An international collaborative research paper published last week in Nature Genetics has identified several new genes associated with breast cancer in women, in the largest study of its kind to date.
These findings could be instrumental in improving the performance of future genetic testing of the disease.
New Genes, Hidden Impact
There are several known genes associated with breast cancer risk: ATM, BARD1, BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, PALB2 and TP53. However, together these account for less than 50% of familial relative risk.
Researchers from the University of Cambridge and Université Laval, Quebec, joined together to identify the remaining 50% by investigating the contribution of rare coding variants to breast cancer risk. Two main categories of variants were investigated: protein truncating variants (PTVs) and rare missense variants.
Data from three large whole-exome sequencing (WES) studies were analysed, including 26,368 female cases and 217,673 female controls of majority European ancestry.
The Tip of the Iceberg
PTV meta-analysis identified 30 genes associated with breast cancer incidence, 28 of which correspond to a higher risk of the disease – much higher than the expected value of ~15. Six genes met exome-wide significance, five of which are already associated with breast cancer risk (ATM, BRCA1, BRCA2, CHEK2, PALB2) and one novel (MAP3K1).
Rare missense variant meta-analysis revealed 28 associated genes, 18 of which correspond to a higher risk of breast cancer, in comparison to ~14 expected by chance. However, no novel genes were found.
Analyses combining PTVs and rare missense variants identified significant associations in four further novel genes: ATRIP, BARD1, CDKN2A and LZTR1. These genes have already been flagged as potential tumour suppressors.
Figure 1 | P-values from the meta-analysis assessing the association between protein truncating variant carriers and breast cancer risk. The X-axis shows the expected P-values, and the Y-axis shows the observed P-values. All highlighted genes have P < 0.0005 and are associated with an increased risk of breast cancer. Adapted from Wilcox et al., 2023.
Further Testing Needed
Heritability analyses suggest that five genes are responsible for most of the contribution of PTVs to breast cancer incidence: BRCA1, BRCA2, ATM, CHEK2 and PALB2. These are already known and tested in a clinical setting. However, the study found many more positive associations than expected. It is likely that the actual number of positive associations, and therefore genes contributing to breast cancer incidence, is much higher. Heritability analyses suggest the number could be in the order of 90!
The estimated risk of some of the new genes, MAP3K1 particularly, would be high enough for clinical relevance but could be over-estimated due to the ‘winner’s curse’. Winner’s curse is a term borrowed from auction theory, where winning bids tend to exceed the item’s actual value. In research, winner’s curse is used to refer to regression toward the mean phenomenon, where the first study to report a significant result is likely to overestimate its significance compared to subsequent replicant studies.
Further replication is needed in larger and more diverse datasets to confirm the findings, as well as indicate whether it is representative of ancestries besides European. Additionally, the study acknowledges that factors not yet understood are likely to be found in the non-coding genome.
“We need additional data to determine more precisely the risks of cancer associated with variants in these genes, to study the characteristics of the tumours, and to understand how these genetic effects combine with other lifestyle factors affecting breast cancer risks,” commented Professor Easton, co-author of the study.