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Major Genes

continued...

Although hereditary breast and ovarian cancer is characterized by early age at onset, a cross-sectional study of BRCA1/BRCA2 carriers in the Netherlands found the persistence of new diagnoses of breast and ovarian cancer after age 60 years.[121]

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/BRCA2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors. Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk.[56,103,122,123,124,125,126,127] (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors.[128,129,130,131,132,133] A large population-based family study found that the risk of breast cancer for relatives of probands with deleterious BRCA1/BRCA2 mutations demonstrated significant interfamilial variation, even when controlling for age at diagnosis of the proband and the presence of contralateral breast cancer.[134] Genetic modifiers of penetrance of breast and ovarian cancer are increasingly under study but are not clinically useful at this time.[135,136,137] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

Table 3 and Table 4 review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Table 3. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer

BCLC = Breast Cancer Linkage Consortium; LOD score = logarithm of the odd score.
a Outcome is breast OR ovarian cancer.
b Incidence to age 55 y.
c Incidence to age 75 y.
d Incidence to age 80 y.
Cumulative Incidence of Breast Cancer to Given Age
BRCA1BRCA2BRCA1/BRCA2
Population50 y70 y50 y70 y50 y70 y
Linkage analysis-maximization of LOD score
-214 breast-ovary families (BCLC) [15]59%82%
-BRCA1-linked families (BCLC) [106]51%85%
-237 breast and breast-ovarian cancer families (BCLC) [107]49%71%28%84%
Incidence of second cancers after breast cancer
-33 BRCA1-linked families (BCLC) [105]73%87%
-BRCA1-linked families (BCLC) [106]50%65%
Analysis of family members
-Jewish ovarian cancer cases, 7 BRCA1, 3 BRCA2[116]30%a50%a16%a23%a
-Jewish breast-ovary families, 16 BRCA1, 9 BRCA2[116]37%a64%a18%a49%a
Kin cohort using family and cancer registries
-Unselected Icelandic breast cancer patients, 56 female and 13 male BRCA2 995del5 [111]17%37%
Second or contralateral cancer incidence; focus was on nonbreast and nonovary outcomes
-173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) [12]37%52%
Modified segregation analysis - all available relatives tested (MENDEL)
-Australian population-based breast cancer, aged <40 y, 9 BRCA1, 9 BRCA2 [112]10%40%
Kin cohort
-Community-based Washington, DC area Jews, 61 BRCA1, 59 BRCA2[55]38%59%26%51%33%56%
-Jewish women with breast cancer, 34 BRCA1, 15 BRCA2[86]60%28%
-Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2[61]31%b44%c6%b37%c
-Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2[52]68%d14%d
Modified segregation analysis (MENDEL)
-Breast cancer cases, aged <55 y, 8 BRCA1, 16 BRCA2[46]32%47%18%56%21%54%
-Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2[108]39%72%19%71%
-Unselected cases ovarian cancer, 12 BRCA1[108]34%50%
-164 BRCA2-positive families from BCLC [114]41%
-Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2[103]38%65%15%45%
-Australian multiple-case families, 28 BRCA1, 23 BRCA2[109]48%74%
Relative risk times population rates
-Jewish hospital-based ovarian cancer patients, 103 BRCA1, 44 BRCA2 founder mutations [113]18%59%6%38%
Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive
-Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2[56]39%69%34%74%
Mendelian retrospective likelihood approach
-U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 [138]46%43%
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WebMD Public Information from the National Cancer Institute

Last Updated: May 16, 2012
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