title: Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma.
abstract: Checkpoint kinase 2 gene (CHEK2) codes for an important mediator of DNA damage response pathway. Mutations in the CHEK2 gene increase the risk of several cancer types, however, their role in Hodgkin lymphoma (HL) has not been studied so far. The most frequent CHEK2 alterations (including c.470T>C; p.I157T) cluster into the forkhead-associated (FHA) domain-coding region of the CHEK2 gene. We performed mutation analysis of the CHEK2 gene segment coding for FHA domain using denaturing high-performance liquid chromatography in 298 HL patients and analyzed the impact of characterized CHEK2 gene variants on the risk of HL development and progression-free survival (PFS). The overall frequency of CHEK2 alterations was significantly higher in HL patients (17/298; 5.7%) compared to the previously analyzed non-cancer controls (19/683; 2.8%; p= 0.04). Presence of any alteration within the analyzed region of the CHEK2 gene was associated with increased risk of HL development (OR = 2.11; 95% CI = 1.08 - 4.13; p= 0.04). The most frequent I157T mutation was found in 4.0% of HL patients and 2.5% of controls (p = 0.22), however, the frequency of 5 other alterations (excluding I157T) was significantly higher in HL cases and associated with increased risk of HL development (OR = 5.81; 95% CI = 1.12 - 30.12; p= 0.03). PFS in HL patients did not differ between CHEK2 mutation carriers and non-carriers. The predominant I157T mutation together with other alterations in its proximity represent moderate genetic predisposition factor increasing the risk of HL development.
authors: Department of Medicine--Department of Hematology, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors: O
authors: O
authors: Havranek
authors: M
authors: M
authors: Spacek
authors: P
authors: P
authors: Hubacek
authors: H
authors: H
authors: Mocikova
authors: J
authors: J
authors: Markova
authors: M
authors: M
authors: Trneny
authors: Z
authors: Z
authors: Kleibl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064447:Checkpoint Kinase 2; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015996:Survival Rate; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases