(original) (raw)

TY - JOUR AU - Meijers-Heijboer, Hanne AU - van den Ouweland, Ans AU - Klijn, Jan AU - Wasielewski, Marijke AU - de Snoo, Anja AU - Oldenburg, Rogier AU - Hollestelle, Antoinette AU - Houben, Mark AU - Crepin, Ellen AU - van Veghel-Plandsoen, Monique AU - Elstrodt, Fons AU - van Duijn, Cornelia AU - Bartels, Carina AU - Meijers, Carel AU - Schutte, Mieke AU - McGuffog, Lesley AU - Thompson, Deborah AU - Easton, Douglas F. AU - Sodha, Nayanta AU - Seal, Sheila AU - Barfoot, Rita AU - Mangion, Jon AU - Chang-Claude, Jenny AU - Eccles, Diana AU - Eeles, Rosalind AU - Evans, D Gareth AU - Houlston, Richard AU - Murday, Victoria AU - Narod, Steven AU - Peretz, Tamara AU - Peto, Julian AU - Phelan, Catherine AU - Zhang, Hong Xiang AU - Szabo, Csilla AU - Devilee, Peter AU - Goldgar, David AU - Futreal, P Andrew AU - Nathanson, Katherine L. AU - Weber, Barbara L. AU - Rahman, Nazneen AU - Stratton, Michael R. AU - The CHEK2-Breast Cancer Consortium AU - Group A AU - Group B AU - Group C PY - 2002 DA - 2002/05/01 TI - Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations JO - Nature Genetics SP - 55 EP - 59 VL - 31 IS - 1 AB - 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. SN - 1546-1718 UR - https://doi.org/10.1038/ng879 DO - 10.1038/ng879 ID - Meijers-Heijboer2002 ER -