Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma
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, encep...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/302 |
| _version_ | 1797495294699503616 |
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| author | Marcus Wölffer Florian Battke Martin Schulze Magdalena Feldhahn Lukas Flatz Peter Martus Andrea Forschner |
| author_facet | Marcus Wölffer Florian Battke Martin Schulze Magdalena Feldhahn Lukas Flatz Peter Martus Andrea Forschner |
| author_sort | Marcus Wölffer |
| collection | DOAJ |
| description | 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: <i>AIRE</i>, <i>TERT</i>, <i>SH2B3</i>, <i>LRRK2</i>, <i>IKZF1</i>, <i>SMAD3</i>, <i>JAK2</i>, <i>PRDM1</i>, <i>CTLA4</i>, <i>TSHR</i>, <i>FAN1</i>, <i>SLCO1B1</i>, <i>PDCD1</i>, <i>IL1RN</i>, <i>CD274</i>, <i>UNG</i>. 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 <i>SMAD3</i> (pancreatitis). Regarding CNVs, significant markers included <i>PRDM1</i> deletions and <i>IL1RN</i> (IRAE), <i>CD274</i> duplications and <i>SLCO1B1</i> (hepatitis), <i>PRDM1</i> and <i>CD274</i> (encephalitis), and <i>PRDM1</i>, <i>CD274</i>, <i>TSHR</i>, and <i>FAN1</i> (myositis). Myositis and encephalitis, both, were associated with alterations of <i>PRDM1</i> and <i>CD274</i>, 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. |
| first_indexed | 2024-03-10T01:46:45Z |
| format | Article |
| id | doaj.art-044779bb6b4343df8ea27c91b337e889 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:46:45Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-044779bb6b4343df8ea27c91b337e8892023-11-23T13:12:42ZengMDPI AGCancers2072-66942022-01-0114230210.3390/cancers14020302Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic MelanomaMarcus Wölffer0Florian Battke1Martin Schulze2Magdalena Feldhahn3Lukas Flatz4Peter Martus5Andrea Forschner6Department of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, GermanyCenter for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, GermanyPractice for Human Genetics, 72076 Tuebingen, GermanyCenter for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, GermanyDepartment of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, GermanyInstitute for Clinical Epidemiology and Applied Biostatistics (IKEaB), 72076 Tuebingen, GermanyDepartment of Dermatology, University Hospital Tuebingen, 72076 Tuebingen, GermanyImmune 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: <i>AIRE</i>, <i>TERT</i>, <i>SH2B3</i>, <i>LRRK2</i>, <i>IKZF1</i>, <i>SMAD3</i>, <i>JAK2</i>, <i>PRDM1</i>, <i>CTLA4</i>, <i>TSHR</i>, <i>FAN1</i>, <i>SLCO1B1</i>, <i>PDCD1</i>, <i>IL1RN</i>, <i>CD274</i>, <i>UNG</i>. 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 <i>SMAD3</i> (pancreatitis). Regarding CNVs, significant markers included <i>PRDM1</i> deletions and <i>IL1RN</i> (IRAE), <i>CD274</i> duplications and <i>SLCO1B1</i> (hepatitis), <i>PRDM1</i> and <i>CD274</i> (encephalitis), and <i>PRDM1</i>, <i>CD274</i>, <i>TSHR</i>, and <i>FAN1</i> (myositis). Myositis and encephalitis, both, were associated with alterations of <i>PRDM1</i> and <i>CD274</i>, 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.https://www.mdpi.com/2072-6694/14/2/302immune-related adverse eventsgenetic alterationsimmunotherapiesmelanoma |
| spellingShingle | Marcus Wölffer Florian Battke Martin Schulze Magdalena Feldhahn Lukas Flatz Peter Martus Andrea Forschner Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma Cancers immune-related adverse events genetic alterations immunotherapies melanoma |
| title | Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma |
| title_full | Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma |
| title_fullStr | Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma |
| title_full_unstemmed | Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma |
| title_short | Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma |
| title_sort | biomarkers associated with immune related adverse events under checkpoint inhibitors in metastatic melanoma |
| topic | immune-related adverse events genetic alterations immunotherapies melanoma |
| url | https://www.mdpi.com/2072-6694/14/2/302 |
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