Dr Shaw on the Heterogeneity Between Paired Primary and Metastatic Solid Tumors

Timothy I Shaw, PhD, assistant member, Moffitt Cancer Center, discusses the genetic heterogeneity between paired primary and metastatic solid tumors, as well as the implications for neoantigen-based personalized vaccines in cancer care.

Certain cancer types have a high overlap between paired primary and metastatic solid tumors. In the analysis, which Shaw presented at the 2023 ASCO Annual Meeting, these included melanoma, bladder cancer, lung cancer, and brain cancer. However, it is possible that this might have been the result of the tissue that was available to investigators, as Shaw notes. Notably, investigators found that some cancers have a consistent overlap of variants. Moreover, there appeared to be a selection against those variants or somatic mutations that resulted in a frameshift, indicating that there are proteins that get drastically altered downstream of the mutation, Shaw expands. This may result in more immunogenicity from the tumor site, prompting the immune system to have a negative selection against these tumors, Shaw adds. Therefore, when comparing the proportion of mutations that are in frame vs those that are out of frame, there's a propensity toward those that are in frame, Shaw says.

The end goal of this research is to identify a good strategy for prioritization, as well as to consider the clonality of these tumors, Shaw continues, meaning that the major clone that harbors the origin or mutations is the one investigators should focus on for therapeutic development. This ensures that all the lineages downstream and all the clones that get generated will still have targetable peptides. Overall, this is a key consideration when prioritizing variants of for RNA vaccines, Shaw concludes.