Grant Details
Grant Number: |
5R01CA218668-05 Interpret this number |
Primary Investigator: |
Khurana, Ekta |
Organization: |
Weill Medical Coll Of Cornell Univ |
Project Title: |
Computational Methods for Identifying Non-Coding Cancer Drivers |
Fiscal Year: |
2022 |
Abstract
Most variants obtained from tumor whole-genome sequences (WGS) occur in non-
coding regions of the genome. Although variants in protein-coding regions have received
the majority of attention, numerous studies have now noted the importance of non-
coding variants in cancer. Identification of functional non-coding variants that drive tumor
growth remains a challenge and a bottleneck for the use of whole-genome sequencing in
the clinic. Cancer drivers are generally identified by the high frequency at which their
mutations occur across patients. However, mutation rate is highly heterogeneous in non-
coding regions and many non-driver elements show higher mutation frequency than
others, such as regions bound by transcription factors in melanoma or regions
replicating late during cell division in colon cancer. In this proposal, we will use high-
throughput pooled CRISPR screen and novel computational methods to predict non-
coding cancer drivers. We will quantitatively measure the impact of thousands of non-
coding mutations using our innovative high-throughput CRISPR screen that directly ties
modifications in the native context of the non-coding genome (i.e. not a reporter assay)
to a cancer relevant phenotype (cell growth). The results of the screen will be used as
training data for the development of NC_Driver, a computational cancer driver prediction
tool. NC_Driver will integrate the signals of high functional impact with the recurrence of
variants across multiple tumor samples to identify the non-coding mutations under
positive selection in cancer. We will identify drivers in promoters, enhancers and CTCF
insulators. CTCF insulators are the most mutated yet least studied regulatory elements
in the cancer genome. Using this integrative experimental and computational approach,
we will identify high-confidence candidate drivers. Finally, we will perform functional
evaluation of prioritized non-coding drivers in colorectal and prostate cancers. We will
use CRISPR/Cas9 genome editing in patient-derived cell cultures to test 20 high-ranking
candidate driver promoter/enhancer/insulator mutations. Overall, this proposal
addresses the critical need to identify drivers in the non-coding genome and over long-
term enable the maximal benefit of genome sequencing for each patient.
Publications
Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells.
Authors: Liang W.W.
, Müller S.
, Hart S.K.
, Wessels H.H.
, Méndez-Mancilla A.
, Sookdeo A.
, Choi O.
, Caragine C.M.
, Corman A.
, Lu L.
, et al.
.
Source: Cell, 2024-11-11 00:00:00.0; , .
EPub date: 2024-11-11 00:00:00.0.
PMID: 39532094
Related Citations
Discovery of therapeutic targets in cancer using chromatin accessibility and transcriptomic data.
Authors: Forbes A.N.
, Xu D.
, Cohen S.
, Pancholi P.
, Khurana E.
.
Source: Cell Systems, 2024-09-18 00:00:00.0; 15(9), p. 824-837.e6.
EPub date: 2024-09-04 00:00:00.0.
PMID: 39236711
Related Citations
Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
Authors: Ferrarone J.R.
, Thomas J.
, Unni A.M.
, Zheng Y.
, Nagiec M.J.
, Gardner E.E.
, Mashadova O.
, Li K.
, Koundouros N.
, Montalbano A.
, et al.
.
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2024-05-21 00:00:00.0; 121(21), p. e2403685121.
EPub date: 2024-05-14 00:00:00.0.
PMID: 38743625
Related Citations
Next-generation forward genetic screens: uniting high-throughput perturbations with single-cell analysis.
Authors: Morris J.A.
, Sun J.S.
, Sanjana N.E.
.
Source: Trends In Genetics : Tig, 2024 Feb; 40(2), p. 118-133.
EPub date: 2023-11-20 00:00:00.0.
PMID: 37989654
Related Citations
Essential transcription factors for induced neuron differentiation.
Authors: Lu C.
, Garipler G.
, Dai C.
, Roush T.
, Salome-Correa J.
, Martin A.
, Liscovitch-Brauer N.
, Mazzoni E.O.
, Sanjana N.E.
.
Source: Nature Communications, 2023-12-15 00:00:00.0; 14(1), p. 8362.
EPub date: 2023-12-15 00:00:00.0.
PMID: 38102126
Related Citations
Recapitulation of patient-specific 3D chromatin conformation using machine learning.
