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 - Kenudson, Mari Mino- 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 AU - , 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.