC
July 2018

Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

Cancer Prev Res (Phila) 2017 Oct 1;10(10):580-587. Epub 2017 Aug 1.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626617PMC
October 2017

Mutational Heterogeneity in and Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis.

Clin Cancer Res 2017 Oct 23;23(19):5936-5947. Epub 2017 Jun 23.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal and driver mutations, thus challenging the prevailing monoclonal monocryptal model. High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of and was performed using nanofluidic PCRs in matched bulk biopsies ( = 59) and crypts ( = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues. Multiple co-occurring truncal and driver alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected mutations that were prominent among carcinomas, whereas abundant wild-type crypts were detected in adenomas. mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed. The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626604PMC
October 2017

Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing.

Nat Med 2017 Jul 19;23(7):878-884. Epub 2017 Jun 19.

Department of Surgery, Weill Cornell Medical College, New York, New York, USA.

With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.
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http://dx.doi.org/10.1038/nm.4355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055224PMC
July 2017

Oncogenic drives invasion and maintains metastases in colorectal cancer.

Genes Dev 2017 02 13;31(4):370-382. Epub 2017 Mar 13.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the gene. To understand the role of oncogenic in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic allele ( ) and conditional null alleles of and (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of -driven invasiveness. Genetic extinction of resulted in specific elimination of the subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease This faithful CRC model provides genetic evidence that drives CRC invasion and maintenance of metastases.
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http://dx.doi.org/10.1101/gad.293449.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358757PMC
February 2017

Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam.

Int J Cancer 2017 Jan 18;140(2):460-468. Epub 2016 Oct 18.

Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX.

Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.
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http://dx.doi.org/10.1002/ijc.30458DOI Listing
January 2017

Genomic Landscape of Colorectal Mucosa and Adenomas.

Cancer Prev Res (Phila) 2016 06 24;9(6):417-27. Epub 2016 May 24.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 417-27. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941624PMC
June 2016

Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

Mol Cancer Ther 2014 Dec 27;13(12):3230-40. Epub 2014 Oct 27.

The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341901PMC
December 2014

Novel somatic and germline mutations in intracranial germ cell tumours.

Nature 2014 Jul 4;511(7508):241-5. Epub 2014 Jun 4.

1] Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas 77030, USA [2] Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.
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http://dx.doi.org/10.1038/nature13296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532372PMC
July 2014

Natural variation in genome architecture among 205 Drosophila melanogaster Genetic Reference Panel lines.

Genome Res 2014 Jul 8;24(7):1193-208. Epub 2014 Apr 8.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030 USA;

The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource of 205 sequenced inbred lines, derived to improve our understanding of the effects of naturally occurring genetic variation on molecular and organismal phenotypes. We used an integrated genotyping strategy to identify 4,853,802 single nucleotide polymorphisms (SNPs) and 1,296,080 non-SNP variants. Our molecular population genomic analyses show higher deletion than insertion mutation rates and stronger purifying selection on deletions. Weaker selection on insertions than deletions is consistent with our observed distribution of genome size determined by flow cytometry, which is skewed toward larger genomes. Insertion/deletion and single nucleotide polymorphisms are positively correlated with each other and with local recombination, suggesting that their nonrandom distributions are due to hitchhiking and background selection. Our cytogenetic analysis identified 16 polymorphic inversions in the DGRP. Common inverted and standard karyotypes are genetically divergent and account for most of the variation in relatedness among the DGRP lines. Intriguingly, variation in genome size and many quantitative traits are significantly associated with inversions. Approximately 50% of the DGRP lines are infected with Wolbachia, and four lines have germline insertions of Wolbachia sequences, but effects of Wolbachia infection on quantitative traits are rarely significant. The DGRP complements ongoing efforts to functionally annotate the Drosophila genome. Indeed, 15% of all D. melanogaster genes segregate for potentially damaged proteins in the DGRP, and genome-wide analyses of quantitative traits identify novel candidate genes. The DGRP lines, sequence data, genotypes, quality scores, phenotypes, and analysis and visualization tools are publicly available.
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http://dx.doi.org/10.1101/gr.171546.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079974PMC
July 2014

Locus of control and peer relationships among Caucasian, Hispanic, Asian, and African American adolescents.

J Youth Adolesc 2015 Jan 19;44(1):184-94. Epub 2013 Dec 19.

University of California, Irvine, Irvine, CA, USA,

Past research has shown that locus of control plays an important role in a wide range of behaviors, such as academic achievement and positive social behaviors. However, little is known about whether locus of control plays the same role in minority adolescents' peer relationships. The current study examined ethnic differences in the associations between locus of control and peer relationships in early adolescence using samples from the Early Childhood Longitudinal Study (ECLS-K: 5,612 Caucasian, 1,562 Hispanic, 507 Asian, and 908 African-American adolescents) and the National Education Longitudinal Study (NELS: 8,484 Caucasian, 1,604 Hispanic, and 860 Asian, and 1,228 African American adolescents). Gender was approximately evenly split in both samples. The results from the two datasets were highly consistent. Significant interactions between ethnicity and locus of control indicated that having a more internal locus of control was particularly important for Caucasian students' peer relationships (ECLS-K) and social status (NELS), but less so for Asian, Hispanic, and African American students. Our findings suggest that the role of locus of control in peer relationship is contingent upon culture.
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http://dx.doi.org/10.1007/s10964-013-0083-6DOI Listing
January 2015
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