Authors: Xu D.
, Forbes A.N.
, Cohen S.
, Palladino A.
, Karadimitriou T.
, Khurana E.
.
Source: Cell Reports Methods, 2023-09-25 00:00:00.0; 3(9), p. 100578.
EPub date: 2023-09-05 00:00:00.0.
PMID: 37673071
Related Citations
Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens.
Authors: Morris J.A.
, Caragine C.
, Daniloski Z.
, Domingo J.
, Barry T.
, Lu L.
, Davis K.
, Ziosi M.
, Glinos D.A.
, Hao S.
, et al.
.
Source: Science (new York, N.y.), 2023-05-19 00:00:00.0; 380(6646), p. eadh7699.
EPub date: 2023-05-19 00:00:00.0.
PMID: 37141313
Related Citations
Efficient combinatorial targeting of RNA transcripts in single cells with Cas13 RNA Perturb-seq.
Authors: Wessels H.H.
, Méndez-Mancilla A.
, Hao Y.
, Papalexi E.
, Mauck W.M.
, Lu L.
, Morris J.A.
, Mimitou E.P.
, Smibert P.
, Sanjana N.E.
, et al.
.
Source: Nature Methods, 2023 Jan; 20(1), p. 86-94.
EPub date: 2022-12-22 00:00:00.0.
PMID: 36550277
Related Citations
Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers.
Authors: Martinez-Fundichely A.
, Dixon A.
, Khurana E.
.
Source: Nature Communications, 2022-09-26 00:00:00.0; 13(1), p. 5640.
EPub date: 2022-09-26 00:00:00.0.
PMID: 36163358
Related Citations
Cancer genes disfavoring T cell immunity identified via integrated systems approach.
Authors: Kishton R.J.
, Patel S.J.
, Decker A.E.
, Vodnala S.K.
, Cam M.
, Yamamoto T.N.
, Patel Y.
, Sukumar M.
, Yu Z.
, Ji M.
, et al.
.
Source: Cell Reports, 2022-08-02 00:00:00.0; 40(5), p. 111153.
PMID: 35926468
Related Citations
Recurrent somatic mutations as predictors of immunotherapy response.
Authors: Gajic Z.Z.
, Deshpande A.
, Legut M.
, Imieliński M.
, Sanjana N.E.
.
Source: Nature Communications, 2022-07-08 00:00:00.0; 13(1), p. 3938.
EPub date: 2022-07-08 00:00:00.0.
PMID: 35803911
Related Citations
Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets.
Authors: Tang F.
, Xu D.
, Wang S.
, Wong C.K.
, Martinez-Fundichely A.
, Lee C.J.
, Cohen S.
, Park J.
, Hill C.E.
, Eng K.
, et al.
.
Source: Science (new York, N.y.), 2022-05-27 00:00:00.0; 376(6596), p. eabe1505.
EPub date: 2022-05-27 00:00:00.0.
PMID: 35617398
Related Citations
The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by repressing pro-differentiation genes.
Authors: Garipler G.
, Lu C.
, Morrissey A.
, Lopez-Zepeda L.S.
, Pei Y.
, Vidal S.E.
, Zen Petisco Fiore A.P.
, Aydin B.
, Stadtfeld M.
, Ohler U.
, et al.
.
Source: Cell Reports, 2022-03-15 00:00:00.0; 38(11), p. 110524.
PMID: 35294876
Related Citations
A genome-scale screen for synthetic drivers of T cell proliferation.
Authors: Legut M.
, Gajic Z.
, Guarino M.
, Daniloski Z.
, Rahman J.A.
, Xue X.
, Lu C.
, Lu L.
, Mimitou E.P.
, Hao S.
, et al.
.
Source: Nature, 2022 03; 603(7902), p. 728-735.
EPub date: 2022-03-16 00:00:00.0.
PMID: 35296855
Related Citations
Transcriptome-wide Cas13 guide RNA design for model organisms and viral RNA pathogens.
Authors: Guo X.
, Rahman J.A.
, Wessels H.H.
, Méndez-Mancilla A.
, Haro D.
, Chen X.
, Sanjana N.E.
.
Source: Cell Genomics, 2021-10-13 00:00:00.0; 1(1), .
EPub date: 2021-09-03 00:00:00.0.
PMID: 35664829
Related Citations
Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.
Authors: Kasela S.
, Daniloski Z.
, Bollepalli S.
