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

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations
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.
1061-4036
55-59
Meijers-Heijboer, Hanne
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Van den, Ans
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Klijn, Jan
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Wasielewski, Marijke
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De Snoo, Anja
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Oldenburg, Rogier
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Hollestelle, Antoinette
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Houben, Mark
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Crepin, Ellen
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Van Veghel-Plandsoen, Monique
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Elstrodt, Fons
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Van Duijn, Cornelia
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Bartels, Carina
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Meijers, Carel
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Schutte, Mieke
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McGuffog, Lesley
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Thompson, Deborah
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Easton, Douglas F.
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Sodha, Nayanta
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Seal, Sheila
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Barfoot, Rita
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Mangion, Jon
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Chang-Claude, Jenny
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Eccles, Diana
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Eeles, Rosalind
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Evans, D. Gareth
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Houlston, Richard
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Murday, Victoria
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Narod, Steven
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Phelan, Catherine
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Zhang, Hong Xiang
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Szabo, Csilla
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Devilee, Peter
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Goldgar, David
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Futreal, P. Andrew
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Nathanson, Katherine L.
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Weber, Barbara L.
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Rahman, Nazneen
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Stratton, Michael R.
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Meijers-Heijboer, Hanne
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Van den, Ans
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Klijn, Jan
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Wasielewski, Marijke
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De Snoo, Anja
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Oldenburg, Rogier
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Hollestelle, Antoinette
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Houben, Mark
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Crepin, Ellen
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Van Veghel-Plandsoen, Monique
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Elstrodt, Fons
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Van Duijn, Cornelia
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Meijers, Carel
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Schutte, Mieke
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McGuffog, Lesley
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Thompson, Deborah
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Easton, Douglas F.
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Seal, Sheila
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Barfoot, Rita
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Mangion, Jon
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Chang-Claude, Jenny
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Eccles, Diana
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Eeles, Rosalind
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Evans, D. Gareth
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Houlston, Richard
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Murday, Victoria
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Narod, Steven
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Peretz, Tamara
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Peto, Julian
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Phelan, Catherine
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Zhang, Hong Xiang
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Szabo, Csilla
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Devilee, Peter
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Goldgar, David
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Futreal, P. Andrew
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Nathanson, Katherine L.
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Weber, Barbara L.
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Rahman, Nazneen
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Stratton, Michael R.
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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).

Record type: Article

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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Published date: 2002

Identifiers

Local EPrints ID: 26478
URI: http://eprints.soton.ac.uk/id/eprint/26478
ISSN: 1061-4036
PURE UUID: 22637026-09f3-4237-abaf-93dc716e068d

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Date deposited: 24 Apr 2006
Last modified: 15 Jul 2019 19:14

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Contributors

Author: Hanne Meijers-Heijboer
Author: Ans Van den
Author: Jan Klijn
Author: Marijke Wasielewski
Author: Anja De Snoo
Author: Rogier Oldenburg
Author: Antoinette Hollestelle
Author: Mark Houben
Author: Ellen Crepin
Author: Monique Van Veghel-Plandsoen
Author: Fons Elstrodt
Author: Cornelia Van Duijn
Author: Carina Bartels
Author: Carel Meijers
Author: Mieke Schutte
Author: Lesley McGuffog
Author: Deborah Thompson
Author: Douglas F. Easton
Author: Nayanta Sodha
Author: Sheila Seal
Author: Rita Barfoot
Author: Jon Mangion
Author: Jenny Chang-Claude
Author: Diana Eccles
Author: Rosalind Eeles
Author: D. Gareth Evans
Author: Richard Houlston
Author: Victoria Murday
Author: Steven Narod
Author: Tamara Peretz
Author: Julian Peto
Author: Catherine Phelan
Author: Hong Xiang Zhang
Author: Csilla Szabo
Author: Peter Devilee
Author: David Goldgar
Author: P. Andrew Futreal
Author: Katherine L. Nathanson
Author: Barbara L. Weber
Author: Nazneen Rahman
Author: Michael R. Stratton

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