According to results from a recent study published in the November 27, 2013 online edition of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, women who are members of families with BRCA2 mutations but who test negative for the family-specific BRCA2 mutations are still at greater risk for developing breast cancer compared with women in the general population.[1]
Women with certain mutations in their BRCA1 or BRCA2 genes are at increased risk for breast cancer and ovarian cancer. There is also a potential increased risks of several other types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25% of hereditary breast cancers [2] and about 5 to 10% of all breast cancers. [3] In addition, mutations in BRCA1 and BRCA2 account for around 15% of ovarian cancers overall. [4] Breast cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than sporadic breast cancers. However, if a woman who comes from a BRCA family tests negative for her family-specific BRCA mutation, her risk for breast cancer is considered to be the same as someone in the general population, according to the National Cancer Institute. The results of this study, however, suggests that this may not always be true.
We… found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors…
Other genetic factors
“We found that women who test negative for family-specific BRCA2 mutations have more than four times the risk for developing breast cancer than the general population,” said Gareth R. Evans, M.B.B.S., M.D., M.R.C.P., F.R.C.P., honorary professor of medical genetics and cancer epidemiology at the Manchester Academic Health Science Center at the University of Manchester in the United Kingdom. “We also found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors.”
“It is likely that these women inherit genetic factors other than BRCA-related genes that increase their breast cancer risk,” he explained. “About 77 single nucleotide polymorphisms [SNPs?genetic variations that can help track the inheritance of disease genes within families] are linked to breast cancer risk. Identification of additional SNPs is necessary to understand why some of the BRCA-negative women from BRCA families are at higher risk.”
The authors of the study note that specialists should use caution when stating that a woman’s breast cancer risk is the same as that of the general population following a negative test, because it may not be true for some women who come from BRCA2 families with a strong family history.
Phenocopies
Evans and colleagues used data from the M6-Inherited Cancer in England study, which has screened families of individuals with breast and/or ovarian cancer for mutations in BRCA1 and 2 since 1996. Details on affected individuals, and all tested and untested relatives, were entered into a Filemaker Pro-7 database. From 807 BRCA families, the researchers identified 49 women who tested negative for the family-specific BRCA mutation, but subsequently developed breast cancer. The researchers called these women phenocopies.
Among the 49 phenocopies identified, 22 were among 279 women who tested negative from BRCA1 families, and 27 were among 251 women who tested negative from BRCA2 families. When the researchers stratified the phenocopies based on their age (30-39, 40-49, 50-59, and 69-80), they found that in each age range there were about twice as many cases of breast cancer as would have been expected from the general population.
Increased risk among BRCA2-negative women
After establishing the increased risk, Evans and colleagues conducted a risk analyses by calculated the so called observed versus expected ratio (O/E), a ratio of observed risk for breast cancer in BRCA-negative women from BRCA families, versus the risk expected for any woman in the general population.
The researchers found that the O/E for phenocopies from BRCA1 families was not substantially higher than that of the general population. However, the O/E for phenocopies from BRCA2 families was 4.57, leading them to conclude that the more than fourfold increased risk for breast cancer among BRCA-negative women is largely limited to BRCA-negative women from BRCA2 families.
When the researchers considered the date of predictive testing (the date on which BRCA testing was done for an individual) instead of the date of family ascertainment (the date the first family member of the individual was referred to genetic service), O/E dropped from 4.57 [95% confidence interval (CI) 2.50?7.67; P < 0.0001; O/E in BRCA1 noncarriers, 1.77] to 2.01 [relative risk (RR), 1.99; 95% CI, 0.54?5.10] Explaining the reason for this difference, Evans noted: “Because there is less follow-up in the predictive test group from time of testing and we may be unaware of breast cancers that have occurred in the near past.”
Study Impact
The researchers believe that their work may help in counseling women from BRCA1/2 families who have tested negative, and could help understanding the individual breast cancer risk of these women.
For more information:
[1] Evans DGR, Ingham SL, Buchan I, Woodward ER, Byers H, Howell A, Maher ER, Newman WG, Lalloo F. Increased Rate of Phenocopies in All Age Groups in BRCA1/BRCA2 Mutation Kindred, but Increased Prospective Breast Cancer Risk Is Confined to BRCA2 Mutation Carriers. Cancer Epidemiol Biomarkers Prev. 2013 Nov. 27; doi: 10.1158/1055-9965.EPI-13-0316-T [Article]
[2] Easton DF. How many more breast cancer predisposition genes are there? Exit Disclaimer Breast Cancer Research 1999; 1(1):14?17. [Article]
[2] Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31?42. [Article][PubMed]
[4] Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005; 104(12):2807?16. [Article][PubMed]
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