, Jordan T.X.
, tenOever B.R.
, Sanjana N.E.
, Lappalainen T.
.
Source: Genome Biology, 2021-08-23 00:00:00.0; 22(1), p. 242.
EPub date: 2021-08-23 00:00:00.0.
PMID: 34425859
Related Citations
Chemically modified guide RNAs enhance CRISPR-Cas13 knockdown in human cells.
Authors: Méndez-Mancilla A.
, Wessels H.H.
, Legut M.
, Kadina A.
, Mabuchi M.
, Walker J.
, Robb G.B.
, Holden K.
, Sanjana N.E.
.
Source: Cell Chemical Biology, 2021-07-27 00:00:00.0; , .
EPub date: 2021-07-27 00:00:00.0.
PMID: 34343484
Related Citations
Tracking cell lineages to improve research reproducibility.
Authors: Zaaijer S.
, Groen S.C.
, Sanjana N.E.
.
Source: Nature Biotechnology, 2021 06; 39(6), p. 666-670.
PMID: 34012093
Related Citations
Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens.
Authors: Liscovitch-Brauer N.
, Montalbano A.
, Deng J.
, Méndez-Mancilla A.
, Wessels H.H.
, Moss N.G.
, Kung C.Y.
, Sookdeo A.
, Guo X.
, Geller E.
, et al.
.
Source: Nature Biotechnology, 2021-04-29 00:00:00.0; , .
EPub date: 2021-04-29 00:00:00.0.
PMID: 33927415
Related Citations
Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.
Authors: Kasela S.
, Daniloski Z.
, Jordan T.X.
, tenOever B.R.
, Sanjana N.E.
, Lappalainen T.
.
Source: Medrxiv : The Preprint Server For Health Sciences, 2021-04-13 00:00:00.0; , .
EPub date: 2021-04-13 00:00:00.0.
PMID: 33880488
Related Citations
Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.
Authors: Sorek M.
, Oweis W.
, Nissim-Rafinia M.
, Maman M.
, Simon S.
, Hession C.C.
, Adiconis X.
, Simmons S.K.
, Sanjana N.E.
, Shi X.
, et al.
.
Source: Genome Biology, 2021-03-04 00:00:00.0; 22(1), p. 73.
EPub date: 2021-03-04 00:00:00.0.
PMID: 33663567
Related Citations
The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types.
Authors: Daniloski Z.
, Jordan T.X.
, Ilmain J.K.
, Guo X.
, Bhabha G.
, tenOever B.R.
, Sanjana N.E.
.
Source: Elife, 2021-02-11 00:00:00.0; 10, .
EPub date: 2021-02-11 00:00:00.0.
PMID: 33570490
Related Citations
Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.
Authors: Carrot-Zhang J.
, Yao X.
, Devarakonda S.
, Deshpande A.
, Damrauer J.S.
, Silva T.C.
, Wong C.K.
, Choi H.Y.
, Felau I.
, Robertson A.G.
, et al.
.
Source: Cell Reports, 2021-02-02 00:00:00.0; 34(5), p. 108707.
PMID: 33535033
Related Citations
CNCDatabase: a database of non-coding cancer drivers.
Authors: Liu E.M.
, Martinez-Fundichely A.
, Bollapragada R.
, Spiewack M.
, Khurana E.
.
Source: Nucleic Acids Research, 2021-01-08 00:00:00.0; 49(D1), p. D1094-D1101.
PMID: 33095860
Related Citations
Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.
Authors: Daniloski Z.
, Jordan T.X.
, Wessels H.H.
, Hoagland D.A.
, Kasela S.
, Legut M.
, Maniatis S.
, Mimitou E.P.
, Lu L.
, Geller E.
, et al.
.
Source: Cell, 2021-01-07 00:00:00.0; 184(1), p. 92-105.e16.
EPub date: 2020-10-24 00:00:00.0.
PMID: 33147445
Related Citations
Massively parallel Cas13 screens reveal principles for guide RNA design.
Authors: Wessels H.H.
, Méndez-Mancilla A.
, Guo X.
, Legut M.
, Daniloski Z.
, Sanjana N.E.
.
Source: Nature Biotechnology, 2020 06; 38(6), p. 722-727.
EPub date: 2020-03-16 00:00:00.0.
PMID: 32518401
Related Citations
Loss-of-function tolerance of enhancers in the human genome.
Authors: Xu D.
, Gokcumen O.
