What question did this study set out to answer?

This research aims to identify co-mutations that contribute to tumor initiation and metastatic progression.

July 12, 2026Nature Genetics0 citationsOpen Access

Evolving patterns of co-mutations from tumor initiation to metastatic progression

AIArvind Iyer MPMiljan Petrović DSDebora Sesia

Key Points

This research aims to identify co-mutations that contribute to tumor initiation and metastatic progression.
Curated oncogenic mutations from over 70,000 human tumors across 119 subtypes.
Developed SelectSim for in silico simulation of mutagenesis to analyze co-mutation patterns.
Validated findings across independent human cohorts and compared co-mutation frequencies among different tumor types.
Identified significant co-mutations that are largely cancer-specific and rare in healthy tissues.
Co-mutations linked to metastatic progression were uncovered across various tumor types.
Analysis suggests that distinct co-mutation patterns can indicate pathways to tumorigenesis.

Abstract

Abstract Phenotypically healthy cells frequently harbor somatic variants at cancer-associated genes, indicating that malignant transformation requires the selection of several alterations. Predicting which combinations of mutations, or co-mutations, exhibit oncogenic capacity requires identifying co-mutations that occur more or less frequently than expected. However, statistical frameworks to solve this problem are hampered by tumor heterogeneity and data availability. Here we curated putative oncogenic mutations in >70,000 human tumors from 119 subtypes, and designed a strategy to search for co-mutations based on in silico simulation of mutagenesis (SelectSim). Using this dataset and tool, we discovered and validated co-mutations across independent human cohorts, compared co-mutations across different tumor types and identified potential risk factors of metastatic progression. Notably, across several cohorts of phenotypically normal tissue samples, we show that, unlike individual oncogenic variants, significantly co-occurring mutations are largely cancer-specific and are observed rarely in healthy tissues, providing clues about the paths to tumorigenesis.

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