The cumulative impact of passenger mutations on cancer development

The traditional binary classification of somatic mutations in cancer as either drivers or passengers overlooks the potential cumulative impact of smaller-effect mutations. Here, we analyze 2,263 whole-genome-sequenced primary tumors across 31 cancer types to assess the functional contribution of passenger mutations in cancer development. We find that in the absence of canonical driver mutations, passenger mutations in cancer genes are significantly enriched, exhibit higher predicted pathogenicity, and are associated with aberrant expression, splicing disruption, altered transcription factor binding, and clinical outcomes that resemble those in the presence of driver mutations. The accumulation of passenger mutations in tumor suppressor genes correlates with significantly reduced expression and poorer prognosis, mirroring the functional outcomes of driver mutations. Notably, this is a previously uncharacterized mechanism of tumor suppressor inactivation, in which the accumulation of somatic mutations results in its progressive inactivation. Our results support a continuum model of mutational impact, where the collective influence of passenger mutations contributes to oncogenesis and clinical outcomes. This work advocates for integrative cancer models that incorporate all somatic mutations to more accurately reflect the complexity of tumor evolution.