The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

We propose that initiating truncal mutations play a special role in tumor formation by both enhancing the survival of the initiating cancer cell and by selecting for secondary mutations that contribute to tumor progression, and that these mutations often act in a tissue-preferred fashion. Here, we explain why inherited mutations often have different tissue specificities compared with spontaneous mutations in the same gene. Initiating truncal mutations make excellent neo-antigens for immunotherapy, and understanding why one mutation selects for a second mutation in a particular tissue type could one day aid in the design of gene-targeted combination therapies.