Attacking Tumors From All Sides: Personalized Multiplex Vaccines to Tackle Intratumor Heterogeneity

In this study, several biopsies from a patient-derived primary renal-cell carcinoma were analyzed by whole-exome sequencing and aligned to healthy tissue. Next to several shared mutations between different subclones, ca. 23% of the mutations were only found in specific regions of the tumor. Strikingly, a single biopsy of that same tumor only covered around 55% of the total mutational diversity, underlining the need for multi-region sampling. Tracing the order of mutations in different subclones revealed that they develop in a branching fashion from the primary tumor clone, harboring the driver mutation, rather than in a linear model. Remarkably, these differentially branched subclones harbored different mutations in the same gene which suggests a mode of convergent evolution (48). These findings emphasize the importance of multi-region sampling of tumor samples, as it can explain the mutational ancestry of a tumor and thereby aid in the selection of neoantigens for tumor vaccination, which ideally target mutations from the trunk of the phylogenetic tree. Besides being able to reconstruct the mutational history, it is also important to correlate this to the developmental stage of the tumor as shown by De Bruin et al. (49). In patients with non-small cell lung cancer (NSCLC) mutational events in the primary tumor coupled to known driver genes could be identified in the context of tobacco-induced carcinogenesis, bearing typical C>T transitions in early development. Mutations...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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