'Cancer represents a disease of the genome;each tumor harbors a distinct set of mutations that activate oncogenes and inactivate tumor suppressor genes. In the era of targeted therapeutics, it is expected that cancer treatment decisions will increasingly be made based on tumor genetic composition as opposed to tissue of origin. However, most molecular diagnostics that detect cancer gene mutations are expensive, informative for only a single genetic locus, and adversely affected by degraded or stromally admixed genomic DNA. Thus, despite the promise of somatic cancer genetics, at the present time it remains impractical to identify critical oncogene mutations on a large scale and in a manner compatible with routine clinical use. To address these limitations, this application aims to adapt a high-throughput, mass spectrometry- based genotyping technology to detect somatic mutations in a large panel of cancer genes.'In the R21 phase, a platform based on SequenomTM iPLEX genotyping will be developed that interrogates over 600 point mutations (or small insertions/deletions) across 50 oncogenes and selected tumor genes. This platform will also be optimized for cancer gene mutation detection in genomic DNA from paraffin-embedded tumor tissue. In the R33 phase, test the feasibility of this mutation detection approach will be demonstrated in a study of a large and diverse tumor collection. Here, high-throughput oncogene mutation detection will be performed on nearly 2,700 frozen and paraffin-embedded tumors spanning many lineages, including several that have not undergone prior genomic characterization. The ability to perform high-throughput mutation detection in clinical tumor samples will enable unprecedented molecular analyses applicable to molecular epidemiology and translational oncology, including patient stratification for targeted cancer therapeutic trials. These studies therefore offer immense potential to benefit investigators and patients alike on the path to rational cancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33CA126674-04
Application #
8110475
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (J1))
Program Officer
Tricoli, James
Project Start
2007-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$315,153
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Huang, Franklin W; Hodis, Eran; Xu, Mary Jue et al. (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957-9
Hodis, Eran; Watson, Ian R; Kryukov, Gregory V et al. (2012) A landscape of driver mutations in melanoma. Cell 150:251-63
Wagle, Nikhil; Berger, Michael F; Davis, Matthew J et al. (2012) High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov 2:82-93
Berger, Michael F; Hodis, Eran; Heffernan, Timothy P et al. (2012) Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485:502-6
Balko, Justin M; Mayer, Ingrid A; Sanders, Melinda E et al. (2012) Discordant cellular response to presurgical letrozole in bilateral synchronous ER+ breast cancers with a KRAS mutation or FGFR1 gene amplification. Mol Cancer Ther 11:2301-5
Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas et al. (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483:603-7
Oberholzer, Patrick A; Kee, Damien; Dziunycz, Piotr et al. (2012) RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 30:316-21
Wagle, Nikhil; Emery, Caroline; Berger, Michael F et al. (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085-96
Berger, Michael F; Lawrence, Michael S; Demichelis, Francesca et al. (2011) The genomic complexity of primary human prostate cancer. Nature 470:214-20