International collaboration identifies four new breast cancer susceptibility genes

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"... Current genetic tests for breast cancer only consider a few genes, such as BRCA1, BRCA2, and PALB2. However, these only explain a minority of the genetic risk, suggesting that more genes remain to be identified.

Researchers looked at genetic changes in all genes in 26,000 women with breast cancer and 217,000 women without breast cancer. These included women from eight countries in Europe and Asia.  ...

The team found evidence for at least four new breast cancer risk genes, with suggestive evidence for many others.  ...

“Although most of the variants identified in these new genes are rare, the risks can be significant for women who carry them. For example, alterations in one of the new genes, MAP3K1, appear to give rise to a particularly high risk of breast cancer.” ..."

From the abstract:

"Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small."

International collaboration identifies new breast cancer susceptibility genes | University of Cambridge A large-scale international collaboration has identified new genes associated with breast cancer that could eventually be included in tests to identify women at increased risk of the disease.

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk (open access)

Fig. 1: Manhattan plot of z scores from the meta-analysis assessing the association between protein-truncating variant carriers within genes and breast cancer risk.