Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors.

Autor: Abdel-Wahab N; Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Diab A; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yu RK; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Futreal A; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Criswell LA; Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Tayar JH; Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dadu R; Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shannon V; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shete SS; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sshete@mdanderson.org.; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sshete@mdanderson.org., Suarez-Almazor ME; Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. msalmazor@mdanderson.org.; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. msalmazor@mdanderson.org.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2021 Jul; Vol. 70 (7), pp. 1939-1949. Date of Electronic Publication: 2021 Jan 07.
DOI: 10.1007/s00262-020-02797-0
Abstrakt: Background: Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs.
Methods: We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10 -3 ), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster.
Results: A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10 -4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases.
Conclusion: Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.
Databáze: MEDLINE
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