Gene Fusions in Solid Cancers
Research Area: Early Detection
Genes fusing together inappropriately were first identified as a cause of leukemia in 1973. As technology advanced, this accidental joining of genes was found to cause cancers of the blood and lymph systems and a few rare soft tissue cancers. But in 2005, Arul Chinnaiyan, M.D., Ph.D., and his team at the University of Michigan found gene fusions in prostate cancer, a common tumor in a solid organ. This changed the way scientists looked at the role of gene fusions and translocations in cancer.
His laboratory’s landmark finding was the discovery of TMPRSS2-ETS gene fusions in a majority of prostate cancers, which was made by using a bioinformatics approach to detect outlier genes in an aggregated tumor gene expression database called ONCOMINE™. TMPRSS2-ETS gene fusions are biomarkers of prostate cancer and an initiating driver alteration for this disease.
His laboratory discovered other gene rearrangements in prostate cancer and was the first to employ transcriptome sequencing to efficiently discover recurrent gene fusions in solid cancers. Following this lead, researchers have found recurrent gene fusions in common cancers, including lung, breast and colon. In 2010, he established the first integrative, comprehensive clinical sequencing approach for advanced cancer patients called MI-ONCOSEQ, which has served as a paradigm for this area of precision medicine. More recently, using integrative genomic analysis of metastatic castration-resistant prostate cancer (mCRPC) samples, they have discovered a subtype of metastatic prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. Patients with this cancer subtype seem to be responsive to immune checkpoint therapies.