Publications by authors named "Matthew Meyerson"

338 Publications

Telomerase as a therapeutic target in glioblastoma.

Neuro Oncol 2021 Sep 2. Epub 2021 Sep 2.

Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.

Glioblastoma is the most common primary malignant brain tumor in adults and it continues to have a dismal prognosis. The development of targeted therapeutics has been particularly challenging, in part due to a limited number of oncogenic mutations and significant intra-tumoral heterogeneity. TERT promoter mutations were first discovered in melanoma and later found to be present in up to 80% of glioblastoma samples. They are also frequent clonal alterations in this tumor. TERT promoter mutations are one of the mechanisms for telomerase reactivation, providing cancers with cellular immortality. Telomerase is a reverse transcriptase ribonucleoprotein complex that maintains telomere length in cells with high proliferative ability. In this article we present genomic and pre-clinical data that supports telomerase as a potential "Achilles' heel" for glioblastoma. We also summarize prior experience with anti-telomerase agents and potential new approaches to tackle this target.
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http://dx.doi.org/10.1093/neuonc/noab203DOI Listing
September 2021

Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase.

Nat Commun 2021 07 16;12(1):4375. Epub 2021 Jul 16.

Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
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http://dx.doi.org/10.1038/s41467-021-24495-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285493PMC
July 2021

Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

Genome Med 2021 Jul 14;13(1):114. Epub 2021 Jul 14.

Department of Pediatrics, Emory University, Atlanta, GA, USA.

Background: Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.

Methods: We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.

Results: We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events.

Conclusions: Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.
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http://dx.doi.org/10.1186/s13073-021-00929-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281718PMC
July 2021

Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence.

Nat Genet 2021 06 10;53(6):881-894. Epub 2021 May 10.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.
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http://dx.doi.org/10.1038/s41588-021-00859-2DOI Listing
June 2021

Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

Cancer Discov 2021 Apr 29. Epub 2021 Apr 29.

Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with p.H167_N173del. Expression of this EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These EIDs are sensitive to FGFR inhibition , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1669DOI Listing
April 2021

Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma.

Gut 2021 Mar 31. Epub 2021 Mar 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Objective: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.

Design: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.

Results: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.

Conclusion: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.
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http://dx.doi.org/10.1136/gutjnl-2020-323276DOI Listing
March 2021

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

Cell Rep 2021 02;34(5):108707

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
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http://dx.doi.org/10.1016/j.celrep.2021.108707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291PMC
February 2021

Characterization of Plasmacytoid Dendritic Cells, Microbial Sequences, and Identification of a Candidate Public T-Cell Clone in Kikuchi-Fujimoto Disease.

Pediatr Dev Pathol 2021 May-Jun;24(3):193-205. Epub 2021 Feb 2.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Objectives: Kikuchi-Fujimoto disease (KFD) is a self-limited lymphadenitis of unclear etiology. We aimed to further characterize this disease in pediatric patients, including evaluation of the CD123 immunohistochemical (IHC) staining and investigation of potential immunologic and infectious causes.

Methods: Seventeen KFD cases and 12 controls were retrospectively identified, and the histologic and clinical features were evaluated. CD123 IHC staining was quantified by digital image analysis. Next generation sequencing was employed for comparative microbial analysis via RNAseq (5 KFD cases) and to evaluate the immune repertoire (9 KFD cases).

Results: In cases of lymphadenitis with necrosis, >0.85% CD123+ cells by IHC was found to be six times more likely in cases with a final diagnosis of KFD (sensitivity 75%, specificity 87.5%). RNAseq based comparative microbial analysis did not detect novel or known pathogen sequences in KFD. A shared complementarity determining region 3 (CDR3) sequence and use of the same T-cell receptor beta variable region family was identified in KFD LNs but not controls, and was not identified in available databases.

Conclusions: Digital quantification of CD123 IHC can distinguish KFD from other necrotizing lymphadenitides. The presence of a unique shared CDR3 sequence suggests that a shared antigen underlies KFD pathogenesis.
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http://dx.doi.org/10.1177/1093526620987961DOI Listing
February 2021

Antigen identification for HLA class I- and HLA class II-restricted T cell receptors using cytokine-capturing antigen-presenting cells.

