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Higher Breast Cancer Risk Linked to Newly Found Mutation


REYKJAVIK, Iceland - Women with a newly discovered genetic mutation have a higher risk of developing breast cancer, perhaps more than one primary, researchers have reported.

REYKJAVIK, Iceland, June 20 ? Women who carry a newly discovered genetic mutation have a higher risk of developing breast cancer, perhaps more than one primary, researchers have reported.

The genetic mutation detected in some Icelandic women conveys on them an elevated breast cancer risk, particularly if they also carry a mutation in the previously known breast cancer susceptibility gene BRCA2, said the researchers.

The newly found genetic variant in the gene BARD1 carries with it a risk for single and multiple primary breast cancers, especially among women with the Icelandic BRCA2 mutation labeled 999del5, reported Simon N. Stacey, Ph.D., and colleagues of deCODE Genetics and National University Hospital here.

"We estimate an approximately 1.8-fold increase in risk conferred by the BARD1 variant, corresponding to a population attributable risk of about 2.5%," the investigators wrote in the July issue of the open-access online journal PLoS Medicine.

While the BARD1 mutation, labeled Cys557Ser, is not as strong a risk factor for breast cancer as BRCA1 or BRCA2 variants, the discovery provides important clues to genetic contributors to breast cancer, the authors wrote.

They investigators found that among the carriers of Cys557ser, a plurality of their ancestors came from a single county in southeast Iceland, and all carriers shared a single nucleotide polymorphism (SNP) haplotype, suggesting that origin of the excess breast cancer risk may have arisen from a single mutation in the past.

The Cys577Ser variant was also identified in three people from Utah who are of western European ancestry and were part of a population studied for comparison purposes. In contrast, the investigators did not find the variant among Asian or African populations, although other BARD1 variants have been seen in these groups, they noted.

"Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation," the investigators wrote.

Cys557Ser is a missense variant of BARD1 that was recently reported to be found more frequently among families with a history of breast cancer.

To determine the gene's penetrance, the investigators looked at a population of 1,090 Icelandic women with invasive breast cancer and 703 controls, and compared the information of a computerized genealogy of the Icelandic population to look for patterns between the presence of the Cys577Ser mutation and familial breast cancer.

They found that that Cys557Ser allele was present at a frequency of 0.028 among patients with invasive breast cancer, compared with 0.016 in controls. The odds ratio for the presence of the variant and breast cancer was 1.82, (95% confidence interval, 1.11-3.01, P=0.014).

Among women with a family history of breast cancer, early onset breast cancer, or multiple primary cancers, the allelic frequency was 0.037 (odds ratio 2.41, 95% CI 1.22-4.75, P=0.015).

Among women with the Icelandic BRCA2 999del5 mutation, the risk was higher still. The frequency of the Cys577Ser allele was 0.047 among carriers of the BRCA2 mutation who had breast cancer, translating into a more than three-fold risk for breast cancers among women who carried both mutations (odd ratio 3.11, 95% CI 1.16-8.40, P=0.046).

"This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty," the investigators wrote.

Women who had the BARD1 Cys557Ser mutation had increased risk for subsequent primary breast tumors after a first breast cancer diagnosis regardless of whether they also had the BRCA2 (999del5) mutation, they added.

The journal editor's summary discussed the clinical significance of these findings.

"Because carrying the Cys557Ser allele only slightly increases a woman's risk of breast cancer, for most women there is no clinical reason to test for this variant. Eventually, when all the low-penetrance genes that contribute to breast cancer risk have been identified, it might be helpful to screen women for the full set to determine whether they are at high risk of developing breast cancer. This will not happen for many years, however."

The editor added, "For women who carry BRCA2 999del5, the situation might be different. It might be worth testing these women for the BARD1 Cys557Ser allele, the researchers explain, because the lifetime probability of developing breast cancer in women carrying both variants might approach 100%.

"However, all these findings need to be confirmed in other groups of patients before anyone is routinely tested for the BARD1 Cys557Ser allele."

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