TY - JOUR
T1 - Origin of metastases
T2 - Subspecies of cancers generated by intrinsic karyotypic variations
AU - Duesberg, Peter
AU - Iacobuzio-Donahue, Christine
AU - Brosnan, Jackie
AU - McCormack, Amanda
AU - Mandrioli, Daniele
AU - Chen, Lewis
N1 - Funding Information:
We gratefully acknowledge Bert Vogelstein (Johns Hopkins Medical Institutions, Baltimore) for encouragement and for offering cultures of the pancreatic cancers and metastases studied here. We thank Kavon Karrobi [University of California at Berkeley (UC Berkeley)] and Rainer Sachs (Dept. Mathematics and Physics, UC Berkeley) for critical reviews of the manuscript. Further we thank Alfred Boecking (Universitätsklinikum Düsseldorf, Duesseldorf, Gemany), Alice Fabarius (University of Heidelberg at Mannheim, Germany), Richard Harland (Dept. Molecular and Cell Biology, UC Berkeley), Ruediger Hehlmann (University of Heidelberg at Mannheim, Germany), Josh Nicholson (Virginia Polytechnic Institute and State University, Blacksburg, VA), Jerry Pollack (University of Washington, Seattle), David Rasnick (Berkeley, former visiting scholar at UC Berkeley) and Richard Strathmann (University of Washington, Seattle) for valuable information and Josh Nicholson in particular for many timely alerts and critical discussions. Bong-Gyoon Han (Lawrence Berkeley Lab) is gratefully acknowledged for the preparation of Figure 1. Our research would not have been possible without the generous support from the philanthropists Dr. Christian Fiala (Vienna, Austria), Rajeev and Christine Joshi (London, UK), Robert Leppo (San Francisco), Peter Rozsa of the Taubert Memorial Foundation (Los Angeles), Howard Urnovitz (Chronix Biomedical, San Jose, CA), a Foundation that prefers to remain anonymous, an anonymous sponsor from Connecticut, other private sources and the Forschungsfonds der Fakultaet fuer Klinische Medizin, University of Heidelberg at Mannheim, Germany.
PY - 2012/3/15
Y1 - 2012/3/15
N2 - Conventional mutation theories do not explain (1) why the karyotypes of metastases are related to those of parental cancers but not to those of metastases of other cancers and (2) why cancers metastasize at rates that often far exceed those of conventional mutations. To answer these questions, we advance here the theory that metastases are autonomous subspecies of cancers, rather than mutations. Since cancers are species with intrinsically flexible karyotypes, they can generate new subspecies by spontaneous karyotypic rearrangements. This phylogenetic theory predicts that metastases are karyotypically related to parental cancers but not to others. Testing these predictions on metastases from two pancreatic cancers, we found: (1) Metastases had individual karyotypes and phenotypes. The karyotypes of metastases were related to, but different from, those of parental cancers in 11 out of 37 and 26 out of 49 parental chromosomal units. Chromosomal units are defined as intact chromosomes with cancer-specific copy numbers and marker chromosomes that are > 50% clonal. (2) Metastases from the two different cancers did not share chromosomal units. Testing the view that multi-chromosomal rearrangements occur simultaneously in cancers, as opposed to sequentially, we found spontaneous non-clonal rearrangements with as many new chromosomal units as in authentic metastases. We conclude that metastases are individual autonomous species differing from each other and parental cancers in species-specific karyotypes and phenotypes. They are generated from parental cancers by multiple simultaneous karyotypic rearrangements, much like new species. The species-specific individualities of metastases explain why so many searches for commonalities have been unsuccessful.
AB - Conventional mutation theories do not explain (1) why the karyotypes of metastases are related to those of parental cancers but not to those of metastases of other cancers and (2) why cancers metastasize at rates that often far exceed those of conventional mutations. To answer these questions, we advance here the theory that metastases are autonomous subspecies of cancers, rather than mutations. Since cancers are species with intrinsically flexible karyotypes, they can generate new subspecies by spontaneous karyotypic rearrangements. This phylogenetic theory predicts that metastases are karyotypically related to parental cancers but not to others. Testing these predictions on metastases from two pancreatic cancers, we found: (1) Metastases had individual karyotypes and phenotypes. The karyotypes of metastases were related to, but different from, those of parental cancers in 11 out of 37 and 26 out of 49 parental chromosomal units. Chromosomal units are defined as intact chromosomes with cancer-specific copy numbers and marker chromosomes that are > 50% clonal. (2) Metastases from the two different cancers did not share chromosomal units. Testing the view that multi-chromosomal rearrangements occur simultaneously in cancers, as opposed to sequentially, we found spontaneous non-clonal rearrangements with as many new chromosomal units as in authentic metastases. We conclude that metastases are individual autonomous species differing from each other and parental cancers in species-specific karyotypes and phenotypes. They are generated from parental cancers by multiple simultaneous karyotypic rearrangements, much like new species. The species-specific individualities of metastases explain why so many searches for commonalities have been unsuccessful.
KW - Cancer autonomy
KW - High rates of karyotypic variation
KW - Intrinsic instability of aneuploidy
KW - Marker chromosomes
KW - Multi-chromosomal rearrangements
KW - Saltational evolution
KW - Speciation
KW - Stabilization of karyotype by selection for autonomy
KW - Stochastic karyotypic variation
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U2 - 10.4161/cc.11.6.19580
DO - 10.4161/cc.11.6.19580
M3 - Article
C2 - 22377695
AN - SCOPUS:84863386341
VL - 11
SP - 1151
EP - 1166
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 6
ER -