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Article

Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma

1
Department of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, Germany
2
Center for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, Germany
3
Practice for Human Genetics, 72076 Tuebingen, Germany
4
Institute for Clinical Epidemiology and Applied Biostatistics (IKEaB), 72076 Tuebingen, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Samia Mourah and Barouyr Baroudjian
Cancers 2022, 14(2), 302; https://doi.org/10.3390/cancers14020302
Received: 17 December 2021 / Accepted: 4 January 2022 / Published: 8 January 2022
(This article belongs to the Collection Targeted Therapies and Immunotherapies in Metastatic Melanoma)
Our aim was to check for possible associations between clinical parameters or NGS-based genetic alterations and the occurrence of immune-related adverse events (IRAE) in melanoma patients with immune checkpoint inhibitors (ICI). We analyzed 95 melanoma patients with ICI and were able to identify several biomarkers associated with the development of IRAE. Female sex was significantly associated with the development of hepatitis, increased total and relative monocytes at ICI initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Furthermore, the following genetic alterations were identified being associated with IRAE: SMAD3 (pancreatitis); CD274, SLCO1B1 (hepatitis); PRDM1, CD274 (encephalitis); PRDM1, CD274, TSHR, FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. Our findings can help to assess the risk for the development of IRAE in melanoma patients with ICI.
Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies. View Full-Text
Keywords: immune-related adverse events; genetic alterations; immunotherapies; melanoma immune-related adverse events; genetic alterations; immunotherapies; melanoma
MDPI and ACS Style

Wölffer, M.; Battke, F.; Schulze, M.; Feldhahn, M.; Flatz, L.; Martus, P.; Forschner, A. Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma. Cancers 2022, 14, 302. https://doi.org/10.3390/cancers14020302

AMA Style

Wölffer M, Battke F, Schulze M, Feldhahn M, Flatz L, Martus P, Forschner A. Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma. Cancers. 2022; 14(2):302. https://doi.org/10.3390/cancers14020302

Chicago/Turabian Style

Wölffer, Marcus, Florian Battke, Martin Schulze, Magdalena Feldhahn, Lukas Flatz, Peter Martus, and Andrea Forschner. 2022. "Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma" Cancers 14, no. 2: 302. https://doi.org/10.3390/cancers14020302

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