ABSTRACT
A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.
Subject(s)
Genetic Predisposition to Disease/genetics , Genetic Variation , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Case-Control Studies , Checkpoint Kinase 2 , DNA Primers , Gene Frequency , Humans , Odds Ratio , Poland , Polymorphism, Restriction Fragment LengthABSTRACT
To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P = 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P = 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.
