Publications by authors named "David A Wheeler"

148 Publications

A High-Throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma.

J Clin Endocrinol Metab 2021 Jun 12. Epub 2021 Jun 12.

Department of Head and Neck surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.

Methods & Methods: Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft models (PDX) were used to validate the selected agents.

Results: Seventeen compounds were effective and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the FDA for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and two PDX models; docetaxel demonstrated significant TGI only in the context of mutant TP53.

Conclusions: HTS identified classes of systemic agents which demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
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http://dx.doi.org/10.1210/clinem/dgab424DOI Listing
June 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 Feb 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

Cancer Cell 2021 Jan 19;39(1):38-53.e7. Epub 2020 Nov 19.

Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2020.10.015DOI Listing
January 2021

ID/HIV Physician Ambassadors: Advancing Policy to Improve Health.

J Pediatric Infect Dis Soc 2021 Apr;10(4):432-439

Infectious Diseases Physicians, Inc., Annandale, Virginia, USA.

ID/HIV physicians and other healthcare professionals advocate within the healthcare system to ensure adults and children receive effective treatment. These advocacy skills can be used to inform domestic and global infectious disease policies to improve healthcare systems and public health. ID/HIV physicians have a unique frontline perspective to share with federal policymakers regarding how programs and policies benefit patients and public health. Providing this input is critical to the enactment of legislation that will maximize the response to infectious diseases. This article discusses the advocacy of ID/HIV physicians and other healthcare professionals in federal health policy. Key issues include funding for ID/HIV programs; the protection of public health and access to health care; improving research opportunities; and advancing the field of ID/HIV, including supporting the next generation of ID/HIV clinicians. The article also describes best practices for advocacy and provides case studies illustrating the impact of ID/HIV physician advocacy.
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http://dx.doi.org/10.1093/jpids/piaa128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087129PMC
April 2021

ID/HIV Physician Ambassadors: Advancing Policy to Improve Health.

Clin Infect Dis 2020 Oct 9. Epub 2020 Oct 9.

Infectious Diseases Physicians, Inc., Virginia Commonwealth University, Co-section Chief, Division of Infectious Diseases, Inova Fairfax Medical Campus, Annandale, VA.

ID/HIV physicians and other healthcare professionals advocate within the healthcare system to ensure adults and children receive effective treatment. These advocacy skills can be used to inform domestic and global infectious diseases policies to improve healthcare systems and public health. ID/HIV physicians have a unique frontline perspective to share with federal policymakers regarding how programs and policies benefit patients and public health. Providing this input is critical to the enactment of legislation that will maximize the response to infectious diseases. This article discusses the advocacy of ID/HIV physicians and other healthcare professionals in federal health policy. Key issues include funding for ID/HIV programs; the protection of public health and access to health care; improving research opportunities; and advancing the field of ID/HIV, including supporting the next generation of ID/HIV clinicians. The article also describes best practices for advocacy and provides case studies illustrating the impact of ID/HIV physician advocacy.
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http://dx.doi.org/10.1093/cid/ciaa1531DOI Listing
October 2020

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples.

Nat Commun 2020 09 21;11(1):4748. Epub 2020 Sep 21.

The McDonnell Genome Institute at Washington University, St. Louis, MO, 63108, USA.

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
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http://dx.doi.org/10.1038/s41467-020-18151-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505971PMC
September 2020

Identification of novel fusion transcripts in meningioma.

J Neurooncol 2020 Sep 19;149(2):219-230. Epub 2020 Sep 19.

Department of Neurosurgery, Baylor College of Medicine, 7200 Cambridge 9th Floor, Houston, TX, 77030, USA.

Introduction: Meningiomas are the most common primary intracranial tumor. Recent next generation sequencing analyses have elaborated the molecular drivers of this disease. We aimed to identify and characterize novel fusion genes in meningiomas.

Methods: We performed a secondary analysis of our RNA sequencing data of 145 primary meningioma from 140 patients to detect fusion genes. Semi-quantitative rt-PCR was performed to confirm transcription of the fusion genes in the original tumors. Whole exome sequencing was performed to identify copy number variations within each tumor sample. Comparative RNA seq analysis was performed to assess the clonality of the fusion constructs within the tumor.

Results: We detected six fusion events (NOTCH3-SETBP1, NF2-SPATA13, SLC6A3-AGBL3, PHF19-FOXP2 in two patients, and ITPK1-FBP2) in five out of 145 tumor samples. All but one event (NF2-SPATA13) led to extremely short reading frames, making these events de facto null alleles. Three of the five patients had a history of childhood radiation. Four out of six fusion events were detected in expression type C tumors, which represent the most aggressive meningioma. We validated the presence of the RNA transcripts in the tumor tissue by semi-quantitative RT PCR. All but the two PHF19-FOXP2 fusions demonstrated high degrees of clonality.

Conclusions: Fusion genes occur infrequently in meningiomas and are more likely to be found in tumors with greater degree of genomic instability (expression type C) or in patients with history of cranial irradiation.
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http://dx.doi.org/10.1007/s11060-020-03599-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553203PMC
September 2020

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.

Nat Commun 2020 07 20;11(1):3644. Epub 2020 Jul 20.

Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA.

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.
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http://dx.doi.org/10.1038/s41467-020-17386-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371703PMC
July 2020

Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression.

Cancer Res 2020 09 8;80(18):3810-3819. Epub 2020 Jul 8.

Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan.

Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including and , early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with mutation associated with downregulation of and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with or gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status. SIGNIFICANCE: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0225DOI Listing
September 2020

The Proximal Airway Is a Reservoir for Adaptive Immunologic Memory in Idiopathic Subglottic Stenosis.

Laryngoscope 2021 03 30;131(3):610-617. Epub 2020 Jun 30.

Department of Medicine, Division of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

Objectives/hypothesis: Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS).

Study Design: Basic Science.

Methods: Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing.

Results: iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69 CD103 CD8 tissue resident memory T cells (T ) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P = .0065). Additionally, subglottic CD8 clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens.

Conclusions: The human subglottis is significantly enriched for CD8 tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610-617, 2021.
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http://dx.doi.org/10.1002/lary.28840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951501PMC
March 2021

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

J Natl Cancer Inst 2021 01;113(1):27-37

Nationwide Children's Hospital, Columbus, OH, USA; Van Andel Research Institute, Grand Rapids, MI, USA.

Background: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.

Methods: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease.

Results: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations.

Conclusion: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
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http://dx.doi.org/10.1093/jnci/djaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781457PMC
January 2021

Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma.

Cancer Res 2020 06 14;80(12):2663-2675. Epub 2020 Apr 14.

Cancer Center and Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Texas.

Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines ( = 104) and patient-derived xenografts ( = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313726PMC
June 2020

The repertoire of mutational signatures in human cancer.

Nature 2020 02 5;578(7793):94-101. Epub 2020 Feb 5.

Wellcome Sanger Institute, Hinxton, UK.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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http://dx.doi.org/10.1038/s41586-020-1943-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054213PMC
February 2020

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

Nature 2020 02 5;578(7793):102-111. Epub 2020 Feb 5.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.

The discovery of drivers of cancer has traditionally focused on protein-coding genes. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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http://dx.doi.org/10.1038/s41586-020-1965-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054214PMC
February 2020

Pathway and network analysis of more than 2500 whole cancer genomes.

Nat Commun 2020 02 5;11(1):729. Epub 2020 Feb 5.

Department of Computer Science, Princeton University, Princeton, NJ, 08540, USA.

The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
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http://dx.doi.org/10.1038/s41467-020-14367-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002574PMC
February 2020

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Cell Rep 2019 11;29(6):1675-1689.e9

Preclinical Neurooncology Research Program, Texas Children's Cancer Research Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.09.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880934PMC
November 2019

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Proc Natl Acad Sci U S A 2019 10 7;116(43):21715-21726. Epub 2019 Oct 7.

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030;

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.
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http://dx.doi.org/10.1073/pnas.1912858116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815170PMC
October 2019

An enhanced genetic model of colorectal cancer progression history.

Genome Biol 2019 08 15;20(1):168. Epub 2019 Aug 15.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Background: The classical genetic model of colorectal cancer presents APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of genomic alterations, such as genomic rearrangements, are still unclear.

Results: Here, we perform comprehensive bioinformatic analysis to dissect the relative timing of somatic genetic alterations in 63 colorectal cancers with whole-genome sequencing data. Utilizing allele fractions of somatic single nucleotide variants as molecular clocks while accounting for the presence of copy number changes and structural alterations, we identify key events in the evolution of colorectal tumors. We find that driver point mutations, gene fusions, and arm-level copy losses typically arise early in tumorigenesis; different mechanisms act on distinct genomic regions to drive DNA copy changes; and chromothripsis-clustered rearrangements previously thought to occur as a single catastrophic event-is frequent and may occur multiple times independently in the same tumor through different mechanisms. Furthermore, our computational approach reveals that, in contrast to recent studies, selection is often present on subclones and that multiple evolutionary models can operate in a single tumor at different stages.

Conclusion: Combining these results, we present a refined tumor progression model which significantly expands our understanding of the tumorigenic process of human colorectal cancer.
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http://dx.doi.org/10.1186/s13059-019-1782-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694562PMC
August 2019

Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas.

