title: The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms.
abstract: BACKGROUND
  Myeloproliferative neoplasms constitute a group of diverse chronic myeloid malignancies that share pathogenic features such as acquired mutations in the JAK2, TET2, CBL and MPL genes. There are recent reports that a JAK2 gene haplotype (GGCC or 46/1) confers susceptibility to JAK2 mutation-positive myeloproliferative neoplasms. The aim of this study was to examine the role of the JAK2 GGCC haplotype and germline mutations of TET2, CBL and MPL in familial myeloproliferative neoplasms.
  
  
  METHODS
  We investigated patients with familial (n=88) or sporadic (n=684) myeloproliferative neoplasms, and a control population (n=203) from the same demographic area in Italy. Association analysis was performed using tagged single nucleotide polymorphisms (rs10974944 and rs12343867) of the JAK2 haplotype. Sequence analysis of TET2, CBL and MPL was conducted in the 88 patients with familial myeloproliferative neoplasms.
  
  
  RESULTS
  Association analysis revealed no difference in haplotype frequency between familial and sporadic cases of myeloproliferative neoplasms (P=0.6529). No germline mutations in TET2, CBL or MPL that segregate with the disease phenotype were identified. As we observed variability in somatic mutations in the affected members of a pedigree with myeloproliferative neoplasms, we postulated that somatic mutagenesis is increased in familial myeloproliferative neoplasms. Accordingly, we compared the incidence of malignant disorders between sporadic and familial patients. Although the overall incidence of malignant disorders did not differ significantly between cases of familial and sporadic myeloproliferative neoplasms, malignancies were more frequent in patients with familial disease aged between 50 to 70 years (P=0.0198) than in patients in the same age range with sporadic myeloproliferative neoplasms.
  
  
  CONCLUSIONS
  We conclude that the JAK2 GGCC haplotype and germline mutations of TET2, CBL or MPL do not explain familial clustering of myeloproliferative neoplasms. As we observed an increased frequency of malignant disorders in patients with familial myeloproliferative neoplasms, we hypothesize that the germline genetic lesions that underlie familial clustering of myeloproliferative neoplasms predispose to somatic mutagenesis that is not restricted to myeloid hematopoietic cells but cause an increase in overall carcinogenesis.
authors.affiliation: Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 14, AKH BT25.3, 1090 Vienna, Austria.
authors.forename: Damla
authors.initials: D
authors.lastname: Olcaydu
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Ashot
authors.initials: A
authors.lastname: Harutyunyan
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pascutto
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Roland
authors.initials: R
authors.lastname: Jäger
authors.forename: Emma
authors.initials: E
authors.lastname: Hammond
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007558:Italy; D053614:Janus Kinase 2 / Q000097:blood / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000097:blood / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000097:blood / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000097:blood / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D053614:Janus Kinase 2