Cancer Mutational Processes Vary in Their Association with Replication Timing and Chromatin Accessibility

Adar Yaacov, Oriya Vardi, Britny Blumenfeld, Avraham Greenberg, Dashiell J. Massey, Amnon Koren, Sheera Adar, Itamar Simon*, Shai Rosenberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of processes sustained within tumors. However, the association of various mutational processes with replication timing (RT) remains an open question. In this study, we systematically analyzed the mutational landscape of 2,787 tumors from 32 tumor types separately for early and late replicating regions using sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences. To account for sequence differences between various genomic regions, an artificial genome–based approach was developed to expand the signature analyses to doublet base substitutions and small insertions and deletions. The association of mutational processes and RT was signature specific: Some signatures were associated with early or late replication (such as SBS7b and SBS7a, respectively), and others had no association. Most associations existed even after normalizing for genome accessibility. A focused mutational signature identification approach was also developed that uses RT information to improve signature identification; this approach found that SBS16, which is biased toward early replication, is strongly associated with better survival rates in liver cancer. Overall, this novel and comprehensive approach provides a better understanding of the etiology of mutational signatures, which may lead to improved cancer prevention, diagnosis, and treatment.

Original languageAmerican English
Pages (from-to)6106-6116
Number of pages11
JournalCancer Research
Volume81
Issue number24
DOIs
StatePublished - 15 Dec 2021

Bibliographical note

Funding Information:
This work was supported by research grants from the Israel Academy of Sciences (grant nos. 184/16 and 1283/21 to I. Simon; grant no. 2479/20 to S. Rosenberg), Israel Science Foundation–Natural Science Foundation of China (grant no. 2555/16 to I. Simon), the Israel Cancer Research Foundation (to I. Simon), the Binational Science Foundation (grant no. 2019688 to I. Simon), the joint fund for the Hebrew University and its affiliated hospitals (to I. Simon and S. Rosenberg), the Trudy Mandel Louis Charitable Trust (S. Rosenberg), and Hadassah France (S. Rosenberg). The authors thank Professor Ben Berman for assistance in data analysis.

Funding Information:
A. Yaacov reports personal fees from Barcode Diagnostics and Ayala Pharmaceuticals outside the submitted work. A. Koren reports grants from NIH during the conduct of the study. S. Rosenberg reports grants from Israel Science Foundation, Hadassah France, Trudy Mandel Louis Charitable Trust, and the joint fund for the Hebrew University and its affiliated hospitals during the conduct of the study, as well as personal fees from AstraZeneca Israel, Barcode Diagnostics, and Rhenium-Oncotest outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
This work was supported by research grants from the Israel Academy of Sciences (grant nos. 184/16 and 1283/21 to I. Simon; grant no. 2479/20 to S. Rosenberg), Israel Science Foundation?Natural Science Foundation of China (grant no. 2555/16 to I. Simon), the Israel Cancer Research Foundation (to I. Simon), the Binational Science Foundation (grant no. 2019688 to I. Simon), the joint fund for the Hebrew University and its affiliated hospitals (to I. Simon and S. Rosenberg), the Trudy Mandel Louis Charitable Trust (S. Rosenberg), and Hadassah France (S. Rosenberg). The authors thank Professor Ben Berman for assistance in data analysis.

Publisher Copyright:
©2021 American Association for Cancer Research

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