Genetic immune escape landscape in primary and metastatic cancer

Francisco Martínez-Jiménez*, Peter Priestley, Charles Shale, Jonathan Baber, Erik Rozemuller, Edwin Cuppen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samples. To address the complexity of the HLA-I locus in the germline and in tumors, we developed LILAC, an open-source integrative framework. One in four tumors harbors GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is generally consistent between primary and metastatic tumors. We reveal that GIE alterations are selected for in tumor evolution and focal loss of heterozygosity of HLA-I tends to eliminate the HLA allele, presenting the largest neoepitope repertoire. Finally, high mutational burden tumors showed a tendency toward focal loss of heterozygosity of HLA-I as the immune evasion mechanism, whereas, in hypermutated tumors, other immune evasion strategies prevail.

Original languageEnglish
Pages (from-to)820-831
Number of pages12
JournalNature Genetics
Issue number5
Publication statusPublished - May 2023


  • Humans
  • Mutation
  • Neoplasms, Second Primary


Dive into the research topics of 'Genetic immune escape landscape in primary and metastatic cancer'. Together they form a unique fingerprint.

Cite this