Whole Exome Sequencing to Map the Genomic Evolution of Metastatic Prostate Cancer


Metastatic castration resistant prostate cancer (mCRPC) is the lethal form of the disease, and as metastatic biopsies are seldom performed, rapid autopsy programs provide a needed source of tissue for genomic study. In addition to supplying ample tissue, these programs allow for the analysis of multiple tumors from the same patient, allowing researchers to trace the genomic evolution of prostate cancer from a localized hormone-sensitive state to a metastatic castration-resistant one.

In this issue, Nickerson et al. (Hum Mutat 34:1231-1241, 2013) perform next generation sequencing (NGS) on the exomes of 5 metastatic CRPC tumors and control kidney tissue taken from one individual at the time of autopsy, validating findings by PCR and Sanger sequencing in the patient's original primary prostate tumor and in additional available metastases. Using these techniques the authors provide insight into the anatomic evolution of prostate cancer, observing that sites colonized late in the metastatic process accumulate new somatic variants not present in sites colonized earlier. In addition to the finding of germline and somatic inactivation of BRCA1, the authors observe somatic alterations in TET2 in mCRPC tumors but not in primary tissue, suggesting a not previously recognized driver role in the early spread of metastatic disease. Additional somatic alterations in a number of genes that regulate methytlation and chromatin remodeling including PBRM1 suggest that epigenetic regulation may be important in the progression of metastatic disease.

Taken together, this work shows that NGS of multiple tumors isolated from the same individual has the potential not only to shed light on the genomic and anatomic evolution of metastatic prostate cancer, but also to allow for the identification of putative driver and passenger mutations, which can potentially aid in the selection of targets for the next generation of therapeutics.