Tumor mutational landscape is a record of the pre-malignant state
Nicholas J. Haradhvala,
Kent W. Mouw,
Lior Z. Braunstein,
Andrew V. Biankin,
Wouter R. Karthaus,
Christopher D. Nogiec,
Mari Mino- Kenudson,
Leif W. Ellisen,
Martijn P. Lolkema,
Carla van Herpen,
Bradley E. Bernstein,
Charles L. Sawyers,
Katherine A. Hoadley,
David N. Louis,
Lincoln D Stein,
William D. Foulkes,
on behalf of the PCAWG Pathology and Clinical Correlates Working Group, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
Posted 11 Jan 2019
bioRxiv DOI: 10.1101/517565
Posted 11 Jan 2019
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.
- Downloaded 3,174 times
- Download rankings, all-time:
- Site-wide: 1,751 out of 92,988
- In genomics: 348 out of 5,863
- Year to date:
- Site-wide: 9,398 out of 92,988
- Since beginning of last month:
- Site-wide: 18,543 out of 92,988
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!