The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families.
The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.
Oldenburg
Rogier A
RA
Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
Kroeze-Jansema
Karin
K
Kraan
Jaennelle
J
Morreau
Hans
H
Klijn
Jan G M
JG
Hoogerbrugge
Nicoline
N
Ligtenberg
Marjolein J L
MJ
van Asperen
Christi J
CJ
Vasen
Hans F A
HF
Meijers
Carel
C
Meijers-Heijboer
Hanne
H
de Bock
Truuske H
TH
Cornelisse
Cees J
CJ
Devilee
Peter
P
D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2; D005260:Female; D016368:Frameshift Mutation; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases