Should We Be Testing Beyond BRCA1/2 in Women of Ashkenazi Jewish Heritage with Breast Cancer?
BACKGROUND AND PURPOSE:
In the Ashkenazi Jewish population, there are 3 ancient founder mutations that occur with high frequency
BRCA1: 185delAG and 5382insC
There is limited data beyond these 3 founder mutations
Walsh et al. (JAMA Oncology 2017) sought to determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among Ashkenazi Jewish with breast cancer
Prospective cohort study
Data derived from the New York Breast Cancer Study (NYBCS)
First diagnosis of invasive breast cancer
All 4 grandparents identified as Ashkenazi Jewish
DNA testing at the time of the original study focused on the 3 founder mutations
Current study sequenced 23 known candidate breast cancer genes
1007 probands were included in the study, 903 of which had no founder mutations
0.8% of these probands carried another pathogenic mutation in BRCA1 or BRCA2
3.4% of these probands carried a pathogenic mutation in another breast cancer gene
29 in CHEK2
Overall, there were 142/1007 (14.1%) women who had a significant germline mutation in the overall cohort and of those
73.8% were due to a BRCA1 or BRCA2 founder mutation
4.9% were due to another BRCA1 or BRCA2 mutation
21.8% of mutations occurred in a non-BRCA gene
Of women with BRCA1 or BRCA2 mutations, 51.4% had a mother or sister with breast/ovarian cancer history while the remainder did not have family history
Based on the above data, in women with of Ashkenazi Jewish background who have breast cancer, approximately 50% of women with pathogenic causative variants did not have a family history of breast cancer
Current guidelines recommend that a woman with breast cancer and of Ashkenazi Jewish heritage should have genetic testing
Due to the finding of a significant number of pathogenic mutations beyond the founder mutations, the authors recommend that in this cohort, breast cancer genetic testing should include a larger panel of genes and not be limited to BRCA genes
In addition, preventative options are now available, and the authors state
To discover a mutation only after cancer is diagnosed is a missed opportunity to have prevented that cancer. Many of these cancers could be prevented by offering genetic testing as described here to all women before they develop breast cancer, as part of routine medical care.
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