Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals

• DOI: 10.1371/journal.pgen.1009368
• Publication Date: 2021-02-09T01:59:27Z
• Authors: Arne Claeys; Tom Luijts; Kathleen Marchal; Jimmy Van den Eynden
• Keywords: Proto-Oncogene Proteins B-raf; Cancer Research; Genotype; Evolution; BLOCKADE; Carcinogenesis; Glycine; QH426-470; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Behavior and Systematics; Gene Frequency; HLA Antigens; CLASS-I; Cell Line, Tumor; Neoplasms; BINDING; Medicine and Health Sciences; Genetics; Humans; Genetics(clinical); Molecular Biology; Alleles; 0303 health sciences; Ecology; Oncogenes; 3. Good health; Mutation; Tumor Suppressor Protein p53; Research Article

Cancer is driven by somatic mutations that result in a cellular fitness advantage. This selective advantage is expected to be counterbalanced by the immune system when these driver mutations simultaneously lead to the generation of neoantigens, novel peptides that are presented at the cancer cell membrane via HLA molecules from the MHC complex. The presentability of these peptides is determined by a patient’s MHC genotype and it has been suggested that this results in MHC genotype-specific restrictions of the oncogenic mutational landscape. Here, we generated a set of virtual patients, each with an identical and prototypical MHC genotype, and show that the earlier reported HLA affinity differences between observed and unobserved mutations are unrelated to MHC genotype variation. We demonstrate how these differences are secondary to high frequencies of 13 hot spot driver mutations in 6 different genes. Several oncogenic mechanisms were identified that lower the peptides’ HLA affinity, including phospho-mimicking substitutions inBRAF, destabilizing tyrosine mutations inTP53and glycine-rich mutational contexts in the GTP-bindingKRASdomain. In line with our earlier findings, our results emphasize that HLA affinity predictions are easily misinterpreted when studying immunogenic selection processes.