Comparative lesion sequencing provides insights into tumor evolution.
We show that the times separating the birth of benign, invasive, and metastatic tumor cells can be determined by analysis of the mutations they have in common. When combined with prior clinical observations, these analyses suggest the following general conclusions about colorectal tumorigenesis: (i) It takes approximately 17 years for a large benign tumor to evolve into an advanced cancer but <2 years for cells within that cancer to acquire the ability to metastasize; (ii) it requires few, if any, selective events to transform a highly invasive cancer cell into one with the capacity to metastasize; (iii) the process of cell culture ex vivo does not introduce new clonal mutations into colorectal tumor cell populations; and (iv) the rates at which point mutations develop in advanced cancers are similar to those of normal cells. These results have important implications for understanding human tumor pathogenesis, particularly those associated with metastasis.
Jones
Siân
S
The Ludwig Center for Cancer Genetics and Therapeutics, Department of Biostatistics, Howard Hughes Medical Institute, and Sidney Kimmel Cancer Center at The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Chen
Wei-Dong
WD
Parmigiani
Giovanni
G
Diehl
Frank
F
Beerenwinkel
Niko
N
Antal
Tibor
T
Traulsen
Arne
A
Nowak
Martin A
MA
Siegel
Christopher
C
Velculescu
Victor E
VE
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Willis
Joseph
J
Markowitz
Sanford D
SD
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D004247:DNA / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009367:Neoplasm Staging; D023041:Xenograft Model Antitumor Assays
D004247:DNA