The mutational footprints of cancer therapies

Area of Science:

• Genomics
• Cancer Biology
• Pharmacology

Background:

• Cancer therapies, including chemotherapy, can induce DNA damage and mutations in both tumor and healthy cells.
• These therapy-induced mutations are implicated in long-term and late adverse effects, such as organ toxicity and secondary cancers.
• The specific contribution of different chemotherapies to the overall mutation burden remains largely unexplored.

Purpose of the Study:

• To identify and characterize the mutational signatures of six widely used anticancer therapies.
• To quantify the contribution of these therapies to the mutation burden in metastatic tumors.
• To assess the risk of therapy-induced mutations in driving coding and potential driver mutations.

Main Methods:

• Analysis of mutational signatures across over 3,500 metastatic tumors from diverse organs.
• Identification of known and novel mutational footprints associated with specific anticancer drugs.
• Utilizing identified signatures to estimate treatment-specific mutation burden and associated genomic risks.

Main Results:

• Discovery of distinct mutational signatures for six common anticancer therapies.
• Identification of new signatures linked to platinum-based drugs and nucleoside metabolic inhibitors.
• Quantification of the mutational contribution of different therapies to tumor genomes.

Conclusions:

• Mutational footprints provide a means to assess the genomic impact of cancer treatments.
• Understanding these signatures aids in evaluating the long-term side effect risks associated with various chemotherapies.
• This research enables a precise assessment of mutational risk for different cancer therapies.