The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers

Simple Summary Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders characterized by the excessive production of differentiated myeloid cells. Other than the well-known propensity for leukemia transformation, MPN patients are also prone to developing second cancers (SCs) that arise from different embryonic dermal origins. This brings up an intriguing question: what is the molecular background leading to the development of SCs in MPN patients? To explore further, we used whole exome sequencing to characterize the genomic landscapes in 26 paired MPN samples stratified by the presence or absence of SCs. We found that mutated genes in MPN-SC samples were enriched in some critical immune-related pathways and inflammatory networks, an observation further supported by the increased plasma levels of cytokines. Our work provides the genomic landscape that profiles the genetic basis for SC tumorigenesis in MPN patients, and also demonstrates that inflammation could be indispensable in MPN-SC pathogenesis. 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-beta and IL-23. Noteworthily, variants of KRT6A, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN-SC patients. Analysis through OncodriveCLUST disclosed that KRT6A replaces JAK2V617F as the more prominent disease driver in MPN-SC, whereas a major mutation in this gene (KRT6A 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.

Automated summary

Patients with Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs) are prone to developing second cancers (SCs), which may be attributed to mutations in genes related to immune pathways and inflammatory networks, as well as increased levels of cytokines. This highlights the importance of inflammation in the pathogenesis of MPN-SC.