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Significance Thanks to improved screening technologies, many small “premalignant” tumors are now detected and treated, which reduces late-stage disease and cancer mortality, but also leads to overdiagnosis. Indeed, it remains uncertain if the starts of benign and malignant tumors differ. Here, we combine mathematical multiscale models with multiregional sequencing to infer that the starts of benign and some malignant tumors differ. The abnormal cell mobility eventually needed for invasion and metastasis is already expressed at the start of growth for some malignant tumors but not benign tumors. Therefore, some malignant tumors start with more invasive potential (“born to be bad”), and this early abnormal cell mobility can potentially be used to identify patients more likely to benefit from aggressive treatment.

Spatial mutation patterns as markers of early colorectal tumor cell mobility