The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers
Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/14/3435 |
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| author | Chia-Chen Hsu Ying-Hsuan Wang Yi-Yang Chen Ying-Ju Chen Chang-Hsien Lu Yu-Ying Wu Yao-Ren Yang Hsing-Yi Tsou Chian-Pei Li Cih-En Huang Chih-Cheng Chen |
| author_facet | Chia-Chen Hsu Ying-Hsuan Wang Yi-Yang Chen Ying-Ju Chen Chang-Hsien Lu Yu-Ying Wu Yao-Ren Yang Hsing-Yi Tsou Chian-Pei Li Cih-En Huang Chih-Cheng Chen |
| author_sort | Chia-Chen Hsu |
| collection | DOAJ |
| description | Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN–SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN–SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-β and IL-23. Noteworthily, variants of <i>KRT6A</i>, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN–SC patients. Analysis through OncodriveCLUST disclosed that <i>KRT6A</i> replaces <i>JAK2</i>V617F as the more prominent disease driver in MPN–SC, whereas a major mutation in this gene (<i>KRT6A</i> c.745T>C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN–SC pathogenesis. |
| first_indexed | 2024-03-09T10:21:02Z |
| format | Article |
| id | doaj.art-31e4dc8c8fa746b9a7351b4a9e56835c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T10:21:02Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-31e4dc8c8fa746b9a7351b4a9e56835c2023-12-01T21:59:26ZengMDPI AGCancers2072-66942022-07-011414343510.3390/cancers14143435The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second CancersChia-Chen Hsu0Ying-Hsuan Wang1Yi-Yang Chen2Ying-Ju Chen3Chang-Hsien Lu4Yu-Ying Wu5Yao-Ren Yang6Hsing-Yi Tsou7Chian-Pei Li8Cih-En Huang9Chih-Cheng Chen10Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanDivision of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, TaiwanPatients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN–SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN–SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-β and IL-23. Noteworthily, variants of <i>KRT6A</i>, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN–SC patients. Analysis through OncodriveCLUST disclosed that <i>KRT6A</i> replaces <i>JAK2</i>V617F as the more prominent disease driver in MPN–SC, whereas a major mutation in this gene (<i>KRT6A</i> c.745T>C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN–SC pathogenesis.https://www.mdpi.com/2072-6694/14/14/3435myeloproliferative neoplasmssecond cancerswhole exome sequencinggenetic predispositioninflammation<i>KRT6A</i> |
| spellingShingle | Chia-Chen Hsu Ying-Hsuan Wang Yi-Yang Chen Ying-Ju Chen Chang-Hsien Lu Yu-Ying Wu Yao-Ren Yang Hsing-Yi Tsou Chian-Pei Li Cih-En Huang Chih-Cheng Chen The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers Cancers myeloproliferative neoplasms second cancers whole exome sequencing genetic predisposition inflammation <i>KRT6A</i> |
| title | The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers |
| title_full | The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers |
| title_fullStr | The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers |
| title_full_unstemmed | The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers |
| title_short | The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers |
| title_sort | genomic landscape in philadelphia negative myeloproliferative neoplasm patients with second cancers |
| topic | myeloproliferative neoplasms second cancers whole exome sequencing genetic predisposition inflammation <i>KRT6A</i> |
| url | https://www.mdpi.com/2072-6694/14/14/3435 |
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