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 Kenudson, Mari Mino- 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 A1 on behalf of the PCAWG Pathology and Clinical Correlates Working Group, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network 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.