title: Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.
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.
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alvin P
authors.initials: AP
authors.lastname: Makohon-Moore
authors.affiliation: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Johannes G
authors.identifier: http://orcid.org/0000-0002-0170-7353
authors.initials: JG
authors.lastname: Reiter
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.|Center for Mathematical Sciences and Applications, Harvard University, Cambridge, Massachusetts, USA.|Department of Mathematics, Emmanuel College, Boston, Massachusetts, USA.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0002-9746-7613
authors.initials: B
authors.lastname: Allen
authors.affiliation: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
authors.forename: Deepanjan
authors.initials: D
authors.lastname: Kundu
authors.affiliation: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chatterjee
authors.affiliation: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Fay
authors.initials: F
authors.lastname: Wong
authors.affiliation: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kohutek
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jungeui
authors.initials: J
authors.lastname: Hong
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Attiyeh
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Breanna
authors.initials: B
authors.lastname: Javier
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Christine A
authors.identifier: http://orcid.org/0000-0002-4672-3023
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
mesh_terms: D006801:Humans; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*