TY - JOUR
T1 - Genetic immune escape landscape in primary and metastatic cancer
AU - Martínez-Jiménez, Francisco
AU - Priestley, Peter
AU - Shale, Charles
AU - Baber, Jonathan
AU - Rozemuller, Erik
AU - Cuppen, Edwin
N1 - Funding Information:
This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation and the Center of Personalised Cancer Treatment have made available to the study. We thank A. Van Hoeck and A. G. Perez for critical reading of the manuscript and their valuable input. We also thank A. Van Hoeck for assistance in the dataset collection and L. Nyguen for help in the mutational signature extraction. We thank H. W. Lee for technical assistance in the TRACERx dataset processing. The present study makes use of data generated by the TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (TRACERx) Consortium and provided by the UCL Cancer Institute and the Francis Crick Institute. The TRACERx study is sponsored by University College London (UCL), funded by Cancer Research UK and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. We also thank N. McGranahan, O. Pich and C. Puttick for sharing the original HLA-I typing and LOHHLA calls used in their original publication. Finally, we thank W. Mulder, M. Penning and H. Merkens for discussions on LILAC’s orthogonal validation.
Funding Information:
This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation and the Center of Personalised Cancer Treatment have made available to the study. We thank A. Van Hoeck and A. G. Perez for critical reading of the manuscript and their valuable input. We also thank A. Van Hoeck for assistance in the dataset collection and L. Nyguen for help in the mutational signature extraction. We thank H. W. Lee for technical assistance in the TRACERx dataset processing. The present study makes use of data generated by the TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (TRACERx) Consortium and provided by the UCL Cancer Institute and the Francis Crick Institute. The TRACERx study is sponsored by University College London (UCL), funded by Cancer Research UK and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. We also thank N. McGranahan, O. Pich and C. Puttick for sharing the original HLA-I typing and LOHHLA calls used in their original publication. Finally, we thank W. Mulder, M. Penning and H. Merkens for discussions on LILAC’s orthogonal validation.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - Humans
KW - Mutation
KW - Neoplasms, Second Primary
UR - https://www.scopus.com/pages/publications/85158846177
U2 - 10.1038/s41588-023-01367-1
DO - 10.1038/s41588-023-01367-1
M3 - Article
C2 - 37165135
SN - 1061-4036
VL - 55
SP - 820
EP - 831
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -