Perspectives on the increased risk of second cancer in patients with essential thrombocythemia, polycythemia vera and myelofibrosis

In recent years, several studies have evidenced that the Philadelphia-negative myeloproliferative neoplasms – essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) – are associated with an increased risk of chronic inflammatory diseases, autoimmune diseases, and second cancers as well (1, 2). Furthermore, most recently it has been hypothesized that chronic inflammation may be a trigger and driver of premature atherosclerosis, clonal evolution, and second cancer in patients with MPNs (3). In this perspective, the MPNs have also been described as ‘A Human Inflammation Model for Cancer Development’ (4), as the MPNs per se generate inflammatory products, which in a self-perpetuating vicious circle may facilitate clonal evolution (3–5). Considering the above and the general contention that chronic inflammation may be a major contributing factor for cancer development and progression (6, 7) the reports on an increased risk of second cancer in patients with MPNs are only supportive of a link between chronic inflammation and the development of cancer in patients with MPNs as well (3–5). Previous studies on the risk of second cancer in MPNs have assessed the cancer risk after the MPN diagnosis (2). In this issue of European Journal of Haematology, Pettersson and collegues provide highly important novel information on the risk of second cancer in patients with MPNs (8). The authors report a large epidemiological study, covering a 3-yr period prior to the MPN diagnosis, including 2213 patients with ET, PV, and PMF. Prior to the MPN diagnosis, this study has shown an increased number of MPN patients with cancer as compared to the general population. The observation of an increased risk of cancer in patients with MPN prior to the MPN diagnosis raises several important questions in regard to causality and topics for future research. Firstly, it is intriguing to consider the possibility that a large proportion of patients with a diagnosis of MPN may actually have carried the disease for several years (5-10-15 yr? ) before the MPN diagnosis. Conceiving a long pre-MPN diagnosis phase to exist – a notion, which is supported by a most recent study, showing that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population (9) – the increased risk of second cancer even prior to the MPN diagnosis might be explained by an impaired ‘tumor immune surveillance’ (3) consequent to a steady expansion of the MPN clone giving rise to a low-grade chronic inflammatory state and immune deregulation (10–12) with elevated levels of several inflammatory cytokines, which have most recently reviewed (5). A persistent but steadily increasing chronic inflammation drive in the pre-MPN diagnosis phase, being subsequently perpetuated by the MPN clone per se (3–5), may constitute the ‘fertile ground’ for mutagenesis and MPN evolution (4). In the context of an inflammation-mediated defective ‘tumor immune surveillance’ in MPNs, the release of the immunosuppressive cytokines vascular endothelial growth factor (VEGF) and transforming growth factor (TGFbeta) may be of particular importance for the increased risk of cancer development, both cytokines inducing qualitative and quantitative alterations in immune cells of utmost importance for intact tumor immune surveillance (e.g., dendritic cells, cytotoxic T cells, regulatory T cells, and NK cells) (3– 5). Secondly, the JAK2V617F mutation has been shown to induce accumulation of reactive oxygen species (ROS) in haematopoietic stem cells (13), which is associated with genomic instability and accordingly a risk of clonal evolution. This propensity may not only imply clonal MPN expansion but also – in general – an increased risk of any cancer, which associates with the JAK2V617F mutation in the general population (14). Thirdly, the MPNs and the systemic inflammatory response that they arise may facilitate the evolution of cancers at other sites. Thus, tumors have been shown to induce complex DNA damage in distant tissues in vivo (15). In this study, it was demonstrated that the presence of a tumor may induce a chronic inflammatory response, leading to increased systemic levels of DNA damage (15). Being ‘systemic cancers’ of the bone marrow and the blood, this propensity may be even more pronounced in patients with MPNs. Of note, considering that both TGFbeta and ROS are elevated in MPNs and both are capable of inducing oxidative DNA lesions, potentially also at ‘distant sites’, one may speculate whether the MPNs – by eliciting a perpetuating and persistent level of systemic inflammation – are associated with an increased cancer risk due to these inflammation-mediated mechanisms as well. Fourthly, Correspondence Hans Carl Hasselbalch, Department of Hematology,