Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Meijers-Heijboer, Hanne, Van den, Ans, Klijn, Jan, Wasielewski, Marijke, De Snoo, Anja, Oldenburg, Rogier, Hollestelle, Antoinette, Houben, Mark, Crepin, Ellen, Van Veghel-Plandsoen, Monique, Elstrodt, Fons, Van Duijn, Cornelia, Bartels, Carina, Meijers, Carel, Schutte, Mieke, McGuffog, Lesley, Thompson, Deborah, Easton, Douglas F., Sodha, Nayanta, Seal, Sheila, Barfoot, Rita, Mangion, Jon, Chang-Claude, Jenny, Eccles, Diana, Eeles, Rosalind, Evans, D. Gareth, Houlston, Richard, Murday, Victoria, Narod, Steven, Peretz, Tamara, Peto, Julian, Phelan, Catherine, Zhang, Hong Xiang, Szabo, Csilla, Devilee, Peter, Goldgar, David, Futreal, P. Andrew, Nathanson, Katherine L., Weber, Barbara L., Rahman, Nazneen and Stratton, Michael R. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genetics, 31 (1), 55-59. (doi:10.1038/ng879).

Abstract

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.

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Contributors

Author: Diana Eccles

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