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Grant Details

Grant Number: 5R01CA227237-03 Interpret this number
Primary Investigator: Gusev, Alexander
Organization: Dana-Farber Cancer Inst
Project Title: (PQ3) a Functional Genomic Approach to Identification and Interpretation of Germline-Tumor Genetic Interactions
Fiscal Year: 2020


Abstract

PROJECT SUMMARY/ABSTRACT Studies of germline genetic variation in cancer cases and controls as well as studies of somatic mutation have transformed our understanding of cancer etiology and lead to the development of life saving cancer interventions. However, even though tumor progression, evolution, and treatment response are influenced by both somatic and germline variation, these data have largely been examined in isolation. In this work, we propose to integrate extensive data collection, novel statistical methods, and cutting-edge functional validation to discover and characterize somatic-germline interactions in a pan-cancer study. Results from our work will significantly benefit both cancer researcher and multiple medical research discipline more broadly. Within the cancer genetics field, identifying somatic-germline interactions will help (i) identify new classes of drugs targets causally upstream of those identified through somatic driver mutations, (ii) precisely treat patients by selecting interventions the basis of germline and somatic genetics as well as tumor RNA- sequencing, (iii) improve risk profiling, especially for tumor recurrence and outcomes, and (iv) develop hypotheses of the germline risk variants mechanism, especially for non-coding variants. To accomplish these goals, we will leverage tumor sequencing from the DFCI Profile Project together with recent innovations in variant imputation to assemble the largest (N>25,000) pan-cancer germline-somatic cohort to date. We will develop novel statistical and computational methods to maximize the value of these data. Because over 90% of germline genetic variation associated with cancer risk and outcomes is in non- coding regions of the genome we especially focus on integration of functional genomic sequencing from both tumor and normal tissues. Our methods will be capable of modelling proximal germline-somatic interactions as well as distal effects of germline variation on trans and global somatic changes. Furthermore, by focusing largely on RNA-sequencing we investigate a gene-centric model that provides specific hypotheses for mechanism that are readily validated via our experimental follow-up of non-coding variation that is otherwise difficult to interpret.



