In the biggest study of its type to date, conducted by researchers from around the world, numerous novel genes related to breast cancer in women were discovered and published in Nature Genetics. These results may be crucial in enhancing the accuracy of genetic testing for illness in the future.
ATM, BARD1, BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, PALB2, and TP53 are genes known to raise the risk of breast cancer. But together, these don’t make up more than half of the relative risk in a family.
Researchers from the University of Cambridge and the Université Laval in Quebec, Canada, worked together to find the other 50 percent by looking into how rare coding variants affect the risk of breast cancer. Protein truncating variants (PTVs) and rare missense variants (RMVs) were the two main types of variants that were looked into.
The results of three large whole-exome sequencing (WES) studies were examined. These studies included 26,368 female cases and 217,673 female controls who were mostly of European descent.
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In a PTV meta-analysis, 30 genes were linked to the risk of breast cancer. There are 28 of them that have been linked to a higher chance of getting the disease. This is much more than the number of 15 that was expected. So far, five of these six genes—ATM, BRCA1, BRCA2, CHEK2, and PALB2—have been linked to an increased risk of breast cancer. A brand-new gene 6 has been found (MAP3K1).
In this meta-analysis of rare missense mutations, 18 of the 28 genes found were linked to a higher risk of breast cancer. This is more likely than a chance of 14 genes. But there were no new genes found.
When PTVs and rare missense variants were looked at together, more strong associations were found in ATRIP, BARD1, CDKN2A, and LZTR1 genes. These genes have been chosen as possible ways to prevent cancer.
Heritability studies show that most of the effect of PTVs on breast cancer is due to five genes: BRCA1, BRCA2, ATM, CHEK2, and PALB2. These are already known and have been tried out in the clinic.
But the study found a lot more positive connections than anyone thought. The number of genes that cause breast cancer is likely much higher than those with positive associations. Analyses of heritability suggest that the number could be around 90!
Some of the new genes, especially MAP3K1, would have risk estimates that are high enough to be clinically important, but these estimates could be too high because of the “winner’s curse.”
The term “winner’s curse” comes from auction theory, where winning bids tend to be higher than what the item is actually worth. In research, the term “winner’s curse” refers to the phenomenon of “regression toward the mean,” in which the first study to report a significant result is likely to overestimate how important it is compared to subsequent studies that find the same result.
More research with bigger and more varied data sets is needed to confirm the results and find out if they are true for ancestries other than Europeans. The study also says that there are likely things in the non-coding genome that we don’t understand yet.
Professor Easton, a co-author of the study, said, “We need more information to figure out more precisely how these gene changes affect cancer risk, to study the characteristics of the tumors, and to figure out how these genetic effects combine with other lifestyle factors to affect breast cancer risk.”
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