Nat Genet. 2017 Mar;49(3):358-366. doi: 10.1038/ng.3764. Epub 2017 Jan 16.

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

Makohon-Moore AP^1,², Zhang M³, Reiter JG^4,⁵, Bozic I^5,⁶, Allen B^5,^7,⁸, Kundu D⁴, Chatterjee K⁴, Wong F³, Jiao Y³, Kohutek ZA⁹, Hong J¹⁰, Attiyeh M¹⁰, Javier B¹⁰, Wood LD^1,², Hruban RH^1,^2,¹¹, Nowak MA^5,^6,¹², Papadopoulos N³, Kinzler KW³, Vogelstein B^1,^3,¹³, Iacobuzio-Donahue CA^10,¹⁴.

Author information

1: Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
3: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
5: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.
6: Department of Mathematics, Harvard University, Cambridge, Massachusetts, USA.
7: Center for Mathematical Sciences and Applications, Harvard University, Cambridge, Massachusetts, USA.
8: Department of Mathematics, Emmanuel College, Boston, Massachusetts, USA.
9: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10: David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
12: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.
13: Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.
14: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Abstract

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.