Ploidy-Seq: inferring mutational chronology by sequencing polyploid tumor subpopulations.
Human cancers are frequently polyploid, containing multiple aneuploid subpopulations that differ in total DNA content. In this study we exploit this property to reconstruct evolutionary histories, by assuming that mutational complexity increases with time. We developed an experimental method called Ploidy-Seq that uses flow-sorting to isolate and enrich subpopulations with different ploidy prior to next-generation genome sequencing. We applied Ploidy-Seq to a patient with a triple-negative (ER-/PR-/HER2-) ductal carcinoma and performed whole-genome sequencing to trace the evolution of point mutations, indels, copy number aberrations, and structural variants in three clonal subpopulations during tumor growth. Our data show that few mutations (8% to 22%) were shared between all three subpopulations, and that the most aggressive clones comprised a minority of the tumor mass. We expect that Ploidy-Seq will have broad applications for delineating clonal diversity and investigating genome evolution in many human cancers.
The Jackson Laboratory for Genomic Medicine, Farmington, CT USA.
Ankit
A
Malhotra
Department of Genetics, MD Anderson Cancer Center, Houston, TX USA.
Yong
Y
Wang
Department of Genetics, MD Anderson Cancer Center, Houston, TX USA.
Jill
J
Waters
Department of Bioinformatics, MD Anderson Cancer Center, Houston, TX USA.
Ken
K
Chen
Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX USA ; Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX USA.
Funda
F
Meric-Bernstam
The Genome Institute, Washington University School of Medicine, St. Louis, MO USA ; Department of Medicine, Washington University School of Medicine, St. Louis, MO USA.
Ira M
IM
Hall
Department of Genetics, MD Anderson Cancer Center, Houston, TX USA ; Department of Bioinformatics, MD Anderson Cancer Center, Houston, TX USA ; Graduate Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX USA.
Nicholas E
NE
Navin