Cell Rep 2019 07;28(5):1370-1384.e5

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

The TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes. Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins. A mutant TP53 RNA expression signature shows significant correlation with reduced survival in 11 cancer types. Thus, TP53 mutation has profound effects on tumor cell genomic structure, expression, and clinical outlook.
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http://dx.doi.org/10.1016/j.celrep.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546539PMC
July 2019

Framework for microRNA variant annotation and prioritization using human population and disease datasets.

Hum Mutat 2019 01 8;40(1):73-89. Epub 2018 Nov 8.

Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.

MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE, which combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes). The pattern of miRNA variation closely resembles protein-coding exonic regions, with no difference between intragenic and intergenic miRNAs (P = 0.56), and high confidence miRNAs demonstrate higher sequence constraint (P < 0.001). Conservation analysis across 100 vertebrates identified 765 highly conserved miRNAs that also have limited genetic variation in gnomAD. We applied ADmiRE to the TCGA PanCancerAtlas WES dataset containing over 10,000 individuals across 33 adult cancers and annotated 1,267 germline (rare in gnomAD) and 1,492 somatic miRNA variants. Several miRNA families with deregulated gene expression in cancer have low levels of both somatic and germline variants, e.g., let-7 and miR-10. In addition to known somatic miR-142 mutations in hematologic cancers, we describe novel somatic miR-21 mutations in esophageal cancers impacting downstream miRNA targets. Through the development of ADmiRE, we present a framework for annotation and prioritization of miRNA variation in disease datasets.
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http://dx.doi.org/10.1002/humu.23668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400659PMC
January 2019

Gene expression profiling and immune cell-type deconvolution highlight robust disease progression and survival markers in multiple cohorts of CTCL patients.

Oncoimmunology 2018;7(8):e1467856. Epub 2018 May 31.

Division of Dermatology, McGill University Health Centre, Montreal, QC, Canada.

CTCL follows different courses depending on the clinical stage at the time of diagnosis. Patients with early stage Mycosis Fungoides (MF) variant of CTCL may experience an indolent course over decades, whereas patients with advanced MF and Sézary Syndrome (SS) disease at diagnosis, often succumb within 5 years. Even within early stage CTCL/MF, a minority of patients will progress to more advanced stages. We recently generated RNA sequencing data on 284 CTCL-relevant genes for 157 patients and identified differentially expressed genes across stages I-IV. In this study, we aim to validate robust molecular markers linked to disease progression and survival. We performed multiple hypothesis testing-corrected analysis of variance (ANOVA) on the expression of individual genes across all CTCL samples and early stage (≤IIA) CTCL/MF patients. We used immune cell-type deconvolution from gene expression data to estimate immune cell populations. Based on the analysis of all CTCL samples, we identified , and as predictors of disease progression and poor survival. Among early stage (≤IIA) CTCL/MF patients, these 3 genes, along with , were valuable to predict disease progression. We validated these 4 genes in 3 independent, external Sézary Syndrome patient cohorts with RNA-Sequencing data. immune cell-type deconvolution revealed that neutrophil infiltration in early stage MF conveyed a higher risk for disease progression. Also, NK cell infiltration in late stage MF/SS correlated with improved survival. and are robust disease progression and decreased survival biomarkers in CTCL.
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http://dx.doi.org/10.1080/2162402X.2018.1467856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136868PMC
May 2018

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

J Thorac Oncol 2018 10 4;13(10):1483-1495. Epub 2018 Jul 4.

Maria Sklodowska-Curie Institute of Oncology Center, Warsaw, Poland.

Background: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior.

Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls.

Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility.

Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
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http://dx.doi.org/10.1016/j.jtho.2018.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366341PMC
October 2018

National Cancer Institute Biospecimen Evidence-Based Practices: Harmonizing Procedures for Nucleic Acid Extraction from Formalin-Fixed, Paraffin-Embedded Tissue.

Biopreserv Biobank 2018 Aug 19;16(4):247-250. Epub 2018 Jun 19.

4 Biorepositories and Biospecimen Research Branch, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, Maryland.

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http://dx.doi.org/10.1089/bio.2018.0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080192PMC
August 2018

Integrated Molecular Characterization of Testicular Germ Cell Tumors.

Cell Rep 2018 06;23(11):3392-3406

The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.
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http://dx.doi.org/10.1016/j.celrep.2018.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075738PMC
June 2018

Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Cell 2018 05 19;173(4):864-878.e29. Epub 2018 Apr 19.

Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.
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http://dx.doi.org/10.1016/j.cell.2018.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935540PMC
May 2018

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.

Cell 2018 04;173(2):305-320.e10

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.
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http://dx.doi.org/10.1016/j.cell.2018.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916814PMC
April 2018

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Cell Rep 2018 04;23(1):313-326.e5

Leukemia Therapeutics LLC., Hull, MA 02045, USA.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
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http://dx.doi.org/10.1016/j.celrep.2018.03.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075733PMC
April 2018