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


Author(s): Makohon-Moore, Alvin P; Zhang, Ming; Reiter, Johannes G; Božić, Ivana; Allen, Benjamin; Kundu, Deepanjan; Chatterjee, Krishnendu; Wong, Fay; Jiao, Yuchen; Kohutek, Zachary A; Hong, Jungeui; Attiyeh, Marc; Javier, Breanna; Wood, Laura D; Hruban, Ralph H; Nowak, Martin A; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Iacobuzio-Donahue, Christine A
Article Title: Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer
Affiliation IST Austria
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.
Journal Title: Nature Genetics
Volume: 49
Issue 3
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2017-03-01
Start Page: 358
End Page: 366
DOI: 10.1038/ng.3764
Notes: We thank the Memorial Sloan Kettering Cancer Center Molecular Cytology core facility for immunohistochemistry staining. This work was supported by Office of Naval Research grant N00014-16-1-2914, the Bill and Melinda Gates Foundation (OPP1148627), and a gift from B. Wu and E. Larson (M.A.N.), National Institutes of Health grants CA179991 (C.A.I.-D. and I.B.), F31 CA180682 (A.P.M.-M.), CA43460 (B.V.), and P50 CA62924, the Monastra Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Center for Pancreatic Cancer Research, the Sol Goldman Sequencing Center, ERC Start grant 279307: Graph Games (J.G.R., D.K., and C.K.), Austrian Science Fund (FWF) grant P23499-N23 (J.G.R., D.K., and C.K.), and FWF NFN grant S11407-N23 RiSE/SHiNE (J.G.R., D.K., and C.K.).
Open access: no