Journal
NATURE GENETICS
Volume 49, Issue 3, Pages 358-366Publisher
NATURE PORTFOLIO
DOI: 10.1038/ng.3764
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Funding
- Office of Naval Research [N00014-16-1-2914]
- Bill and Melinda Gates Foundation [OPP1148627]
- National Institutes of Health [CA179991, F31 CA180682, CA43460, P50 CA62924]
- ERC Start grant [279307: Graph Games]
- Austrian Science Fund (FWF) [P23499-N23]
- FWF NFN grant [S11407-N23 RiSE/SHiNE]
- Bill and Melinda Gates Foundation [OPP1148627] Funding Source: Bill and Melinda Gates Foundation
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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 60x 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.
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