Although the relatively low frequency of genomic PTEN alterations in CRC has limited analysis of selection pressures in this tumor type, the large cohort analyzed in this study allows us to separate distinct contributions of mutational signature frequency and effect on protein function on the relative abundance of PTEN changes observed in MT-L and MT-H tumors, to establish co-segregation patterns with driver mutations, and to correlate PTEN alterations with overall survival. The gene discussed is PTEN; the disease is neoplasm.