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UW Study Examines Prevalence of Non-Founder BRCA1, BRCA2, Other Mutations in Breast Cancer

NEW YORK (GenomeWeb) – A portion of women of Jewish ancestry who develop breast cancer have disease-predisposing variants that are not the BRCA1 or BRCA2 founder alleles, according to a new study. This has led the University of Washington's Mary-Claire King and her colleagues to suggest that all women undergo more comprehensive genetic screening.

Three BRCA1 and BRCA2 gene variants can greatly increase a woman's risk of developing breast cancer and these variants are more common among women of Ashkenazi Jewish ancestry. However, these three mutations only account for about 10 percent of invasive breast cancers among Ashkenazi Jewish women, the researchers noted.

In a new study, King and her colleagues examined 23 known and candidate breast cancer risk genes in a cohort of more than 1,000 women of Ashkenazi Jewish ancestry who had developed breast cancer. As they reported in JAMA Oncology today, the researchers found that of the 142 women with a disease-predisposing variant, 74 percent harbored a BRCA1 or BRCA2 founder mutation, five percent had a different BRCA1 or BRCA2 mutation, and 22 percent had a variant in another gene altogether. This suggested to King and her colleagues that Ashkenazi Jewish women might benefit from broader genetic screening.

"Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer," the researchers wrote in their paper.

For this study, the researchers conducted gene panel testing on 1,007 women from the New York Breast Cancer Study Cohort. All of the women identified themselves and all four of their grandparents as Ashkenazi Jewish and each woman had been diagnosed with invasive breast cancer.

Using a specialized version of the BROCA gene panel test developed by UW researchers, they targeted 23 established and candidate breast cancer genes including BRCA1, BRCA2, CHEK1, CHEK2, and TP53, among others, for sequencing.

Most of the women in the cohort — 903 women — did not harbor any of the three BRCA1 or BRCA2 founder mutations. Instead, 0.8 percent of them had a different pathogenic BRCA1 or BRCA2 mutation and 3.4 percent had a damaging mutation in another breast cancer gene.

Of the seven non-founder BRCA1 or BRCA2 mutations uncovered, one had not been reported before — indicating it might be a private mutation — and the six others had been reported as rare alleles among non-Jewish populations.

For the 32 women with a damaging mutation in a non-BRCA gene, 29 of these alterations were in CHEK2 and 24 of those were CHEK2 p.S428F, which has also been identified as an Ashkenazi Jewish founder allele that increases breast cancer risk by two- to three-fold. Other altered genes were BRIP1 and NBN.

Based on this, King and her colleagues estimated that an Ashkenazi Jewish woman with cancer who tests negative for a BRCA1 or BRCA2 founder mutation has about a 1 percent chance of harboring a different damaging BRCA1 or BRCA2 mutation. Additionally, the chance that she might have a damaging mutation in CHEK 2 or other moderate penetrance gene is some 3 percent to 4 percent. This risk, they noted, might fall below the threshold for considering additional testing.

One family in the study, however, illustrated to the researchers that expanded testing might be beneficial. One woman diagnosed with bilateral breast cancer was a compound heterozygote for two CHEK2 mutations. Three of her sisters had also been diagnosed with breast cancer, and each was also found to carry at least one of those CHEK 2 mutations. While the researchers noted that finding these mutations might not affect the treatment of the affected women, it would be informative for their children.

Based on their findings, King and her colleagues argued that Ashkenazi Jewish women who have not yet undergone genetic testing be offered more comprehensive testing. They further said that testing shouldn't be limited to women who've already developed breast cancer, as that would curtail prevention efforts.

Additionally, as they reported half the women in their study with BRCA1 or BRCA2 mutations — either founder or other mutations — didn't have family histories that suggested an inherited predisposition, the researchers argued that all women should receive genetic testing for breast cancer risk as part of routine medical care.

This expands upon what King called for in a 2014 JAMA editorial. At that time, she and her colleagues said that all women over the age of 30 should undergo testing for BRCA1 and BRCA2 mutations.