Sci Immunol 2021 Jan;6(55)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

A major limitation to understanding the associations of human leukocyte antigen (HLA) and CD8 and CD4 T cell receptor (TCR) genes with disease pathophysiology is the technological barrier of identifying which HLA molecules, epitopes, and TCRs form functional complexes. Here, we present a high-throughput epitope identification system that combines capture of T cell-secreted cytokines by barcoded antigen-presenting cells (APCs), cell sorting, and next-generation sequencing to identify class I- and class II-restricted epitopes starting from highly complex peptide-encoding oligonucleotide pools. We engineered APCs to express anti-cytokine antibodies, a library of DNA-encoded peptides, and multiple HLA class I or II molecules. We demonstrate that these engineered APCs link T cell activation-dependent cytokines with the DNA that encodes the presented peptide. We validated this technology by showing that we could select known targets of viral epitope-, neoepitope-, and autoimmune epitope-specific TCRs, starting from mixtures of peptide-encoding oligonucleotides. Then, starting from 10 TCRβ sequences that are found commonly in humans but lack known targets, we identified seven CD8 or CD4 TCR-targeted epitopes encoded by the human cytomegalovirus (CMV) genome. These included known epitopes, as well as a class I and a class II CMV epitope that have not been previously described. Thus, our cytokine capture-based assay makes use of a signal secreted by both CD8 and CD4 T cells and allows pooled screening of thousands of encoded peptides to enable epitope discovery for orphan TCRs. Our technology may enable identification of HLA-epitope-TCR complexes relevant to disease control, etiology, or treatment.
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http://dx.doi.org/10.1126/sciimmunol.abf4001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320540PMC
January 2021

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Clin Cancer Res 2021 Mar 7;27(6):1695-1705. Epub 2021 Jan 7.

Division of Gastrointestinal Cancers, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer.

Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results.

Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in and wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled V600E-mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an L1196Q gatekeeper mutation. The second patient, whose tumor contained an fusion, continues to benefit from entrectinib after 9 months of therapy.

Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in and wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4073DOI Listing
March 2021

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

Cancer Discov 2021 Mar 2;11(3):591-598. Epub 2020 Dec 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in , and . A local Native American ancestry risk score was more strongly correlated with mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic and mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in and mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933062PMC
March 2021

Pervasive generation of non-canonical subgenomic RNAs by SARS-CoV-2.

Genome Med 2020 12 1;12(1):108. Epub 2020 Dec 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: SARS-CoV-2, a positive-sense RNA virus in the family Coronaviridae, has caused a worldwide pandemic of coronavirus disease 2019 or COVID-19. Coronaviruses generate a tiered series of subgenomic RNAs (sgRNAs) through a process involving homology between transcriptional regulatory sequences (TRS) located after the leader sequence in the 5' UTR (the TRS-L) and TRS located near the start of ORFs encoding structural and accessory proteins (TRS-B) near the 3' end of the genome. In addition to the canonical sgRNAs generated by SARS-CoV-2, non-canonical sgRNAs (nc-sgRNAs) have been reported. However, the consistency of these nc-sgRNAs across viral isolates and infection conditions is unknown. The comprehensive definition of SARS-CoV-2 RNA products is a key step in understanding SARS-CoV-2 pathogenesis.

Methods: Here, we report an integrative analysis of eight independent SARS-CoV-2 transcriptomes generated using three sequencing strategies, five host systems, and seven viral isolates. Read-mapping to the SARS-CoV-2 genome was used to determine the 5' and 3' coordinates of all junctions in viral RNAs identified in these samples.

Results: Using junctional abundances, we show nc-sgRNAs make up as much as 33% of total sgRNAs in cell culture models of infection, are largely consistent in abundance across independent transcriptomes, and increase in abundance over time during infection. By assessing the homology between sequences flanking the 5' and 3' junction points, we show that nc-sgRNAs are not associated with TRS-like homology. By incorporating read coverage information, we find strong evidence for subgenomic RNAs that contain only 5' regions of ORF1a. Finally, we show that non-canonical junctions change the landscape of viral open reading frames.

