Exome Sequencing and Integrative Mutational Profiling of Lethal ...

UM File # 5095

Background
According to the American Cancer Society, nearly 34,000 men in the US will die from prostate cancer in 2011. Castration-resistant prostate cancer (CRPC) is a progression of disease that no longer responds to decreasing levels of androgen and testosterone, thereby complicating treatment. A number of gene fusions, translocations, or gain/loss of copy number have been linked to the development of certain types of cancer, including CRPC. However, it is unclear how gene mutations play a role in disease progression. Identification of gene mutations leading to CRPC will illuminate gene products that could be targeted for treatment of the disease. Classification of cancers by their underlying molecular mechanisms, rather than the formation by organ site or cell origin, will also guide physicians to administer personalized treatments for their patients.

Technology Description
Researchers at the University of Michigan have demonstrated the low overall mutation rates of lethal CRPCs, confirmed the monoclonal origin of lethal CRPC, and identified three known (AR, TP53, and ZFHX3) and two novel genes (CDK12 and C10orf46) as significantly mutated in prostate cancer. Through integration with a compendium of related genomic data, the researchers confirmed deregulation of genes known to play driving roles in prostate cancer and nominated genes recurrently disrupted, including FRY, CNOT1, GRM1, STAG2, the ETS family member ETS2 and genes at 5q21 (in ETS fusion-/PTEN deletion- cancers). Finally, researchers identified novel recurrent mutations in the AR collaborating factor FOXA 1, and showed that mutated FOXA 1 disrupts androgen signaling and increases proliferation.

Applications
? Prostate cancer therapeutic targets
? Diagnostic biomarkers

Advantages
? First global description of mutational landscape
? Targeted therapy
? Promotes personalized treatment

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