Model of emergence of mutational hotspots suggests a therapy

Though the mutations in cancer cells are believed to occur randomly, certain regions of genes essential to cancer growth are more frequently mutated than others in established tumors. A study co-led by Ludwig MSK’s Taha Merghoub modeled the evolution of mutational hotspots and experimentally verified the interplay between the selection of such mutations and their tendency to invite an immune attack on tumor cells. Its findings, reported in a May issue of Nature, reveal a tradeoff that guides tumor evolution and might potentially be exploited for both cancer prevention and therapy. Modeling the emergence of mutational hotspots in the tumor suppressor TP53, Taha and his colleagues showed that mutations that alter protein function in ways that benefit tumors cannot simultaneously evade immune surveillance. Their model anticipated overall survival of patients in several cohorts in The Cancer Genome Atlas and correctly estimated the age of cancer onset for people diagnosed with Li-Fraumeni syndrome, who tend to develop cancer due to inherited mutations in their TP53 genes. Their study also suggests that, early in their growth, tumors favor the proliferative boost offered by certain driver gene mutations over the risk they pose of immune detection. Because such targetable neoantigens are more often displayed in precancerous tissues, their immunotherapeutic targeting might help prevent the emergence of malignancy, especially in people who have an inherited proclivity for cancer.

Read the study: Fundamental immune–oncogenicity trade-offs define driver mutation fitness, Nature, 2022 May 11 Epub

This article appeared in the September 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).


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