Conclusions: We identify canonical and non-canonical junctions in SARS-CoV-2 sgRNAs and show that these RNA products are consistently generated by many independent viral isolates and sequencing approaches. These analyses highlight the diverse transcriptional activity of SARS-CoV-2 and offer important insights into SARS-CoV-2 biology.
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http://dx.doi.org/10.1186/s13073-020-00802-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704119PMC
December 2020

Quantification of aneuploidy in targeted sequencing data using ASCETS.

Bioinformatics 2021 08;37(16):2461-2463

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02215 MA, USA.

Summary: The expansion of targeted panel sequencing efforts has created opportunities for large-scale genomic analysis, but tools for copy-number quantification on panel data are lacking. We introduce ASCETS, a method for the efficient quantitation of arm and chromosome-level copy-number changes from targeted sequencing data.

Availability And Implementation: ASCETS is implemented in R and is freely available to non-commercial users on GitHub: https://github.com/beroukhim-lab/ascets, along with detailed documentation.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388019PMC
August 2021

Bacterial invaders drive CRC progression.

Authors:
Matthew Meyerson

Sci Signal 2020 08 11;13(644). Epub 2020 Aug 11.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

The oral bacterium is often found in colorectal cancer (CRC). In the 21 July 2020 issue of , Casasanta show that CRC cell-resident promotes cytokine secretion that may potentiate tumor growth and metastatic progression in patients.
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http://dx.doi.org/10.1126/scisignal.abc4218DOI Listing
August 2020

Genomic Profiling of Prostate Cancers from Men with African and European Ancestry.

Clin Cancer Res 2020 09 10;26(17):4651-4660. Epub 2020 Jul 10.

Division of Hematology/Oncology, Department of Medicine; Helen Diller Family Comprehensive Cancer Center; Bakar Computational Health Sciences Institute; Institute for Human Genetics; San Francisco Veterans Affairs Medical Center; University of California, San Francisco, San Francisco, California.

Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.

Experimental Design: To identify genomic alterations associated with race, we compared the frequencies of somatic alterations in PCa obtained from four publicly available datasets comprising 250 AFR and 611 European American (EUR) men and a targeted sequencing dataset from a commercial platform of 436 AFR and 3018 EUR men.

Results: Mutations in as well as focal deletions in were more frequent in tumors from AFR men. mutations were associated with increasing Gleason score. amplifications were more frequent in tumors from AFR men with metastatic PCa, whereas deletions in and rearrangements in were less frequent in tumors from AFR men. truncations and amplifications were more frequent in primary PCa from AFR men. Genomic features that could impact clinical decision making were not significantly different between the two groups including tumor mutation burden, MSI status, and genomic alterations in select DNA repair genes, , and in .

Conclusions: Although we identified some novel differences in AFR men compared with other populations, the frequencies of genomic alterations in current therapeutic targets for PCa were similar between AFR and EUR men, suggesting that existing precision medicine approaches could be equally beneficial if applied equitably.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597977PMC
September 2020

Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

Nat Cancer 2020 Feb 20;1(2):235-248. Epub 2020 Jan 20.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.
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http://dx.doi.org/10.1038/s43018-019-0018-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328899PMC
February 2020

Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors.

Genes Chromosomes Cancer 2020 09 27;59(9):535-539. Epub 2020 Apr 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.
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http://dx.doi.org/10.1002/gcc.22850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384092PMC
September 2020

Comprehensive metagenomic analysis of blastic plasmacytoid dendritic cell neoplasm.

Blood Adv 2020 03;4(6):1006-1011

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from plasmacytoid dendritic cells (pDCs), the immune cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel cell polyomavirus in Merkel cell carcinoma, human papillomavirus in head and neck squamous cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
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http://dx.doi.org/10.1182/bloodadvances.2019001260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094006PMC
March 2020

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Clin Cancer Res 2020 06 13;26(11):2556-2564. Epub 2020 Mar 13.

Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.

Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).

Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654718PMC
June 2020

Mutational signature in colorectal cancer caused by genotoxic pks E. coli.

Nature 2020 04 27;580(7802):269-273. Epub 2020 Feb 27.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.

Various species of the intestinal microbiota have been associated with the development of colorectal cancer, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin. This compound is believed to alkylate DNA on adenine residues and induces double-strand breaks in cultured cells. Here we expose human intestinal organoids to genotoxic pks E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
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http://dx.doi.org/10.1038/s41586-020-2080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142898PMC
April 2020

Genomic basis for RNA alterations in cancer.

