Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.
The checkpoint kinase 2 gene (CHEK2) codes for the CHK2 protein, an important mediator of the DNA damage response pathway. The CHEK2 gene has been recognized as a multi-cancer susceptibility gene; however, its role in non-Hodgkin lymphoma (NHL) remains unclear. We performed mutation analysis of the entire CHEK2 coding sequence in 340 NHL patients using denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Identified hereditary variants were genotyped in 445 non-cancer controls. The influence of CHEK2 variants on disease risk was statistically evaluated. Identified CHEK2 germline variants included four truncating mutations (found in five patients and no control; P = 0.02) and nine missense variants (found in 21 patients and 12 controls; P = 0.02). Carriers of non-synonymous variants had an increased risk of NHL development [odds ratio (OR) 2.86; 95% confidence interval (CI) 1.42-5.79] and an unfavorable prognosis [hazard ratio (HR) of progression-free survival (PFS) 2.1; 95% CI 1.12-4.05]. In contrast, the most frequent intronic variant c.319+43dupA (identified in 22% of patients and 31% of controls) was associated with a decreased NHL risk (OR = 0.62; 95% CI 0.45-0.86), but its positive prognostic effect was limited to NHL patients with diffuse large B-cell lymphoma (DLBCL) treated by conventional chemotherapy without rituximab (HR-PFS 0.4; 94% CI 0.17-0.74). Our results show that germ-line CHEK2 mutations affecting protein coding sequence confer a moderately-increased risk of NHL, they are associated with an unfavorable NHL prognosis, and they may represent a valuable predictive biomarker for patients with DLBCL.
First Department of Medicine-Department of Hematology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Ondrej
O
Havranek
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Petra
P
Kleiblova
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Jan
J
Hojny
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Filip
F
Lhota
Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic.
Pavel
P
Soucek
First Department of Medicine-Department of Hematology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Marek
M
Trneny
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Zdenek
Z
Kleibl
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005854:Germ Cells; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human