Christine Iacobuzio-Donahue and colleagues report a detailed analysis of whole-genome sequencing data from primary and metastatic tumors in four patients with pancreatic cancer. They find that in each patient primary tumors and metastases have identical mutations in known driver genes. The extent of heterogeneity among driver gene mutations present in naturally occurring metastases—that is, treatment-naive metastatic disease—is largely unknown. To address this issue, we carried out 60× whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.

Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer