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Genome Medicine 2009
Germline and somatic JAK2 mutations and susceptibility to chronic myeloproliferative neoplasmsDOI: 10.1186/gm55 Abstract: Although many cancers show familial clustering, identification of the predisposing germline genes is challenging. Mutations in genes such as p53, BRCA1, CDKN2 and HNPCC causing high risk of tumors (often at an early age) were discovered from studies of rare families with striking tumor clusters [1]. However, these mutations explain only a small fraction of cancer susceptibility in the general population. More common cancers among older individuals also show familial aggregation and are probably the result of a combination of germline genes and environmental or other factors. The attempt to identify common susceptibility genes with smaller effects has been facilitated by the ability to conduct large-scale genome-wide association studies in cases and controls.Somatic changes found in tumors may also be a result of germline susceptibility genes in the same region. Three recent articles in Nature Genetics [2-4] successfully demonstrate the potential of this approach by identifying a gene involved in susceptibility to developing chronic myeloproliferative neoplasms (MPNs) that is likely to have both germline and somatic effects. It is useful to review the recent history around this discovery and determine the lessons learned that could be applied to other cancers.On the basis of the current World Health Organization criteria, MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (MF) [5]. They are all stem-cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction because of acquired somatic mutations [6]. They are uncommon tumors with yearly incident rates of 2.3 in 100,000 in the United States [7] and primarily affect older adults, with a variable clinical presentation. For example, approximately half of all MPN patients are reported to be asymptomatic at diagnosis [5,8]. Among PV and ET patients, the major symptoms are associated with hyper
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