Elsevier

Cancer Genetics

Volume 208, Issue 9, September 2015, Pages 455-463
Cancer Genetics

Original Article
Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies

https://doi.org/10.1016/j.cancergen.2015.06.001Get rights and content

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.

Section snippets

Study strategy and approach

All methods for this meta-analysis follow the guidelines proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (22). Data was extracted by one reviewer (F.O.) and a second independent reviewer (D.M.).

To identify all the relevant publications, we used a two-stage strategy (see Figure 1). The first stage was a general approach in which we queried terms (inherited OR familial OR hereditary OR family OR young OR “early onset” OR bilateral) AND (mutation OR

Characteristics of published studies

We retrieved a total of 10,209 studies: 9,713 from the general approach (querying mutation and breast cancer) and 496 from the gene-targeted approach (querying breast cancer and one of the moderate-susceptibility genes ATM, CHEK2, BRIP1, PALB2, NBS1, or RAD50). However, only 129 unique eligible studies met our criteria for inclusion and had sufficient data available for extraction (Figure 1). We further filtered to 64 studies where the whole coding region of the gene was sequenced and excluded

Discussion

We performed a comprehensive meta-analysis on six genes that were repeatedly identified as moderate-susceptibility genes for breast cancer, focusing on high-risk breast cancer patients in case-control full gene/exon sequencing studies. Using methods based on the PRISMA guidelines, we searched for studies in a two-stage approach: general high-risk breast cancer studies and a gene-targeted approach (Figure 1). This two-stage approach resulted in a total pool of 25,418 cases and 52,322 controls

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