Several “moderate-risk breast cancer susceptibility genes” have been conclusively
identified. Pathogenic mutations in these genes are thought to cause a two to fivefold
increased risk of breast cancer. In light of the current development and use of multigene
panel testing, the authors wanted to systematically obtain robust estimates of the
cancer risk associated with loss-of-function mutations within these genes. An electronic
search was conducted to identify studies that sequenced the full coding regions of
ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that
sequenced the germline DNA in both high-risk cases and geographically matched controls.
A meta-analysis was then performed on protein-truncating variants (PTVs) identified
in the studies for an association with breast cancer risk. A total of 10,209 publications
were identified, of which 64 studies comprising a total of 25,418 cases and 52,322
controls in the 6 interrogated genes were eligible under our selection criteria. The
pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally,
mutations in these genes have shown geographic and ethnic variation. This comprehensive
study emphasizes the fact that caution should be taken when identifying certain genes
as moderate susceptibility with the lack of sufficient data, especially with regard
to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies,
are warranted.
Keywords
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Article info
Publication history
Published online: June 13, 2015
Accepted:
June 3,
2015
Received in revised form:
June 2,
2015
Received:
December 5,
2014
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
