6 research outputs found
The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype
Because of genetic heterogeneity, the identification of breast
cancer-susceptibility genes has proven to be exceedingly difficult. Here,
we define a new subset of families with breast cancer characterized by the
presence of colorectal cancer cases. The 1100delC variant of the cell
cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with
hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380
families with non-HBCC (P<.001), thus providing genetic evidence for the
HBCC phenotype. The CHEK2 1100delC mutation was, however, not the major
predisposing factor for the HBCC phenotype but appeared to act in synergy
with another, as-yet-unknown susceptibility gene(s). The unequivocal
definition of the HBCC phenotype opens new avenues to search for thi
The CHEK2 1100delC Mutation Identifies Families with a Hereditary Breast and Colorectal Cancer Phenotype
Because of genetic heterogeneity, the identification of breast cancerâsusceptibility genes has proven to be exceedingly difficult. Here, we define a new subset of families with breast cancer characterized by the presence of colorectal cancer cases. The 1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380 families with non-HBCC (P<.001), thus providing genetic evidence for the HBCC phenotype. The CHEK2 1100delC mutation was, however, not the major predisposing factor for the HBCC phenotype but appeared to act in synergy with another, as-yet-unknown susceptibility gene(s). The unequivocal definition of the HBCC phenotype opens new avenues to search for this putative HBCC-susceptibility gene
Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations
Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer1, but account for only a small fraction of breast cancer susceptibility1, 2. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2 *1100delC, a truncating variant that abrogates the kinase activity6, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2 *1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway