Skip to main content
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Genomics and Target Discovery

Abstract PR07: Towards precision functional genomics via next-generation functional mapping of cancer variants

Alice H. Berger, Eejung Kim, Angela Brooks, Nina Ilic, Yashaswi Shrestha, Yuen-Yi Tseng, Xiaoyun Wu, Lihua Zou, Atanas Kamburov, Xiaoping Yang, Cong Zhu, Paula Keskula, Sara Seepo, Andrew Hong, Philip Kantoff, Keith L. Ligon, Levi A. Garraway, John G. Doench, David E. Root, Matthew Meyerson, William C. Hahn, Gad Getz, Todd R. Golub and Jesse S. Boehm
Alice H. Berger
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eejung Kim
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Angela Brooks
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nina Ilic
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yashaswi Shrestha
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuen-Yi Tseng
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaoyun Wu
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lihua Zou
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Atanas Kamburov
Massachusetts General Hospital, Boston, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaoping Yang
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cong Zhu
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paula Keskula
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sara Seepo
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew Hong
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip Kantoff
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keith L. Ligon
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Levi A. Garraway
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John G. Doench
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David E. Root
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew Meyerson
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William C. Hahn
Dana-Farber Cancer Institute, Boston, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gad Getz
Massachusetts General Hospital, Boston, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Todd R. Golub
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jesse S. Boehm
Broad Institute of Harvard and MIT, Cambridge, MA,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.TRANSCAGEN-PR07 Published November 2015
  • Article
  • Info & Metrics
Loading
Abstracts: AACR Special Conference: Translation of the Cancer Genome; February 7-9, 2015; San Francisco, CA

Abstract

With the comprehensive analysis of cancer genomes approaching completion, the research community stands poised to rapidly advance genome-guided therapeutic hypotheses into clinical settings. However, for the vast majority of cancer patients, existing knowledge of the function(s) of the newly discovered mutant genes harbored by their tumor is incomplete or non-existent since most cancer mutations are exceedingly rare. As a result, we now have long lists of candidate alleles but a paucity of targets whose biology is sufficiently well understood to guide therapeutics.

Here we present an interim progress report on a pilot effort aiming to create a generalizable framework to systematically map the molecular consequences of cancer variants at scale (Target Accelerator). First, we created an efficient pipeline to generate cancer variants and generated an initial library of 1300 mutant cDNA clones corresponding to variants in lung cancer and diffuse large B-cell lymphoma as well as those nominated by “pan-cancer” computational analyses.

Second, we established an industry-scale, next-generation pipeline to generate new cancer models (Cell Line Factory) directly from patient samples. We have leveraged this pipeline to process over 330 samples from 208 patients across 16 cancer types, with over 60% growing through at least 5 population doublings. We show that tumor genomics can be retained in such patient-derived models and that drug testing to discover clinically validated dependencies within 3 months is feasible. In addition, we use combinatorial molecular barcoding to rapidly generate a panel of pathway-primed human tumorigenesis models that are suitable for massively parallel multiplexed tumorigenesis assays in vivo (TumorPlex).

We hypothesized that this integrated framework could be utilized to generate meaningful functional hypotheses from cancer variants of unknown significance in a high-throughput manner. To test this hypothesis, we introduced over 1000 cancer mutations into cell models and created gene expression signatures together with phenotypic data. In lung cancer, we show that the mutational impact of mutant alleles with known and unknown functions can be rapidly assessed by comparing signatures of wild-type and mutant alleles. We show that this generalizable approach, which does not require prior knowledge, can place variants of unknown significance into dominant gain-of-function and loss-of-function categories. As a complementary approach, we have used TumorPlex assays to test the tumorigenic potential of 550 mutant alleles nominated by Pan-Cancer computational analyses and discovered unexpected variants in the KRAS, AKT1, MAP2K1, ERBB2, PIK3CB, NFE2L2, FAM200A and POT1 genes as being potently tumorigenic.

These proof-of-concept studies demonstrate initial feasibility of mapping cancer variant function at scale. Importantly, they demarcate a path by which mapping variant function and predicting vulnerabilities might soon be possible on a patient-by-patient basis, achieving the promise of precision functional genomics.

Citation Format: Alice H. Berger, Eejung Kim, Angela Brooks, Nina Ilic, Yashaswi Shrestha, Yuen-Yi Tseng, Xiaoyun Wu, Lihua Zou, Atanas Kamburov, Xiaoping Yang, Cong Zhu, Paula Keskula, Sara Seepo, Andrew Hong, Philip Kantoff, Keith L. Ligon, Levi A. Garraway, John G. Doench, David E. Root, Matthew Meyerson, William C. Hahn, Gad Getz, Todd R. Golub, Jesse S. Boehm. Towards precision functional genomics via next-generation functional mapping of cancer variants. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR07.

  • ©2015 American Association for Cancer Research.
Previous
Back to top
Cancer Research: 75 (22 Supplement 1)
November 2015
Volume 75, Issue 22 Supplement 1
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Abstract PR07: Towards precision functional genomics via next-generation functional mapping of cancer variants
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Abstract PR07: Towards precision functional genomics via next-generation functional mapping of cancer variants
Alice H. Berger, Eejung Kim, Angela Brooks, Nina Ilic, Yashaswi Shrestha, Yuen-Yi Tseng, Xiaoyun Wu, Lihua Zou, Atanas Kamburov, Xiaoping Yang, Cong Zhu, Paula Keskula, Sara Seepo, Andrew Hong, Philip Kantoff, Keith L. Ligon, Levi A. Garraway, John G. Doench, David E. Root, Matthew Meyerson, William C. Hahn, Gad Getz, Todd R. Golub and Jesse S. Boehm
Cancer Res November 15 2015 (75) (22 Supplement 1) PR07; DOI: 10.1158/1538-7445.TRANSCAGEN-PR07

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract PR07: Towards precision functional genomics via next-generation functional mapping of cancer variants
Alice H. Berger, Eejung Kim, Angela Brooks, Nina Ilic, Yashaswi Shrestha, Yuen-Yi Tseng, Xiaoyun Wu, Lihua Zou, Atanas Kamburov, Xiaoping Yang, Cong Zhu, Paula Keskula, Sara Seepo, Andrew Hong, Philip Kantoff, Keith L. Ligon, Levi A. Garraway, John G. Doench, David E. Root, Matthew Meyerson, William C. Hahn, Gad Getz, Todd R. Golub and Jesse S. Boehm
Cancer Res November 15 2015 (75) (22 Supplement 1) PR07; DOI: 10.1158/1538-7445.TRANSCAGEN-PR07
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Genomics and Target Discovery

  • Abstract PR06: Functional prioritization of rare gene aberration drivers of cancer
  • Abstract A2-15: Gain-of-function kinase library screen identifies mechanisms of resistance to antiestrogen therapies in ER+ breast cancer
  • Abstract A2-22: Mitochondrial dysfunction induces cancer stem-like phenotypes in Hep3B hepatocellular carcinoma cell line
Show more 3

Genomics and Target Discovery: Oral Presentations - Proffered Abstracts

  • Abstract PR06: Functional prioritization of rare gene aberration drivers of cancer
  • Abstract PR12: High-throughput gene expression profiling as a generalizable assay for determination of mutation impact on gene function
  • Abstract PR05: Using genome-scale CRISPR-mediated loss-of-function and gain-of-function screens to analyze gene-drug interactions in cancer
Show more 3
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement