4.7 Article

Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes

Journal

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.768981

Keywords

mutational process; mutational signature; mutation; homologous recombination proficient; APOBEC mutational signature

Funding

  1. National Key R&D Program of China
  2. National Natural Science Foundation of China [61873075, 32070673]
  3. Heilongjiang Provincial Natural Science Foundation
  4. Heilongjiang Postdoctoral Foundation
  5. HMU Marshal Initiative Funding
  6. Heilongjiang Touyan Innovation Team Program
  7. Foundation of Harbin Medical University

Ask authors/readers for more resources

In cancer cells, mutational processes lead to various somatic mutations, with some processes causing frequent mutations in cancer genes, while others result in non-driver mutations. Additionally, specific mutations are induced by certain mutational processes, leading to dysregulation of cancer signaling pathways. The APOBEC mutational process also disrupts DNA repair pathways.
Somatic mutations accumulate over time in cancer cells as a consequence of mutational processes. However, the role of mutational processes in carcinogenesis remains poorly understood. Here, we infer the causal relationship between mutational processes and somatic mutations in 5,828 samples spanning 34 cancer subtypes. We found most mutational processes cause abundant recurrent mutations in cancer genes, while exceptionally ultraviolet exposure and altered activity of the error-prone polymerase bring a large number of recurrent non-driver mutations. Furthermore, some mutations are specifically induced by a certain mutational process, such as IDH1 p.R132H which is mainly caused by spontaneous deamination of 5-methylcytosine. At the pathway level, clock-like mutational processes extensively trigger mutations to dysregulate cancer signal transduction pathways. In addition, APOBEC mutational process destroys DNA double-strand break repair pathway, and bladder cancer patients with high APOBEC activity, though with homologous recombination proficient, show a significantly longer overall survival with platinum regimens. These findings help to understand how mutational processes act on the genome to promote carcinogenesis, and further, presents novel insights for cancer prevention and treatment, as our results showing, APOBEC mutagenesis and HRD synergistically contributed to the clinical benefits of platinum-based treatment.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available