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

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.