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Germline CHEK2*1100delC mutations in breast cancer patients with multiple primary cancers
  1. J Huang1,
  2. S M Domchek2,
  3. M S Brose2,
  4. T R Rebbeck3,
  5. K L Nathanson4,
  6. B L Weber2
  1. 1Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
  2. 2Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA, USA
  3. 3Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
  4. 4Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  1. Correspondence to:
 Dr Barbara L Weber
 Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, 514 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA;

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CHEK2 is a human homologue of yeast Cds1 and Rad53 which encodes the cell cycle checkpoint kinase. CHEK2 is activated by phosphorylation by ATM in response to double-strand DNA breaks.1,2 Activated CHEK2 in turn phosphorylates and activates p53, which triggers cell cycle arrest at G1 or apoptosis.3,4 CHEK2 also phosphorylates Cdc25C, preventing cellular entry into mitosis after DNA damage.2 Thus, CHEK2 plays an important role in the network of cell cycle regulation and DNA damage repair, which are crucial processes in preventing cancer development.

CHEK2*1100delC leads to premature termination of translation and abolishes the kinase activity of the encoded protein. Although an initial report described germline CHEK2 mutations in Li-Fraumeni syndrome (LFS),5 subsequent studies have shown that CHEK2*1100delC is a low penetrance variant conferring an increased susceptibility to breast cancer with a relative risk of 2.0, not a high penetrance allele responsible for LFS.6,7 In addition, CHEK2*1100delC also may be associated with other cancers. A recent study suggested that CHEK2*1100delC may contribute significantly to familial prostate cancer (p = 0.02).8 Another study suggests that CHEK2*1100delC is over-represented in breast cancer families with colorectal cancers (hereditary breast and colorectal cancer, HBCC) as compared with families with breast cancer only (non-HBCC).9 We previously reported that women with multiple primary cancers (breast and any other cancer) are more likely to have BRCA1 and BRCA2 mutations than matched individuals with breast cancer only.10 Here we asked whether a similar sample of women with multiple primary cancers, one of which was breast cancer, had an excess of CHEK2*1100delC compared to controls. Thus, we examined the frequency of CHEK2*1100delC in constitutional DNA from 161 women with multiple primary cancers (one primary was always breast cancer) as compared to a matched …

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  • This work was supported by grants from the Breast Cancer Research Foundation to BLW.

  • Conflict of interest: none declared.