Nature 2020 02 5;578(7793):129-136. Epub 2020 Feb 5.

BGI-Shenzhen, Shenzhen, China.

Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
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http://dx.doi.org/10.1038/s41586-020-1970-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054216PMC
February 2020

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.

J Biol Chem 2020 03 31;295(11):3431-3446. Epub 2020 Jan 31.

Cancer Program, Broad Institute, Cambridge, Massachusetts 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215. Electronic address:

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.
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http://dx.doi.org/10.1074/jbc.RA119.011191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076209PMC
March 2020

Multi-Omics Analysis Identifies MGA as a Negative Regulator of the MYC Pathway in Lung Adenocarcinoma.

Mol Cancer Res 2020 04 20;18(4):574-584. Epub 2019 Dec 20.

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Genomic analysis of lung adenocarcinomas has revealed that the gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated or deleted in lung adenocarcinomas. Most of the mutations are loss of function for MGA, suggesting that MGA may act as a tumor suppressor. Here, we characterize both the molecular and cellular role of MGA in lung adenocarcinomas and illustrate its functional relevance in the MYC pathway. Although MGA and MYC interact with the same binding partner, MAX, and recognize the same E-box DNA motif, we show that the molecular function of MGA appears to be antagonistic to that of MYC. Using mass spectrometry-based affinity proteomics, we demonstrate that MGA interacts with a noncanonical PCGF6-PRC1 complex containing MAX and E2F6 that is involved in gene repression, while MYC is not part of this MGA complex, in agreement with previous studies describing the interactomes of E2F6 and PCGF6. Chromatin immunoprecipitation-sequencing and RNA sequencing assays show that MGA binds to and represses genes that are bound and activated by MYC. In addition, we show that, as opposed to the MYC oncoprotein, MGA acts as a negative regulator for cancer cell proliferation. Our study defines a novel MYC/MAX/MGA pathway, in which MYC and MGA play opposite roles in protein interaction, transcriptional regulation, and cellular proliferation. IMPLICATIONS: This study expands the range of key cancer-associated genes whose dysregulation is functionally equivalent to activation and places MYC within a linear pathway analogous to cell-cycle or receptor tyrosine kinase/RAS/RAF pathways in lung adenocarcinomas.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219472PMC
April 2020

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

Nat Commun 2019 11 29;10(1):5472. Epub 2019 Nov 29.

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.
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http://dx.doi.org/10.1038/s41467-019-13460-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884501PMC
November 2019

Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.

ACS Med Chem Lett 2019 Nov 18;10(11):1537-1542. Epub 2019 Oct 18.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.

6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2)-one, or , potently and selectively inhibits phosphodiesterases 3A and 3B (PDE3A and PDE3B) and kills cancer cells by inducing PDE3A/B interactions with SFLN12. The structure-activity relationship (SAR) of analogs was evaluated using a phenotypic viability assay, resulting in several compounds with suitable pharmacokinetic properties for analysis. One of these compounds, , was active in an SK-MEL-3 xenograft model of cancer.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862344PMC
November 2019

Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening.

Nat Commun 2019 09 5;10(1):3991. Epub 2019 Sep 5.

Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Seoul, South Korea.

Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.
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http://dx.doi.org/10.1038/s41467-019-11867-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728380PMC
September 2019

Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer.

Mol Cancer Res 2019 11 28;17(11):2281-2293. Epub 2019 Aug 28.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including (BCL-XL) and (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. IMPLICATIONS: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-1243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825578PMC
November 2019

Circulating Tumor DNA Provides a Sneak Peek into Treatment Responses in Non-Small Cell Lung Cancer.

Cancer Res 2019 03;79(6):1038-1040

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Circulating tumor DNA (ctDNA) holds great promise as a noninvasive diagnostic tool to guide treatment for patients with lung cancer. Two studies by Phallen and colleagues and Anagnostou and colleagues correlated sensitive measures of ctDNA with clinical responses to tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors, respectively, in patients with non-small cell lung cancer (NSCLC). Together, these studies further highlight the potential clinical utility of serial ctDNA monitoring in patients with NSCLC undergoing treatment with both targeted therapies and immunotherapies..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0231DOI Listing
March 2019
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