Publications

Constructing germline research cohorts from the discarded reads of clinical tumor sequences.
Authors: Gusev A. , Groha S. , Taraszka K. , Semenov Y.R. , Zaitlen N. .
Source: Genome medicine, 2021-11-08; 13(1), p. 179.
EPub date: 2021-11-08.
PMID: 34749793
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Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms.
Authors: Shetty A. , Seo J.H. , Bell C.A. , O'Connor E.P. , Pomerantz M.M. , Freedman M.L. , Gusev A. .
Source: American journal of human genetics, 2021-11-04; 108(11), p. 2071-2085.
EPub date: 2021-10-25.
PMID: 34699744
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Multitrait transcriptome-wide association study (TWAS) tests.
Authors: Feng H. , Mancuso N. , Pasaniuc B. , Kraft P. .
Source: Genetic epidemiology, 2021 09; 45(6), p. 563-576.
EPub date: 2021-06-03.
PMID: 34082479
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Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE.
Authors: Caggiano C. , Celona B. , Garton F. , Mefford J. , Black B.L. , Henderson R. , Lomen-Hoerth C. , Dahl A. , Zaitlen N. .
Source: Nature communications, 2021-05-11; 12(1), p. 2717.
EPub date: 2021-05-11.
PMID: 33976150
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A model and test for coordinated polygenic epistasis in complex traits.
Authors: Sheppard B. , Rappoport N. , Loh P.R. , Sanders S.J. , Zaitlen N. , Dahl A. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2021-04-13; 118(15), .
PMID: 33833052
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Leveraging expression from multiple tissues using sparse canonical correlation analysis and aggregate tests improves the power of transcriptome-wide association studies.
Authors: Feng H. , Mancuso N. , Gusev A. , Majumdar A. , Major M. , Pasaniuc B. , Kraft P. .
Source: PLoS genetics, 2021 04; 17(4), p. e1008973.
EPub date: 2021-04-08.
PMID: 33831007
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Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.
Authors: Carrot-Zhang J. , Soca-Chafre G. , Patterson N. , Thorner A.R. , Nag A. , Watson J. , Genovese G. , Rodriguez J. , Gelbard M.K. , Corrales-Rodriguez L. , et al. .
Source: Cancer discovery, 2021 03; 11(3), p. 591-598.
EPub date: 2020-12-02.
PMID: 33268447
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Ancestry-associated transcriptomic profiles of breast cancer in patients of African, Arab, and European ancestry.
Authors: Roelands J. , Mall R. , Almeer H. , Thomas R. , Mohamed M.G. , Bedri S. , Al-Bader S.B. , Junejo K. , Ziv E. , Sayaman R.W. , et al. .
Source: NPJ breast cancer, 2021-02-08; 7(1), p. 10.
EPub date: 2021-02-08.
PMID: 33558495
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Disentangling selection on genetically correlated polygenic traits via whole-genome genealogies.
Authors: Stern A.J. , Speidel L. , Zaitlen N.A. , Nielsen R. .
Source: American journal of human genetics, 2021-02-04; 108(2), p. 219-239.
EPub date: 2021-01-12.
PMID: 33440170
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Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: Evidence for "polygenic epistasis".
Authors: Rau C.D. , Gonzales N.M. , Bloom J.S. , Park D. , Ayroles J. , Palmer A.A. , Lusis A.J. , Zaitlen N. .
Source: PLoS genetics, 2020 10; 16(10), p. e1009165.
EPub date: 2020-10-26.
PMID: 33104702
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GBAT: a gene-based association test for robust detection of trans-gene regulation.
Authors: Liu X. , Mefford J.A. , Dahl A. , He Y. , Subramaniam M. , Battle A. , Price A.L. , Zaitlen N. .
Source: Genome biology, 2020-08-24; 21(1), p. 211.
EPub date: 2020-08-24.
PMID: 32831138
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A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.
Authors: Walavalkar K. , Saravanan B. , Singh A.K. , Jayani R.S. , Nair A. , Farooq U. , Islam Z. , Soota D. , Mann R. , Shivaprasad P.V. , et al. .
Source: Nature communications, 2020-07-17; 11(1), p. 3598.
EPub date: 2020-07-17.
PMID: 32680982
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Quantifying genetic effects on disease mediated by assayed gene expression levels.
Authors: Yao D.W. , O'Connor L.J. , Price A.L. , Gusev A. .
Source: Nature genetics, 2020 06; 52(6), p. 626-633.
EPub date: 2020-05-18.
PMID: 32424349
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Secure large-scale genome-wide association studies using homomorphic encryption.
Authors: Blatt M. , Gusev A. , Polyakov Y. , Goldwasser S. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2020-05-26; 117(21), p. 11608-11613.
EPub date: 2020-05-12.
PMID: 32398369
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Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.
Authors: Carrot-Zhang J. , Chambwe N. , Damrauer J.S. , Knijnenburg T.A. , Robertson A.G. , Yau C. , Zhou W. , Berger A.C. , Huang K.L. , Newberg J.Y. , et al. .
Source: Cancer cell, 2020-05-11; 37(5), p. 639-654.e6.
PMID: 32396860
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Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women.
Authors: Marker K.M. , Zavala V.A. , Vidaurre T. , Lott P.C. , Vásquez J.N. , Casavilca-Zambrano S. , Calderón M. , Abugattas J.E. , Gómez H.L. , Fuentes H.A. , et al. .
Source: Cancer research, 2020-05-01; 80(9), p. 1893-1901.
EPub date: 2020-04-03.
PMID: 32245796
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Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex.
Authors: Werling D.M. , Pochareddy S. , Choi J. , An J.Y. , Sheppard B. , Peng M. , Li Z. , Dastmalchi C. , Santpere G. , Sousa A.M.M. , et al. .
Source: Cell reports, 2020-04-07; 31(1), p. 107489.
PMID: 32268104
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Efficient Estimation and Applications of Cross-Validated Genetic Predictions to Polygenic Risk Scores and Linear Mixed Models.
Authors: Mefford J. , Park D. , Zheng Z. , Ko A. , Ala-Korpela M. , Laakso M. , Pajukanta P. , Yang J. , Witte J. , Zaitlen N. .
Source: Journal of computational biology : a journal of computational molecular cell biology, 2020 04; 27(4), p. 599-612.
EPub date: 2020-02-20.
PMID: 32077750
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The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network.
Authors: Heng Y.J. , Hankinson S.E. , Wang J. , Alexandrov L.B. , Ambrosone C.B. , de Andrade V.P. , Brufsky A.M. , Couch F.J. , King T.A. , Modugno F. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 03; 29(3), p. 599-605.
EPub date: 2020-01-13.
PMID: 31932411
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Allele-Specific QTL Fine Mapping with PLASMA.
Authors: Wang A.T. , Shetty A. , O'Connor E. , Bell C. , Pomerantz M.M. , Freedman M.L. , Gusev A. .
Source: American journal of human genetics, 2020-02-06; 106(2), p. 170-187.
EPub date: 2020-01-30.
PMID: 32004450
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A Robust Method Uncovers Significant Context-Specific Heritability in Diverse Complex Traits.
Authors: Dahl A. , Nguyen K. , Cai N. , Gandal M.J. , Flint J. , Zaitlen N. .
Source: American journal of human genetics, 2020-01-02; 106(1), p. 71-91.
PMID: 31901249
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A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.
Authors: Gallois A. , Mefford J. , Ko A. , Vaysse A. , Julienne H. , Ala-Korpela M. , Laakso M. , Zaitlen N. , Pajukanta P. , Aschard H. .
Source: Nature communications, 2019-10-21; 10(1), p. 4788.
EPub date: 2019-10-21.
PMID: 31636271
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Ultrarare variants drive substantial cis heritability of human gene expression.
Authors: Hernandez R.D. , Uricchio L.H. , Hartman K. , Ye C. , Dahl A. , Zaitlen N. .
Source: Nature genetics, 2019 09; 51(9), p. 1349-1355.
EPub date: 2019-09-02.
PMID: 31477931
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A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.
Authors: Gusev A. , Lawrenson K. , Lin X. , Lyra P.C. , Kar S. , Vavra K.C. , Segato F. , Fonseca M.A.S. , Lee J.M. , Pejovic T. , et al. .
Source: Nature genetics, 2019 05; 51(5), p. 815-823.
EPub date: 2019-05-01.
PMID: 31043753
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