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Breast, ovarian cancer risks vary by BRCA mutation location, type
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The risks for breast and ovarian cancers varied based on the type and location of BRCA1 and BRCA2 mutations, according to the results of an observational study.
Women with BRCA1 and BRCA2 mutations have elevated risks for breast and ovarian cancers; however, the relationship between specific mutations and level of risk was undetermined, according to study background.
Timothy R. Rebbeck, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and colleagues evaluated data from 19,581 women who harbored BRCA1 mutations and 11,900 women who harbored BRCA2 mutations from 33 countries. A majority (92%-93%) of women in both groups were white.
Women who carried both a BRCA1 and BRCA2 mutation (n = 84) were excluded.
Among women with a BRCA1 mutation, 46% (n = 9,052) were diagnosed with breast cancer and 12% (n = 2,317) were diagnosed with ovarian cancer. Five percent (n = 1,041) of these women were diagnosed with breast and ovarian cancer, and 37% (n = 7,171) were cancer-free.
More than half (52%; n = 6,180) of women with a BRCA2 mutation were diagnosed with breast cancer, 6% (n = 682) were diagnosed with ovarian cancer and 2% (n=272) were diagnosed with both. Forty percent (n = 4,766) of these women did not have cancer.
The mean age of women at the time of a breast cancer diagnosis was 39.9 years in women with a BRCA1 mutation and 42.8 years in BRCA2 carriers. For women with ovarian cancer diagnoses, the mean age at the time of diagnosis was 50 years for BRCA1 carriers and 54.5 years for BRCA2 carriers.
Researchers estimated the ratio of breast vs. ovarian cancer HRs (RHR) for mutation type, function and nucleotide position. An RHR greater than 1 was associated with an increased risk for breast cancer, whereas a value less than 1 was associated with an elevated risk for ovarian cancer.
The researchers located three breast cancer cluster regions for BRCA1 carriers. The regions were located at c.179 to c.505 (RHR = 1.46; 95% CI, 1.22-1.74), c.4328 to c.4945 (RHR = 1.34; 95% CI, 1.01-1.78) and c.5261 to c.5563 (RHR = 1.38; 95% CI, 1.22-1.55). Researchers identified an ovarian cancer cluster for BRCA1 from c.1380 to c.4062 (RHR = 0.62; 95% CI, 0.56-0.7).
BRCA2 carriers displayed multiple breast cancer cluster regions. The regions spanned from c.1 to c.596 (RHR = 1.71; 95% CI, 1.06-2.78), c.772 to c.1806 (RHR = 1.63; 95% CI, 1.1-2.4) and c.7394 to c.8904 (RHR = 2.31; 95% CI, 1.69-3.16). Researchers observed BRCA2 ovarian cancer cluster regions from c.3249 to c.5681 and adjacent to c.5946delT (RHR = 0.51; 95% CI, 0.44-0.6) and from c.6645 to c.7471 (RHR = 0.57; 95% CI, 0.41-0.8).
Researchers also noted that mutations with nonsense-mediated decay were linked to differential breast or ovarian cancer risks as well as a younger age of breast cancer diagnosis for women with BRCA1 or BRCA2 mutations.
The researchers acknowledged these data may be limited by their inability to investigate certain mutation and risk groups with statistical power. The study results also represent women tested for BRCA mutations rather than the general population.
“This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations,” Rebbeck and colleagues wrote. “Pending additional mechanistic insights into the observed associations, knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers, but further systemic studies will be required to determine the absolute cancer risks associated with different mutations. It is yet to be determined what level of absolute risk change will influence decision making among carriers of BRCA1/2 mutations. Additional research will be required to better understand what level of risk difference will change decision making and standard of care, such as preventive surgery, for carriers of BRCA1 and BRCA2 mutations.” – by Cameron Kelsall
Disclosure: Rebbeck reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
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