medwireNews: Ashkenazi Jewish women with breast cancer may benefit from comprehensive genetic screening for all breast cancer genes, not just founder mutations in BRCA1 or BRCA2, US researchers report.
They found that around one in 25 women of Ashkenazi Jewish ancestry with breast cancer not linked to founder mutations in BRCA1 or BRCA2 carried either a different pathogenic BRCA1 or BRCA2 mutation or a pathogenic mutation in another breast cancer gene.
Of 1007 Ashkenazi Jewish women participating in the New York Breast Cancer Study who did not carry any of the three BRCA1 and BRCA2 founder alleles, seven (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, detected using a targeted multiplexed gene panel that included 23 known and candidate breast cancer genes.
A further 31 (3.4%) women carried a pathogenic mutation in another breast cancer gene: 29 in CHEK2, and one each in BRIP1 and NBN.
Among the women with CHEK2 mutations, 24 carried CHEK2 p.S428F, which the researchers say has previously been identified as an Ashkenazi Jewish founder allele that can triple breast cancer risk. Four mutations were CHEK2 c.1100delC, and one was CHEK2 c.444 (+1)G>A, both of which are common in Europe.
Mary-Claire King and colleagues from the University of Seattle in Washington, also report that 73.8% of the 142 women with an inherited predisposition to breast cancer carried a BRCA1 or BRCA2 founder mutation, 4.9% had another BRCA1 or BRCA2 mutation, and 21.8% had a mutation in another gene.
However, the researchers point out in JAMA Oncology that the likelihood of an Ashkenazi Jewish patient with breast cancer without a founder mutation in BRCA1 or BRCA2 carrying a different mutation in the genes is only around 1%, increasing to 3% if she was diagnosed before 40 years of age, a frequency which “may be below the threshold of consideration for additional testing for most patients.”
But such testing is “strongly suggested”, they believe, when “multiple cases of breast cancer in a family remain unresolved by the mutation of the proband.”
King et al also note that current US national screening guidelines recommend genetic testing for all Ashkenazi Jewish patients with breast cancer.
“This recommendation is fine, but testing women only after they develop cancer severely limits the power of precision medicine,” they remark.
“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,” the researchers conclude.
By Laura Cowen
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