, Khurana E.
.
Source: Plos Genetics, 2020 Apr; 16(4), p. e1008663.
EPub date: 2020-04-03 00:00:00.0.
PMID: 32243438
Related Citations
DeepMILO: a deep learning approach to predict the impact of non-coding sequence variants on 3D chromatin structure.
Authors: Trieu T.
, Martinez-Fundichely A.
, Khurana E.
.
Source: Genome Biology, 2020-03-26 00:00:00.0; 21(1), p. 79.
EPub date: 2020-03-26 00:00:00.0.
PMID: 32216817
Related Citations
Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy.
Authors: Lek A.
, Zhang Y.
, Woodman K.G.
, Huang S.
, DeSimone A.M.
, Cohen J.
, Ho V.
, Conner J.
, Mead L.
, Kodani A.
, et al.
.
Source: Science Translational Medicine, 2020-03-25 00:00:00.0; 12(536), .
PMID: 32213627
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Passenger Mutations in More Than 2,500 Cancer Genomes: Overall Molecular Functional Impact and Consequences.
Authors: Kumar S.
, Warrell J.
, Li S.
, McGillivray P.D.
, Meyerson W.
, Salichos L.
, Harmanci A.
, Martinez-Fundichely A.
, Chan C.W.Y.
, Nielsen M.M.
, et al.
.
Source: Cell, 2020-03-05 00:00:00.0; 180(5), p. 915-927.e16.
EPub date: 2020-02-20 00:00:00.0.
PMID: 32084333
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High-Throughput Screens of PAM-Flexible Cas9 Variants for Gene Knockout and Transcriptional Modulation.
Authors: Legut M.
, Daniloski Z.
, Xue X.
, McKenzie D.
, Guo X.
, Wessels H.H.
, Sanjana N.E.
.
Source: Cell Reports, 2020-03-03 00:00:00.0; 30(9), p. 2859-2868.e5.
PMID: 32130891
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Pathway and network analysis of more than 2500 whole cancer genomes.
Authors: Reyna M.A.
, Haan D.
, Paczkowska M.
, Verbeke L.P.C.
, Vazquez M.
, Kahraman A.
, Pulido-Tamayo S.
, Barenboim J.
, Wadi L.
, Dhingra P.
, et al.
.
Source: Nature Communications, 2020-02-05 00:00:00.0; 11(1), p. 729.
EPub date: 2020-02-05 00:00:00.0.
PMID: 32024854
Related Citations
Pan-cancer analysis of whole genomes.
Authors: ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium
.
Source: Nature, 2020 02; 578(7793), p. 82-93.
EPub date: 2020-02-05 00:00:00.0.
PMID: 32025007
Related Citations
Patterns of somatic structural variation in human cancer genomes.
Authors: Li Y.
, Roberts N.D.
, Wala J.A.
, Shapira O.
, Schumacher S.E.
, Kumar K.
, Khurana E.
, Waszak S.
, Korbel J.O.
, Haber J.E.
, et al.
.
Source: Nature, 2020 02; 578(7793), p. 112-121.
EPub date: 2020-02-05 00:00:00.0.
PMID: 32025012
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Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.
Authors: Rheinbay E.
, Nielsen M.M.
, Abascal F.
, Wala J.A.
, Shapira O.
, Tiao G.
, Hornshøj H.
, Hess J.M.
, Juul R.I.
, Lin Z.
, et al.
.
Source: Nature, 2020 02; 578(7793), p. 102-111.
EPub date: 2020-02-05 00:00:00.0.
PMID: 32025015
Related Citations
Generation of a knock-in MAP2-tdTomato reporter human embryonic stem cell line with inducible expression of NEUROG2/1 (NYGCe001-A).
Authors: Lu C.
, Sanjana N.E.
.
Source: Stem Cell Research, 2019 12; 41, p. 101643.
EPub date: 2019-11-01 00:00:00.0.
PMID: 31707212
Related Citations
Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes.
Authors: Liu E.M.
, Martinez-Fundichely A.
, Diaz B.J.
, Aronson B.
, Cuykendall T.
, MacKay M.
, Dhingra P.
, Wong E.W.P.
, Chi P.
, Apostolou E.
, et al.
.
Source: Cell Systems, 2019-05-22 00:00:00.0; 8(5), p. 446-455.e8.
EPub date: 2019-05-08 00:00:00.0.
PMID: 31078526
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