Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers.
Mutations in the CHEK2 gene have been associated with increased risks of breast, prostate and colon cancer. In contrast, a previous report suggests that individuals with the I157T missense variant of the CHEK2 gene might be at decreased risk of lung cancer and upper aero-digestive cancers. To confirm this hypothesis, we genotyped 895 cases of lung cancer, 430 cases of laryngeal cancer and 6391 controls from Poland for four founder alleles in the CHEK2 gene, each of which has been associated with an increased risk of cancer at several sites. The presence of a CHEK2 mutation was protective against both lung cancer [odds ratio (OR) = 0.3; 95% confidence interval (CI) 0.2-0.5; P = 3 x 10(-8)] and laryngeal cancer (OR = 0.6; 95% CI 0.3-0.99; P = 0.05). The basis of the protective effect is unknown, but may relate to the reduced viability of lung cancer cells with a CHEK2 mutation. Lung cancers frequently possess other defects in genes in the DNA damage response pathway (e.g. p53 mutations) and have a high level of genotoxic DNA damage induced by tobacco smoke. We speculate that lung cancer cells with impaired CHEK2 function undergo increased rates of cell death.
Cybulski
Cezary
C
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, ul. Połabska 4, 70-115 Szczecin, Poland. cezarycy@sci.pam.szczecin.pl
Masojc
Bartlomiej
B
Oszutowska
Dorota
D
Jaworowska
Ewa
E
Grodzki
Tomasz
T
Waloszczyk
Piotr
P
Serwatowski
Piotr
P
Pankowski
Juliusz
J
Huzarski
Tomasz
T
Byrski
Tomasz
T
Górski
Bohdan
B
Jakubowska
Anna
A
Debniak
Tadeusz
T
Wokolorczyk
Dominika
D
Gronwald
Jacek
J
Tarnowska
Czeslawa
C
Serrano-Fernández
Pablo
P
Lubinski
Jan
J
Narod
Steven A
SA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D002648:Child; D016001:Confidence Intervals; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D018703:Founder Effect; D006801:Humans; D007822:Laryngeal Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012016:Reference Values; D040242:Risk Reduction Behavior
D004273:DNA, Neoplasm; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases