PT  - JOURNAL ARTICLE
AU  - Kübler, Kirsten
AU  - Karlić, Rosa
AU  - Haradhvala, Nicholas J.
AU  - Ha, Kyungsik
AU  - Kim, Jaegil
AU  - Kuzman, Maja
AU  - Jiao, Wei
AU  - Gakkhar, Sitanshu
AU  - Mouw, Kent W.
AU  - Braunstein, Lior Z.
AU  - Elemento, Olivier
AU  - Biankin, Andrew V.
AU  - Rooman, Ilse
AU  - Miller, Mendy
AU  - Karthaus, Wouter R.
AU  - Nogiec, Christopher D.
AU  - Juvenson, Edouard
AU  - Curry, Edward
AU  - Mino-Kenudson, Mari
AU  - Ellisen, Leif W.
AU  - Brown, Robert
AU  - Gusev, Alexander
AU  - Tomasetti, Cristian
AU  - Lolkema, Martijn P.
AU  - Steeghs, Neeltje
AU  - van Herpen, Carla
AU  - Kim, Hong-Gee
AU  - Lee, Hwajin
AU  - Vlahoviček, Kristian
AU  - Bernstein, Bradley E.
AU  - Sawyers, Charles L.
AU  - Hoadley, Katherine A.
AU  - Cuppen, Edwin
AU  - Koren, Amnon
AU  - Arndt, Peter F.
AU  - Louis, David N.
AU  - Stein, Lincoln D.
AU  - Foulkes, William D.
AU  - Polak, Paz
AU  - Getz, Gad
TI  - Tumor mutational landscape is a record of the pre-malignant state
AID  - 10.1101/517565
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 517565
4099  - http://biorxiv.org/content/early/2019/01/11/517565.short
4100  - http://biorxiv.org/content/early/2019/01/11/517565.full
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.