RT Journal Article
SR Electronic
T1 Tumor mutational landscape is a record of the pre-malignant state
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 517565
DO 10.1101/517565
A1 Kübler, Kirsten
A1 Karlić, Rosa
A1 Haradhvala, Nicholas J.
A1 Ha, Kyungsik
A1 Kim, Jaegil
A1 Kuzman, Maja
A1 Jiao, Wei
A1 Gakkhar, Sitanshu
A1 Mouw, Kent W.
A1 Braunstein, Lior Z.
A1 Elemento, Olivier
A1 Biankin, Andrew V.
A1 Rooman, Ilse
A1 Miller, Mendy
A1 Karthaus, Wouter R.
A1 Nogiec, Christopher D.
A1 Juvenson, Edouard
A1 Curry, Edward
A1 Mino-Kenudson, Mari
A1 Ellisen, Leif W.
A1 Brown, Robert
A1 Gusev, Alexander
A1 Tomasetti, Cristian
A1 Lolkema, Martijn P.
A1 Steeghs, Neeltje
A1 van Herpen, Carla
A1 Kim, Hong-Gee
A1 Lee, Hwajin
A1 Vlahoviček, Kristian
A1 Bernstein, Bradley E.
A1 Sawyers, Charles L.
A1 Hoadley, Katherine A.
A1 Cuppen, Edwin
A1 Koren, Amnon
A1 Arndt, Peter F.
A1 Louis, David N.
A1 Stein, Lincoln D.
A1 Foulkes, William D.
A1 Polak, Paz
A1 Getz, Gad
YR 2019
UL http://biorxiv.org/content/early/2019/01/11/517565.abstract
AB Chromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.