Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 110, Issue 6, Pages 677-681Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djx271
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Funding
- Deutsche Krebshilfe [70111402]
- European Union's Horizon 2020 research and innovations program under Marie Sklodowska-Curie grant [641458]
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Poor clinical responses to checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies in melanoma have recently been associated with acquired IFN gamma resistance that protects tumor cells from the antiproliferative and pro-apoptotic cytokine activity. IFN gamma-resistant melanoma cells very often lack functional expression of the IFN gamma signaling pathway gene JAK2 due to gene deletions or inactivating gene mutations. Analyzing melanoma cell lines (n = 46, applying next-generation targeted sequencing and single nucleotide polymorphism arrays) as well as available genomic data sets from The Cancer Genome Atlas (TCGA) tumor tissue samples (cutaneous melanoma n = 367, lung squamous cell carcinoma n = 501, bladder urothelial carcinoma n = 408, breast invasive carcinoma n = 768, colorectal adenocarcinoma n = 257), we demonstrate that the frequent chromosomal losses of the tumor suppressor CDKN2A in melanoma and other tumor entities enhance the susceptibility to IFN gamma resistance by concomitant deletion of the JAK2 gene (odds ratio = 223.17, 95% confidence interval = 66.91 to 1487.38, twosided P = 7.6x 10(-46)). Tumors with JAK2 mutations or homozygous JAK2 deletions demonstrate allelic losses covering both CDKN2A and JAK2. This suggests that patients with tumor chromosomal CDKN2A losses are susceptible to developing immunotherapy resistance and should be screened for JAK2 deficiency prior to and under immune checkpoint blocking therapy.
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