CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer.
OBJECTIVE
The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk.


METHODS
CHEK2 1100delC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease.


RESULTS
None of the FAP/FAP-related cases carried the CHEK2 1100delC variant. In contrast, CHEK2 1100delC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P = 0.002). Nine of the 10 CHEK2 1100delC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 1100delC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21 cases with other tumor types.


CONCLUSIONS
Our analysis provides strong evidence that the 1100delC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.
Wasielewski
Marijke
M
Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
Vasen
Hans
H
Wijnen
Juul
J
Hooning
Maartje
M
Dooijes
Dennis
D
Tops
Carli
C
Klijn
Jan G M
JG
Meijers-Heijboer
Hanne
H
Schutte
Mieke
M
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases