Work

Double-base deletions and signatures associated with platinum adducts in metastatic cancer

Year: 2026

Type: article

Abstract: Platinum compounds preferably create intrastrand G-G adducts to halt replication in cancer cells. When successfully bypassed, resulting somatic variants end up in the genome. Unexpectedly, current double-base substitution signatures associated with platinum lack a GG component, and we hypothesized that deletion was missing from the possible solutions to circumvent a double-base lesion. We investigated a large pan-cancer metastatic cohort and generated platinum specific de novo double-base substitution and deletion (DBSD) signatures. One of the oxaliplatin associated DBSD signatures had GG deletion as dominant characteristic and also included new and known substitutions associated with platinum. Unforeseen among the additional results, DBSD signatures with deletion of TT as singular characteristic were strongly associated with microsatellite instability in multiple cohorts and provisionally in liquid biopsies. This study showed that DBSD signatures increase our understanding and cataloging of the effects caused by platinum and, in general, may aid in the discovery of new biological insights.

Source: Nucleic Acids Research

DOI: 10.1093/nar/gkag945

Authors: Marcel Smid, Lotte van Leeuwen, Saskia M Wilting, John W M Martens

Institutions: Erasmus MC, Erasmus MC Cancer Institute

Language: English

Topic: Cancer Genomics and Diagnostics

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,992